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Sample records for necrosis factor inhibitors

  1. Tumor necrosis factor inhibitors – state of knowledge

    PubMed Central

    Lis, Krzysztof; Kuzawińska, Olga

    2014-01-01

    Tumor necrosis factor (TNF) is considered a major proinflammatory cytokine, affecting various aspects of the immune reaction. All five TNF inhibitors currently available on the market (i.e., etanercept, infliximab, adalimumab, certolizumab and golimumab) are top sellers, although indicated only in autoimmune diseases, including rheumatoid arthritis, Crohn's disease and psoriasis. This article briefly discusses the background and place for TNF inhibitors in modern therapy. The main safety aspects of TNF inhibitor administration are described in particular, with special consideration of the available meta-analyses. Finally, perspectives on the next-generation TNF inhibitors and their use in the clinic are given. PMID:25624856

  2. Treatment of rheumatoid arthritis with tumour necrosis factor inhibitors

    PubMed Central

    Mewar, Devesh; Wilson, Anthony G

    2011-01-01

    Advances in our understanding of the key mediators of chronic inflammation and tissue damage characteristic of rheumatoid arthritis (RA) have resulted in the development of novel therapies primarily targeting pro-inflammatory cytokines. Inhibitors of tumour necrosis factor (TNF) are the most widely used of the biological therapies at present with five different agents currently available; four are based on monoclonal anti-TNF antibodies and a soluble TNF receptor-Fc fusion protein. Long-term use of these molecules has proven to be highly effective in the majority of patients; however, around one-third have a suboptimal response potentially leading to further cartilage and bone damage, furthermore these agents are expensive compared with conventional therapies such as methotrexate. Many recent studies have attempted to identify therapeutic response biomarkers of TNF inhibitors which could be used to improve therapeutic targeting. The presence of rheumatoid factor and anti-cyclic citullinated protein antibodies, present in around 65% of RA patients, are associated with a poorer response to anti-TNF agents. Poorer response is also associated with levels of C-reactive protein and cartilage degradation product at initiation of treatment. Intriguingly, genetic studies of variants of TNF and of genes encoding members of the Toll-like receptors, nuclear factor-kappa B and p38 mitogen-activated protein kinase signalling families have been associated with response to individual anti-TNF agents. Continued advances in technologies such as ultra high throughput sequencing and proteomics should facilitate the discovery of additional biomarkers of response to anti-TNF resulting in improved disease control and quality of life for RA patients and reduced costs for healthcare funders. PMID:21039421

  3. Use of tumor necrosis factor (TNF) inhibitors in patients with HIV/AIDS.

    PubMed

    Gallitano, Stephanie M; McDermott, Laura; Brar, Kanwaljit; Lowenstein, Eve

    2016-05-01

    Patients with HIV and AIDS are living longer because of advancements in antiretroviral therapy. These patients are often susceptible to debilitating inflammatory disorders that are refractory to standard treatment. We discuss the relationship of tumor necrosis factor-alpha and HIV and then review 27 published cases of patients with HIV being treated with tumor necrosis factor-alpha inhibitors. This review is limited because no randomized controlled trials have been performed with this patient population. Regardless, we propose that reliable seropositive patients, who are adherent to medication regimens and frequent monitoring and have failed other treatment modalities, should be considered for treatment with tumor necrosis factor-alpha inhibitors. PMID:26774690

  4. Drug Survival Rates of Tumor Necrosis Factor Inhibitors in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis

    PubMed Central

    2014-01-01

    We investigated the compliance of Korean patients using tumor necrosis factor (TNF) inhibitors to treat rheumatoid arthritis (RA) and ankylosing spondylitis (AS), and identified potential predictors associated with treatment discontinuation. The study population comprised 114 RA and 310 AS patients treated with TNF inhibitors at a single tertiary center for at least 1 yr from December 2002 to November 2011. Of the 114 RA patients, 64 (56.1%) discontinued their first TNF inhibitors with a mean duration of 18.1 months. By contrast, 65 of 310 patients (21.0%) with AS discontinued their first TNF inhibitors, with a mean duration of 84 months. Although the survival rate did not differ among the three TNF inhibitors in the AS patients, the etanercept group had a lower discontinuation rate than the infliximab group in the RA patients. In addition, RA patients who received corticosteroids in combination with TNF inhibitors were more likely to discontinue their TNF inhibitors. The independent predictors of drug discontinuation in AS patients were male gender and complete ankylosis on radiographs of the sacroiliac joint. Our results provide further evidence that real-life treatment outcomes of RA and AS patients may be different from those observed in randomized clinical trials. Graphical Abstract PMID:25246737

  5. Polymer-conjugated inhibitors of tumor necrosis factor-α for local control of inflammation.

    PubMed

    Washburn, Newell R; Prata, Joseph E; Friedrich, Emily E; Ramadan, Mohamed H; Elder, Allison N; Sun, Liang Tso

    2013-01-01

    Burns, chronic wounds, osteoarthritis, and uveitis are examples of conditions characterized by local, intense inflammatory responses that can impede healing or even further tissue degradation. The most powerful anti-inflammatory drugs available are often administered systemically, but these carry significant side effects and are not compatible for patients that have underlying complications associated with their condition. Conjugation of monoclonal antibodies that neutralize pro-inflammatory cytokines to high molecular weight hydrophilic polymers has been shown to be an effective strategy for local control of inflammation. Lead formulations are based on antibody inhibitors of tumor necrosis factor-α conjugated to hyaluronic acid having molecular weight greater than 1 MDa. This review will discuss fundamental aspects of medical conditions that could be treated with these conjugates and design principles for preparing these cytokine-neutralizing polymer conjugates. Results demonstrating that infliximab, an approved inhibitor of tumor necrosis factor-α, can be incorporated into the conjugates using a broad range of water-soluble polymers are also presented, along with a prospectus for clinical translation. PMID:23903893

  6. Response of early active rheumatoid arthritis to tumor necrosis factor inhibitors: evaluation by magnetic resonance imaging.

    PubMed

    Hirose, Wataru; Nishikawa, Kenichiro; Hirose, Masuko; Nanki, Toshihiro; Sugimoto, Hideharu

    2009-01-01

    Inflammatory changes (synovitis and bone marrow edema) and destructive changes (bone erosion) were evaluated by magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA), and their relations with disease activity were assessed during treatment with tumor necrosis factor (TNF) inhibitors. Ten patients with early active RA underwent MRI at 0 and 16 weeks of TNF-inhibitor treatment. The carpal bones of the dominant hand were evaluated by the outcome measures in rheumatology clinical trials MRI score for RA. After 16 weeks, the mean disease activity score (DAS 28) decreased significantly from 5.54 to 2.70, while the number of tender joints, number of swollen joints, and inflammatory parameters were also significantly improved. The mean synovitis and marrow edema scores determined by MRI showed a significant decrease from 6.1 to 2.2 and 12.8 to 6.2, respectively, while the annual bone-erosion progression score decreased from 12.6 to 2.0. Although synovitis persisted in some patients, imaging remission was achieved in two patients. In conclusion, TNF-inhibitor therapy achieved an early decrease of disease activity and MRI revealed amelioration of joint destruction. The MRI score for RA is useful for assessing the early response to TNF inhibitors. PMID:18762862

  7. Unusual location of tuberculosis in the course of tumor necrosis factor α inhibitor therapy

    PubMed Central

    Brzezicki, Jan; Rymko, Marcin; Jeka, Sławomir

    2015-01-01

    Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis complex mycobacteria. Extrapulmonary tuberculosis usually develops more than two years after infection or many years later. Factors favoring onset of the disease are malnutrition, older age, renal failure, diabetes, cancer, immunosuppression and biological treatment, e.g. tumor necrosis factor α (TNF-α) inhibitors. The paper presents a case of a 56-year-old patient with ankylosing spondylitis treated with infliximab, diagnosed with tuberculosis of the spleen. The unusual location and uncharacteristic symptoms created a lot of diagnostic difficulties, particularly as during qualification for biological treatment tests are performed to exclude infection with Mycobacterium tuberculosis. Pharmacological treatment of tuberculosis is typical, but in the case of tuberculosis of the spleen, splenectomy also is a method of treatment. The decision was made to implement pharmacological treatment, which proved to be effective, so the patient avoided surgery.

  8. Bilateral diaphragmatic paralysis associated with the use of the tumor necrosis factor-alpha inhibitor adalimumab

    PubMed Central

    Martin, Alan William; Rosenblatt, Randall Lee

    2014-01-01

    A 51-year-old woman was referred for evaluation of progressive dyspnea of 3 months— duration. She had received 3 doses of adalimumab for treatment of rheumatoid arthritis prior to the onset of her dyspnea. Her chest examination revealed absent diaphragmatic movement with inspiration. Spirometry showed a severe restrictive defect. Radiologic studies confirmed the diagnosis of bilateral diaphragmatic paralysis. Laboratory and radiologic workup excluded other possible causes of the diagnosis. Adalimumab was discontinued, and she was treated with bilevel positive airway pressure ventilation and intravenous immunoglobulin. Three months later, the diaphragmatic paralysis persisted. This is the second reported case of bilateral diaphragmatic paralysis occurring in a patient who had received adalimumab. Acute neuropathies are rare side effects of tumor necrosis factor-alpha inhibitors. PMID:24688191

  9. Fullerenes and their derivatives as inhibitors of tumor necrosis factor-α with highly promoted affinities.

    PubMed

    Wu, Gaoyin; Gao, Xuejiao J; Jang, Joonkyung; Gao, Xingfa

    2016-07-01

    Tumor necrosis factor-α (TNF-α) is a cell signalling protein involved in systemic inflammation in infectious and other malignant diseases. Physiologically, it plays an important role in regulating host defence, but its overexpression can lead to serious illnesses including cancer, autoimmune disease and inflammatory disease. Gadolinium-based metallofullerenols, e.g., Gd@C82(OH) x (x ≈ 22), are well known for their abundant biological activities with low toxicity experimentally and theoretically; however, their activity in direct TNF-α inhibition has not been explored. In this work, we investigated the inhibiting effects of four types of fullerene-based ligands: fullerenes, fullerenols, metallofullerenes, and metallofullerenols. We reported previously that fullerenes, metallofullerenes and their hydroxylated derivatives (fullerenols) can reside in the same pocket of the TNF-α dimer as that of SPD304-a known inhibitor of TNF-α [He et al. (2005) Science 310:1022, 18]. Ligand docking and binding free energy calculations suggest that, with a similar nonpolar interaction dominated binding pattern, the fullerene-based ligands, C60, C60(OH)12, Gd@C60, C82, C82(OH)12, Gd@C82, Gd@C82(OH)13 and Gd@C82(OH)21, have larger affinity than currently known inhibitors, and could be used to design novel inhibitors of TNF-α in the future. Graphical Abstract Fullerene-material/TNF-α. PMID:27316702

  10. A stonemason with accelerated silicosis in the setting of tumour necrosis factor alpha inhibitor therapy.

    PubMed

    Baird, Timothy; Putt, Michael; Dettrick, Andrew

    2016-09-01

    We present the case of a 26-year-old stonemason with accelerated silicosis in the setting of treatment for psoriasis with the tumour necrosis factor alpha (TNF-alpha) inhibitor adalimumab. Accelerated silicosis is an important occupational lung disease with a poor prognosis and limited treatment options [1]. Although the exact pathogenesis remains unknown, it is suggested that secretion of cytokines, including TNF-alpha, plays a central role in disease progression [1,2]. Importantly, however, TNF-alpha inhibitors, in addition to resulting in an increased risk of infection, are also now being seen to cause interstitial lung disease [3,4]. To our knowledge, this is the first documented patient to develop silicosis whilst on TNF-alpha inhibitor therapy. This case challenges the theory behind TNF-alpha's exact role in the pathogenesis of silicosis and lung fibrosis, highlights the importance of monitoring individuals with both occupational and drug exposures, and illustrates the increasing difficulties physicians face in investigating patients with pulmonary infiltrates and multiple possible aetiologies. PMID:27516887

  11. The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors.

    PubMed Central

    Kettelhut, I C; Fiers, W; Goldberg, A L

    1987-01-01

    Tumor necrosis factor (TNF) is a macrophage product under active study as an anticancer drug. However, this agent can be very toxic and has been implicated in the pathogenesis of endotoxic shock. After intravenous injection of human recombinant TNF (4 micrograms/g), growing rats showed an unusual constellation of physiological responses, and all died within 2-4 hr. In 1 hr, TNF caused a sharp fall (2.5 degrees C) in body temperature and a large increase in plasma prostaglandin E2 levels. Blood glucose initially increased, but then a profound hypoglycemia developed by 2 hr. The TNF-treated animals also showed diarrhea, cyanosis, and a severe metabolic acidosis. A single injection of the cyclooxygenase inhibitors indomethacin or ibuprofen before the TNF treatment completely prevented the rapid killing and reduced eventual lethality by 70%. These agents blocked prostaglandin E2 production and prevented the hypothermia, changes in blood glucose, acidosis, and other symptoms. Since similar physiological changes have been reported after endotoxin injection, our data support the suggestion that TNF production is a critical factor in the development of septic shock. These findings also indicate that increased production of prostaglandins or thromboxanes is important in endotoxic shock and argue that cyclooxygenase inhibitors should be useful in its therapy. Indomethacin did not block the cytotoxic effects of TNF in vitro on several transformed cell lines (HeLa, Me 180, or L929). Therefore, combined use of TNF with a cyclooxygenase inhibitor may allow safer administration of high doses of this polypeptide to cancer patients. PMID:3108890

  12. Tumor necrosis factorinhibitor therapy and fetal risk: A systematic literature review

    PubMed Central

    Marchioni, Renée M; Lichtenstein, Gary R

    2013-01-01

    Tumor necrosis factorinhibitors (anti-TNFs) are effective in the treatment of inflammatory bowel disease (IBD) recalcitrant to conventional medical therapy. As the peak incidence of IBD overlaps with the prime reproductive years, it is crucial to establish pharmacologic regimens for women of childbearing age that achieve effective disease control without posing significant fetal harm. A systematic literature review was performed to identify all human studies with birth outcomes data after maternal exposure to infliximab, adalimumab, or certolizumab pegol within 3 mo of conception or during any trimester of pregnancy. Live births, spontaneous abortions or stillbirths, preterm or premature births, low birth weight or small for gestational age infants, and congenital abnormalities were recorded. Fifty selected references identified 472 pregnancy exposures. The subsequent review includes general information regarding anti-TNF therapy in pregnancy followed by a summary of our findings. The benefits of biologic modalities in optimizing disease control during pregnancy must be weighed against the potential toxicity of drug exposure on the developing fetus. Although promising overall, there is insufficient evidence to prove absolute safety for use of anti-TNFs during pregnancy given the limitations of available data and lack of controlled trials. PMID:23674866

  13. Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Ankylosing Spondylitis

    PubMed Central

    Caetano-Lopes, Joana; Vieira-Sousa, Elsa; Campanilho-Marques, Raquel; Ponte, Cristina; Canhão, Helena; Ainola, Mari; Fonseca, João E.

    2015-01-01

    Introduction Ankylosing Spondylitis (AS) is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF) plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi) have ongoing local bone formation. The aim of this study was to assess the effect of TNFi in the differentiation and activity of osteoclasts (OC) in AS patients. Methods 13 AS patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 25 healthy donors were recruited as controls. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines, in vitro OC differentiation assay and qRT-PCR for OC specific genes were performed. Results RANKL+ circulating lymphocytes (B and T cells) and IL-17A, IL-23 and TGF-β levels were decreased after TNFi treatment. We found no differences in the frequency of the different monocyte subpopulations, however, we found decreased expression of CCR2 and increased expression of CD62L after TNFi treatment. OC number was reduced in patients at baseline when compared to controls. OC specific gene expression was reduced in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiating conditions, OC precursors from AS TNFi-treated patients showed increased activity as compared to baseline. Conclusion In AS patients, TNFi treatment reduces systemic pro osteoclastogenic stimuli. However, OC precursors from AS patients exposed to TNFi therapy have increased in vitro activity in response to osteoclastogenic stimuli. PMID:26674064

  14. Complicated Whipple’s disease and endocarditis following tumor necrosis factor inhibitors

    PubMed Central

    Marth, Thomas

    2014-01-01

    AIM: To test whether treatment with tumor necrosis factor inhibitors (TNFI) is associated with complications of Tropheryma whipplei (T. whipplei) infection. METHODS: Because unexplained arthritis is often the first Whipple’s disease (WD) symptom, patients may undergo treatment with TNFI before diagnosis. This may influence the course of infection with T. whipplei, which causes WD, because host immune defects contribute to the pathogenesis of WD. A literature search and cross referencing identified 19 reports of TNFI treatment prior to WD diagnosis. This case-control study compared clinical data in patients receiving TNFI therapy (group I, n = 41) with patients not receiving TNFI therapy (group II, n = 61). Patients from large reviews served as controls (group III, n = 1059). RESULTS: The rate of endocarditis in patient group I was significantly higher than in patient group II (12.2% in group I vs 1.6% in group II, P < 0.05), and group III (12.2% in group I vs 0.16% in group III, P < 0.01). Other, severe systemic or local WD complications such as pericarditis, fever or specific organ manifestations were increased also in group I as compared to the other patient groups. However, diarrhea and weight loss were somewhat less frequent in patient group I. WD is typically diagnosed with duodenal biopsy and periodic acid Schiff (PAS) staining. PAS-stain as standard diagnostic test had a very high percentage of false negative results (diagnostic failure in 63.6% of cases) in group I. Polymerase chain reaction (PCR) for T. whipplei was more accurate than PAS-stainings (diagnostic accuracy, rate of true positive tests 90.9% for PCR vs 36.4% for PAS, P < 0.01). CONCLUSION: TNFI trigger severe WD complications, particularly endocarditis, and lead to false-negative PAS-tests. In case of TNFI treatment failure, infection with T. whipplei should be considered. PMID:25548618

  15. The development of novel inhibitors of tumor necrosis factor-alpha production based on substituted [5,5]-bicyclic pyrozolones

    SciTech Connect

    Laufersweiler, Matthew; Brugel, Todd; Clark, Michael; Golebiowski, Adam; Bookland, Roger; Laughlin, Steven; Sabat, Mark; Townes, Jennifer; VanRens, John; De, Biswanath; Hsieh, Lily; Heitmeyer, Sandra; Juergens, Karen; Brown, Kimberly; Mekel, Marlene; Walter, Richard; Janusz, Michael

    2010-11-16

    Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-{alpha} (TNF-{alpha}) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-{alpha} production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.

  16. Association Between Ischemic Stroke and Tumor Necrosis Factor Inhibitor Therapy in Patients With Rheumatoid Arthritis

    PubMed Central

    Low, Audrey S. L.; Lunt, Mark; Mercer, Louise K.; Watson, Kath D.; Dixon, William G.; Symmons, Deborah P. M.

    2016-01-01

    Objective Patients with rheumatoid arthritis (RA) are at an increased risk of ischemic stroke. Tumor necrosis factor inhibitors (TNFi) may influence risk and mortality after ischemic stroke by reducing inflammation. This study was undertaken to examine the association of TNFi with the risk of incident ischemic stroke and with 30‐day and 1‐year mortality after ischemic stroke. Methods Patients with RA starting therapy with TNFi and a biologics‐naive comparator group treated with synthetic disease‐modifying antirheumatic drugs (DMARDs) only were recruited to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis from 2001 to 2009. Patients were followed up via clinical and patient questionnaires as well as the national death register. Incident strokes were classified as ischemic if brain imaging reports suggested ischemia or if ischemic stroke was reported as the underlying cause of death on a death certificate. Patients with a previous stroke were excluded. Risk of ischemic stroke was compared between patients receiving synthetic DMARDs only and those ever‐exposed to TNFi using a Cox proportional hazards regression model adjusted for potential confounders. Mortality after ischemic stroke was compared between synthetic DMARD–treated patients and TNFi‐treated patients using logistic regression, adjusted for age and sex. Results To April 2010, 127 verified incident ischemic strokes (21 in 3,271 synthetic DMARD–treated patients and 106 in 11,642 TNFi‐treated patients) occurred during 11,973 and 61,226 person‐years of observation, respectively (incidence rate 175 versus 173 per 100,000 person‐years). After adjustment for confounders, there was no association between ever‐exposure to TNFi and ischemic stroke (hazard ratio 0.99 [95% confidence interval (95% CI) 0.54–1.81]). Mortality 30 days or 1 year after ischemic stroke was not associated with concurrent TNFi exposure (odds ratio 0.18 [95% CI 0.03–1.21] and 0.60 [95

  17. Pericardial effusions with tamponade and visceral constriction in patients with rheumatoid arthritis on tumour necrosis factor (TNF)-inhibitor therapy.

    PubMed

    Soh, May Ching; Hart, Hamish H; Corkill, Michael

    2009-04-01

    Tumour necrosis factor-inhibitor (TNF-inhibitor) therapy is increasingly used for the treatment of rheumatoid arthritis. While it is effective for the articular manifestations of rheumatoid arthritis we have reason to believe that it is less effective for extra-articular disease. We present two cases of life-threatening cardiac tamponade in two patients with well-controlled rheumatoid arthritis on adalimumab. An extensive literature search was carried out and three other patients were found. We believe that these cases highlight the need for rheumatologists to be vigilant for extra-articular manifestations of rheumatoid arthritis even in the presence of quiescent joint disease while on TNF-inhibitors. PMID:20374322

  18. A Novel Small-molecule Tumor Necrosis Factor α Inhibitor Attenuates Inflammation in a Hepatitis Mouse Model*

    PubMed Central

    Ma, Li; Gong, Haiyan; Zhu, Haiyan; Ji, Qing; Su, Pei; Liu, Peng; Cao, Shannan; Yao, Jianfeng; Jiang, Linlin; Han, Mingzhe; Ma, Xiaotong; Xiong, Dongsheng; Luo, Hongbo R.; Wang, Fei; Zhou, Jiaxi; Xu, Yuanfu

    2014-01-01

    Overexpression of tumor necrosis factor α (TNFα) is a hallmark of many inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and septic shock and hepatitis, making it a potential therapeutic target for clinical interventions. To explore chemical inhibitors against TNFα activity, we applied computer-aided drug design combined with in vitro and cell-based assays and identified a lead chemical compound, (E)-4-(2-(4-chloro-3-nitrophenyl) (named as C87 thereafter), which directly binds to TNFα, potently inhibits TNFα-induced cytotoxicity (IC50 = 8.73 μm) and effectively blocks TNFα-triggered signaling activities. Furthermore, by using a murine acute hepatitis model, we showed that C87 attenuates TNFα-induced inflammation, thereby markedly reducing injuries to the liver and improving animal survival. Thus, our results lead to a novel and highly specific small-molecule TNFα inhibitor, which can be potentially used to treat TNFα-mediated inflammatory diseases. PMID:24634219

  19. Hepatitis B and C reactivation with tumor necrosis factor inhibitors: synopsis and interpretation of screening and prophylaxis recommendations.

    PubMed

    Fuchs, Inbal; Abu-Shakra, Mahmoud; Sikuler, Emanuel

    2013-06-01

    Information on reactivation of chronic viral hepatitis infection in patients who are candidates for tumor necrosis factor alpha inhibitors (TNFi) is in a constant state of flux. We retrieved the most updated guidelines (in English) of prominent rheumatological and gastroenterological professional socienties for the mangement of chronic hepatitis B (HBV) and hepatitis C virus (HCV) infection in the context of treatment with TNFi. Subsequently, the major areas of uncertainty and absence of consensus in the guidelines were located and a secondary search for additional studies addressing those areas was performed. Based on our search we formulated a personal interpretation applicable to health care settings with virological laboratories capable of performing viral load measurements, and health systems that can support use of potent nucleoside/tide analogues in well-defined patient populations. PMID:23882898

  20. Systematic Review of Tumor Necrosis Factor Inhibitor Discontinuation Studies in Rheumatoid Arthritis

    PubMed Central

    Navarro-Millán, Iris; Sattui, Sebastian E.; Curtis, Jeffrey R

    2013-01-01

    Background Anti-tumor necrosis factor agents (anti-TNFs) have changed the course of rheumatoid arthritis (RA) for more than a decade. Use of these medications often results in remission, or at least low disease activity (LDA), but at substantial cost. It has been postulated that discontinuation of these medications among RA patients in remission or LDA may be possible without an associated increase in RA disease activity. Objective The goal of this systematic literature review is to summarize published articles regarding discontinuation of anti-TNFs in patients with RA. Methods A systematic literature review was conducted to identify English-language articles indexed in Pubmed from July 1999 through June 2013 reporting results regarding anti-TNF discontinuation in patients with RA. Study designs included observational longitudinal studies and clinical trials. Outcomes had to include one of the following: time to flare after anti-TNF discontinuation, failure to remain in remission, or LDA at the end of the study. Results Ten studies examined discontinuation of anti-TNF therapies in RA. Inclusion criteria varied significantly across studies in terms of disease activity status (remission or LDA) and duration of this disease status (1 year or 1 month) prior to discontinuation being attempted. Results from larger studies (e.g. > 100 patients) suggest that the proportion of patients who discontinued and did not have an increase in disease activity ranged between 24%-81%. In 2 studies that evaluated durability of LDA or remission after anti-TNF discontinuation, the mean time to relapse varied from 15 weeks to 14 months. In studies that analyzed radiographic data, once therapies were reinitiated after an increase in disease activity was detected, patients generally did not experience progression in structural damage. Conclusion Discontinuation of anti-TNF therapy is achievable for many RA patients who start in clinical remission or LDA. However, heterogeneous inclusion

  1. Detection of Legionella pneumophila serogroup 1 in blood cultures from a patient treated with tumor necrosis factor-alpha inhibitor.

    PubMed

    Kaku, Norihito; Yanagihara, Katsunori; Morinaga, Yoshitomo; Sato, Tsuyoshi; Nakashima, Munetoshi; Sakai, Takahiro; Tominaga, Hiroo; Wakigawa, Fumiko; Nagashima, Seiji; Fukuda, Minoru; Hashiguchi, Kohji; Kohno, Shigeru

    2013-02-01

    A 65-year-old man was admitted to our hospital with a temperature of 39.3 °C, cough, sputum, and pharyngeal discomfort that had persisted for 3 days. He had been treated with methotrexate and adalimumab (a tumor necrosis factor-alpha [TNF-α] inhibitor) for rheumatoid arthritis for 2 years, and he had also been treated with S-1 (tegafur, gimeracil, and oteracil potassium) for pancreatic metastasis of gastric cancer for 2 months. Regardless of the underlying pathologies, his general condition was good and he had worked as an electrician until 2 days before admission. However, his appetite had suddenly decreased from the day before admission, and high fever and hypoxia were also evident upon admission. A chest X-ray and computed tomography scan revealed left pleural effusion and consolidation in both lungs. The pneumonia severity index score was 165 and the risk class was V. Accordingly, we started to treat the pneumonia with a combination of levofloxacin and meropenem. Thereafter, we received positive urinary antigen test findings for Legionella pneumophila. After hospitalization, hypoxia was progressed and hypotension was emerged. Despite the application of appropriate antibiotics, vasopressors, and oxygenation, the patient died 8 h after admission. Even after his death, blood cultures were continued to consider the possibility of bacterial co-infection. Although no bacteria were detected from blood cultures, Gimenez staining revealed pink bacteria in blood culture fluids. Subsequent blood fluid culture in selective medium revealed L. pneumophila serogroup 1. Recently, TNF-α inhibitors have been described as a risk factor for Legionnaires' disease. In consideration of the increased frequency of TNF-α inhibitors, we may need to recognize anew that L. pneumophila might be a pathogen of severe community-acquired pneumonia. PMID:22911089

  2. The evaluation of inhibitive effectiveness of the tumour necrosis factor-α converting enzyme selective inhibitors by HPLC.

    PubMed

    Zhao, Yunbin; Yu, Jin; Gu, Jiuling; Huang, Wei

    2011-04-01

    A novel high-performance liquid chromatography (HPLC) method based on the internal standard method was established for assaying the tumour necrosis factor-α converting enzyme (TACE) activity and matrix metalloprotease-9 (MMP-9) activity, and was used to evaluate the inhibitive effectiveness of inhibitors to TACE and MMP-9. In the assay method for TACE and MMP-9, peptides labelled with the ultraviolet group-Dpa were used as substrates. Alanine-Dpa was synthesised and was used as the internal standard for quantitative analysis. After the peptide substrates were hydrolysed by TACE (MMP-9) for 15 min (25 min) at 37 °C, the amount of remaining substrates were determined by reversed-phased HPLC with UV detection at 353 nm. The relative peak area of the substrate was linearly dependent on the substrate concentration. This method was then applied to determine the 50% inhibitory concentration (IC₅₀) of GM6001 and inhibitor A for both TACE and MMP-9. PMID:21406033

  3. Identification of an Iridium(III)-Based Inhibitor of Tumor Necrosis Factor-α.

    PubMed

    Kang, Tian-Shu; Mao, Zhifeng; Ng, Chan-Tat; Wang, Modi; Wang, Wanhe; Wang, Chunming; Lee, Simon Ming-Yuen; Wang, Yitao; Leung, Chung-Hang; Ma, Dik-Lung

    2016-04-28

    The novel iridium(III) complex 1 was verified as a potent inhibitor of the TNF-α-TNFR protein-protein interaction in vitro and in cellulo. The iridium(III) center plays a critical role in organizing the structure of the bioactive metal complex, as the isolated ligands were found to be completely inactive. Both iridium enantiomers inhibited TNF-α-induced NF-κB activity and TNF-α-TNFR binding. 1 represents a promising scaffold for the further development of more potent organometallic TNF-α inhibitors. PMID:27054262

  4. Purification and characterization of an inhibitor (soluble tumor necrosis factor receptor) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients

    SciTech Connect

    Gatanaga, Tetsuya; Whang, Chenduen; Cappuccini, F.; Lucci, J.A. III; Jeffes, E.W.B. ); Kohr, W. ); Lentz, R. ); Tomich, J. ); Yamamoto, R.S. ); Granger, G.A. Memorial Cancer Inst., Long Beach, CA )

    1990-11-01

    Serum ultrafiltrates (SUF) from human patients with different types of cancer contain a blocking factor (BF) that inhibits the cytolytic activity of human tumor necrosis factor {alpha} (TNF-{alpha}) in vitro. BF is a protein with a molecular mass of 28kDa on reducing sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE). The active material was purified to homogeneity by a combination of affinity chromatography, PAGE, and high-pressure liquid chromatography. Amino acid sequence analysis revealed that BF is derived from the membrane TNF receptor. Purified BF blocks the lytic activity of recombinant human and mouse TNF-{alpha} and recombinant human lymphotoxin activity of TNF-{alpha} and recombinant human lymphotoxin on murine L929 cells in vitro. However, BF inhibits the lytic activity of TNF-{alpha} more effectively than it does that of lymphotoxin. The BF also inhibits the necrotizing activity of recombinant human TNF-{alpha} when coinjected into established cutaneous Meth A tumors in BALB/c mice. The BF may have an important role in (i) the regulation and control of TNF-{alpha} and lymphotoxin activity in cancer patients, (ii) interaction between the tumor and the host antitumor mechanisms, and (iii) use of systemically administered TNF-{alpha} in clinical trials with human cancer patients.

  5. CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis

    PubMed Central

    Citro, Alessandra; Scrivo, Rossana; Martini, Helene; Martire, Carmela; De Marzio, Paolo; Vestri, Anna Rita; Sidney, John; Sette, Alessandro; Barnaba, Vincenzo; Valesini, Guido

    2015-01-01

    CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factorinhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control). The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factorinhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factorinhibitor therapy to validate in a larger cohort of patients. PMID:26061065

  6. The impact of disease activity and tumour necrosis factorinhibitor therapy on cytokine levels in juvenile idiopathic arthritis.

    PubMed

    Walters, H M; Pan, N; Lehman, T J A; Adams, A; Kalliolias, G D; Zhu, Y S; Santiago, F; Nguyen, J; Sitaras, L; Cunningham-Rundles, S; Walsh, T J; Toussi, S S

    2016-06-01

    The aim of this study was to evaluate prospectively cytokine levels and disease activity in juvenile idiopathic arthritis (JIA) patients treated with and without tumour necrosis factor (TNF)-α inhibitors. TNF-α inhibitor-naive JIA subjects were followed prospectively for 6 months. Cytokine levels of TNF-α, interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-17 were measured at baseline for JIA subjects and healthy controls (HCs). Cytokine levels were then measured at four time-points after initiation of TNF-α inhibition for anti-TNF-α-treated (anti-TNF) JIA subjects, and at two subsequent time-points for other JIA (non-TNF) subjects. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Sixteen anti-TNF, 31 non-TNF and 16 HCs were analysed. Among JIA subjects, those with higher baseline disease activity (subsequent anti-TNFs) had higher baseline TNF-α, IL-6 and IL-8 than those with lower disease activity (non-TNFs) (P < 0·05). TNF-α and IL-10 increased, and IL-6 and IL-8 no longer remained significantly higher after TNF-α inhibitor initiation in anti-TNF subjects. Subgroup analysis of etanercept versus adalimumab-treated subjects showed that TNF-α and IL-17 increased significantly in etanercept but not adalimumab-treated subjects, despite clinical improvement in both groups of subjects. JIA subjects with increased disease activity at baseline had higher serum proinflammatory cytokines. TNF-α inhibition resulted in suppression of IL-6 and IL-8 in parallel with clinical improvement in all anti-TNF-treated subjects, but was also associated with elevated TNF-α and IL-17 in etanercept-treated subjects. PMID:26934060

  7. Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial

    PubMed Central

    Ibrahim, Fowzia; Farewell, Vern; O’Keeffe, Aidan G; Walker, David; Kelly, Clive; Birrell, Fraser; Chakravarty, Kuntal; Maddison, Peter; Heslin, Margaret; Patel, Anita; Kingsley, Gabrielle H

    2015-01-01

    Objective To determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs. Design Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months. Setting 24 rheumatology clinics in England. Participants Patients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy. Interventions Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders. Main outcome measure Primary outcome: reduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy. Secondary outcomes: quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data. Results 432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of −0.30 with the

  8. Uveitis Reactivation in Children Treated with Tumor Necrosis FactorInhibitors

    PubMed Central

    Lerman, Melissa A.; Lewen, Michael D.; Kempen, John H.; Mills, Monte D.

    2016-01-01

    PURPOSE To evaluate reactivation of pediatric uveitis during/following treatment with TNF-alpha inhibition (anti-TNFα). DESIGN Retrospective cohort study. METHODS We assessed the incidence of uveitis reactivation in children ≤18 years who had achieved uveitis quiescence under anti-TNFα. Survival analysis was used to calculate reactivation rates while still on (primary outcome), and following discontinuation of (secondary outcome), anti-TNFα. Potential predictive factors were assessed. RESULTS Among 50 children observed to develop quiescence of uveitis under anti-TNFα, 39 met criteria to be “at risk” of the primary (19 for the secondary) outcome. 60% were female, ~half had Juvenile Idiopathic Arthritis, and most were treated with infliximab. Overall, the estimated proportion relapsing within 12 months was 27.8% (95% confidence interval [CI]: 15.9-45.8%); the estimated probability of reactivation was higher following (63.8% [95% CI: 38.9-87.7%]), than before (21.6% [95% CI: 10.8-40.2%]), anti-TNFα discontinuation. Amongst those who discontinued anti-TNFα, the likelihood of reactivation was higher for those treated with adalimumab vs. infliximab (Hazard Ratio [HR] 13.4, p=0.01, 95% CI: 2.2-82.5) and those with older age at uveitis-onset (HR 1.3, p=0.09, 95% CI: 1.0-1.7). The duration of suppression, on medication, did not significantly affect the likelihood of reactivation when quiescence was maintained for ≥1.5 years. CONCLUSIONS Approximately 75% of children remaining on anti-TNFα following achievement of uveitis quiescence remain quiescent at one year. However, most reactivate following anti-TNFα discontinuation. These results suggest that infliximab more often is followed by remission, off medication, than adalimumab. The data do not suggest that maintenance of suppression, for more than 1.5 years decreases the reactivation risk. PMID:25892124

  9. Ketoconazole attenuates radiation-induction of tumor necrosis factor

    SciTech Connect

    Hallahan, D.E.; Virudachalam, S.; Kufe, D.W.; Weichselbaum, R.R.

    1994-07-01

    Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation-induced arachidonic acid production, protein kinase C activation, and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, the authors analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cycloxygenase (indomethacine) were added to cell culture 1 h prior to irradiation. Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2 inhibitors (quinicrine, bromphenylbromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. The authors propose therefore, that ketoconazole may reduce acute radiation sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity. 25 refs., 2 figs.

  10. Dose Optimization for Single Intradiscal Administration of the Tumor Necrosis FactorInhibitor, Etanercept, in Rat Disc Injury Models

    PubMed Central

    Orita, Sumihisa; Yamauchi, Kazuyo; Suzuki, Takane; Suzuki, Miyako; Sakuma, Yoshihiro; Kubota, Go; Oikawa, Yasuhiro; Sainoh, Takeshi; Sato, Jun; Fujimoto, Kazuki; Shiga, Yasuhiro; Abe, Koki; Kanamoto, Hirohito; Inoue, Masahiro; Kinoshita, Hideyuki; Takahashi, Kazuhisa; Ohtori, Seiji

    2016-01-01

    Study Design Experimental animal study. Purpose We aimed to determine the optimal dose of a single direct injection of the tumor necrosis factor (TNF)-α inhibitor, etanercept, by using the rat model of degenerative intervertebral disc from injury. Overview of Literature The pain-related peptide expression was suppressed in the etanercept (100 µg and 1,000 µg)-administered groups in a dose-dependent manner. Methods The neurotracer FluoroGold (FG) was applied to the surfaces of L4/5 discs to label their innervating dorsal root ganglion (DRG) neurons (n=50). Ten rats were included in the nonpunctured disc sham surgery control group, whereas the other 40 were included in the experimental group in which intervertebral discs were punctured with a 23-gauge needle. Saline or etanercept (10 µg, 100 µg, or 1,000 µg) was injected into the punctured discs (n=10 for each treatment). After 14 days of surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for calcitonin gene-related peptide (CGRP). The proportion of FG-labeled CGRP-immunoreactive DRG neurons was evaluated in all the groups. Results There were no significant differences between the puncture+saline group and the puncture+10-µg etanercept group (p >0.05). However, a significant decrease in the percentage of FG and CGRP double-positive cells in FG-positive cells was observed in the etanercept (100 µg and 1,000 µg)-administered groups in a dose-dependent manner (p <0.05). Conclusions When a low dose of the TNF-α inhibitor (10 µg of etanercept) was directly administered to the rat intervertebral disc in the rat model of degenerative intervertebral disc from injury, no suppressive effect on the pain-related peptide expression was observed. However, when a higher dose of etanercept (100 µg and 1,000 µg) was administered, the pain-related peptide expression was suppressed in a dose-dependent manner. PMID:27559439

  11. Invasive Salmonellosis by the Very Rare Salmonella choleraesuis in a Returning Traveler on a Tumor Necrosis FactorInhibitor

    PubMed Central

    Eke, Uzoamaka A.; Conte, Harry; Anderson, Paula; Lyons, Robert W.

    2014-01-01

    Salmonella choleraesuis is one of the least commonly reported nontyphoidal salmonellae in the United States, accounting for only 0.08% and ranking lower than 20th place among all human source salmonellosis reported to the CDC in 2009. In the state of Connecticut, only 12 cases have been reported since 1998 and our case is the only case since 2008. We report a case of invasive Salmonellosis caused by Salmonella choleraesuis in a patient on an antitumor necrosis factor-α agent (adalimumab) who recently returned from a trip to the Dominican Republic. PMID:24715927

  12. Screening Bicyclic Peptide Libraries for Protein-Protein Interaction Inhibitors: Discovery of a Tumor Necrosis Factor-alpha Antagonist

    PubMed Central

    Rhodes, Curran A.; Liu, Yusen; Pei, Dehua

    2013-01-01

    Protein-protein interactions represent a new class of exciting but challenging drug targets, because their large, flat binding sites lack well defined pockets for small molecules to bind. We report here a methodology for chemical synthesis and screening of large combinatorial libraries of bicyclic peptides displayed on rigid small-molecule scaffolds. With planar trimesic acid as the scaffold, the resulting bicyclic peptides are effective for binding to protein surfaces such as the interfaces of protein-protein interactions. Screening of a bicyclic peptide library against tumor necrosis factor-alpha (TNFα) identified a potent antagonist that inhibits the TNFα-TNFα receptor interaction and protects cells from TNFα-induced cell death. Bicyclic peptides of this type may provide a general solution for inhibition of protein-protein interactions. PMID:23865589

  13. Case Report of Lichen Planopilaris Occurring in a Pediatric Patient Receiving a Tumor Necrosis Factor α Inhibitor and a Review of the Literature.

    PubMed

    Jayasekera, Prativa S A; Walsh, Maeve L; Hurrell, Daniel; Parslew, Richard A G

    2016-03-01

    A 12-year-old girl with extended oligoarthritis treated with adalimumab presented with a short history of a progressive cutaneous eruption involving the legs and scalp. Physical examination and histologic results were consistent with lichen planopilaris. The adalimumab was discontinued. She received treatment with topical clobetasol propionate and the majority of the lesions resolved. Residual lesions and the extended oligoarthritis were then treated with sulfasalazine. Adalimumab is a tumor necrosis factor α (TNF-α) inhibitor used for the treatment of a variety of immunologically mediated conditions, including lichen planus and lichen planopilaris. TNF-α antagonists have been associated with paradoxical psoriasiform, lichenoid, eczematous, granulomatous, and acneiform eruptions. We detail this case and review the literature of lichenoid reactions secondary to TNF-α inhibitors. PMID:26840781

  14. Vialinin A and thelephantin G, potent inhibitors of tumor necrosis factor-α production, inhibit sentrin/SUMO-specific protease 1 enzymatic activity.

    PubMed

    Yoshioka, Yasukiyo; Namiki, Daisuke; Makiuchi, Mao; Sugaya, Kouichi; Onose, Jun-Ichi; Ashida, Hitoshi; Abe, Naoki

    2016-09-01

    Several p-terphenyl compounds have been isolated from the edible Chinese mushroom Thelephora vialis. Vialinin A, a p-terphenyl compound, strongly inhibits tumor necrosis factor-α production and release. Vialinin A inhibits the enzymatic activity of ubiquitin-specific peptidase 5, one of the target molecules in RBL-2H3 cells. Here we examined the inhibitory effect of p-terphenyl compounds, including vialinin A, against sentrin/SUMO-specific protease 1 (SENP1) enzymatic activity. The half maximal inhibitory concentration values of vialinin A and thelephantin G against full-length SENP1 were 1.64±0.23μM and 2.48±0.02μM, respectively. These findings suggest that p-terphenyl compounds are potent SENP1 inhibitors. PMID:27491710

  15. Genetic polymorphisms of tumour necrosis factor alpha (TNF-α) promoter gene and response to TNF-α inhibitors in Spanish patients with inflammatory bowel disease.

    PubMed

    López-Hernández, R; Valdés, M; Campillo, J A; Martínez-Garcia, P; Salama, H; Salgado, G; Boix, F; Moya-Quiles, M R; Minguela, A; Sánchez-Torres, A; Miras, M; Garcia, A; Carballo, F; Álvarez-López, M R; Muro, M

    2014-02-01

    Tumour necrosis factor alpha (TNF-α) has an important role in inflammatory response. Alterations in the regulation of TNF-α have been implicated in a variety of inflammatory disorders, including Inflammatory bowel disease (IBD). Indeed, a common treatment for IBD is the use of TNF-α inhibitors. Polymorphisms in the TNF-α promoter region are known to affect the level of gene expression. Our aim was to investigate the influence of these single nucleotide polymorphisms (SNPs) in TNF-α promoter gene play in the risk of IBD in a Spanish population and their individual response to anti-TNF-α treatment. DNA samples from patients with IBD and controls were screened for TNF-α -238G/A (rs361525) and -308G/A (rs1800629) SNPs by PCR-SSOP using a microbeads luminex assay and compared with response to TNF-α inhibitors. There were not statistical differences in -238G/A and -308G/A allele and genotype frequencies between patients. However, we found an increased frequency of -308A allele and -308GA genotype in these nonresponders patients to TNF-α inhibitors with respect to responders patients (Pc < 0.05). This -308GA genotype has been classified as high producer of this cytokine. This fact could actually be interesting to explain the different response of patients with IBD with respect to TNF-α inhibitors. TNF-α promoter gene polymorphism does not seem to play a role in IBD susceptibility, but particular TNF-α genotypes may be involved in the different responses to TNF-α inhibitor treatment in Spanish patients with IBD. PMID:23590430

  16. Cyclooxygenase-2 or tumor necrosis factorinhibitors attenuate the mechanotransductive effects of pulsed focused ultrasound to suppress mesenchymal stromal cell homing to healthy and dystrophic muscle

    PubMed Central

    Tebebi, Pamela A.; Burks, Scott R.; Kim, Saejeong J.; Williams, Rashida A.; Nguyen, Ben A.; Venkatesh, Priyanka; Frenkel, Victor; Frank, Joseph A.

    2014-01-01

    Maximal homing of infused stem cells to diseased tissue is critical for regenerative medicine. Pulsed focused ultrasound (pFUS) is a clinically relevant platform to direct stem cell migration. Through mechanotransduction, pFUS establishes local gradients of cytokines, chemokines, trophic factors (CCTF) and cell adhesion molecules (CAM) in treated skeletal muscle that subsequently infused mesenchymal stromal cells (MSC) can capitalize to migrate into the parenchyma. Characterizing molecular responses to mechanical pFUS effects revealed tumor necrosis factor-alpha (TNFα) drives cyclooxygenase-2 (COX2) signaling to locally increase CCTF/CAM that are necessary for MSC homing. pFUS failed to increase chemoattractants and induce MSC homing to treated muscle in mice pretreated with ibuprofen (non-specific COX inhibitor) or etanercept (TNFα inhibitor). pFUS-induced MSC homing was also suppressed in COX2-knockout mice, demonstrating ibuprofen blocked the mechanically-induced CCTF/CAM by acting on COX2. Anti-inflammatory drugs, including ibuprofen, are administered to muscular dystrophy (MD) patients and ibuprofen also suppressed pFUS-induced homing to muscle in a mouse model of MD. Drug interactions with cell therapies remain unexplored and are not controlled for during clinical cell therapy trials. This study highlights potentially negative drug-host interactions that suppress stem cell homing and could undermine cell-based approaches for regenerative medicine. PMID:25534849

  17. Structure-based rational design of peptide hydroxamic acid inhibitors to target tumor necrosis factor-α converting enzyme as potential therapeutics for hepatitis.

    PubMed

    Wu, Dan; Gu, Qiuhong; Zhao, Ning; Xia, Fei; Li, Zhiwei

    2015-12-01

    The human tumor necrosis factor-α converting enzyme (TACE) has recently been raised as a new and promising therapeutic target of hepatitis and other inflammatory diseases. Here, we reported a successful application of the solved crystal structure of TACE complex with a peptide-like ligand INN for rational design of novel peptide hydroxamic acid inhibitors with high potency and selectivity to target and inhibit TACE. First, the intermolecular interactions between TACE catalytic domain and INN were characterized through an integrated bioinformatics approach, with which the key substructures of INN that dominate ligand binding were identified. Subsequently, the INN molecular structure was simplified to a chemical sketch of peptide hydroxamic acid compound, which can be regarded as a linear tripeptide capped by a N-terminal carboxybenzyl group (chemically protective group) and a C-terminal hydroxamate moiety (coordinated to the Zn(2+) at TACE active site). Based on the sketch, a virtual combinatorial library containing 180 peptide hydroxamic acids was generated, from which seven samples were identified as promising candidates by using a knowledge-based protein-peptide affinity predictor and were then tested in vitro with a standard TACE activity assay protocol. Consequently, three designed peptide hydroxamic acids, i.e. Cbz-Pro-Ile-Gln-hydroxamic acid, Cbz-Leu-Ile-Val-hydroxamic acid and Cbz-Phe-Val-Met-hydroxamic acid, exhibited moderate or high inhibitory activity against TACE, with inhibition constants Ki of 36 ± 5, 510 ± 46 and 320 ± 26 nM, respectively. We also examined the structural basis and non-bonded profile of TACE interaction with a designed peptide hydroxamic acid inhibitor, and found that the inhibitor ligand is tightly buried in the active pocket of TACE, forming a number of hydrogen bonds, hydrophobic forces and van der Waals contacts at the interaction interface, conferring both stability and specificity for TACE-inhibitor complex

  18. Assessing the likelihood of new-onset inflammatory bowel disease following tumor necrosis factor-alpha inhibitor therapy for rheumatoid arthritis and juvenile rheumatoid arthritis.

    PubMed

    Krishnan, Asha; Stobaugh, Derrick J; Deepak, Parakkal

    2015-04-01

    The association between inhibition of tumor necrosis factor-alpha (TNF-α) in patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) and the onset of inflammatory bowel disease (IBD) is unclear. We sought to evaluate this association by analyzing adverse events (AEs) reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) with a standardized scoring tool for drug-induced AEs. A search of the FAERS for RA or JRA (January 2003-December 2011) reported with adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab was performed. This dataset was then queried for cases indicating IBD. Full-length reports were accessed using the Freedom of Information Act and organized by age, sex, concomitant medications, co-morbidities, type of TNF-α inhibitor used, and diagnosis/treatment details. The Naranjo score was used to determine whether the drug-induced AEs were definite, probable, possible, or doubtful. There were 158 cases of IBD after TNF-α inhibitor exposure in RA or JRA patients. Use of the Naranjo score revealed that, in a majority of the cases (71.5 %), TNF-α inhibitor exposure was considered a 'possible' cause. A majority of the 'probable cases' in JRA were reported with etanercept (40 patients, 90.91 %). There were no 'definite' cases of anti-TNF-induced IBD. After applying the Naranjo scale, a weak association between new-onset IBD and TNF-α inhibitor therapy in RA patients and a moderately strong association especially with etanercept exposure in JRA patients was observed. However, causality cannot be determined due to limitations of the FAERS and the Naranjo score. PMID:25228459

  19. Tumor necrosis factor-α-induced apoptosis of gastric cancer MKN28 cells: accelerated degradation of the inhibitor of apoptosis family members.

    PubMed

    Kitagawa, Maki; Shiozaki, Atsushi; Ichikawa, Daisuke; Nakashima, Shingo; Kosuga, Toshiyuki; Konishi, Hirotaka; Komatsu, Shuhei; Fujiwara, Hitoshi; Okamoto, Kazuma; Otsuji, Eigo

    2015-01-15

    The role of the inhibitor of apoptosis (IAP) family members in tumor necrosis factor-α (TNF-α)-induced apoptosis of human gastric cancer MKN28 cells was explored. TNF-α induced up-regulation of cIAP2, whereas cycloheximide (CHX) induced down-regulation of XIAP and survivin. Degradation of cIAP1 and XIAP, but not survivin, was accelerated by co-treatment of cells with TNF-α and CHX, and TNF-α-induced up-regulation of cIAP2 was inhibited by BMS-345541 (NF-κB inhibitor). Treatment of MKN28 cells with TNF-α plus CHX induced degradation of survivin and activation of caspase-8 and -3, followed by degradation of cIAP1 and XIAP and apoptosis. Proteasome inhibitors (MG132 and epoxomicin) suppressed TNF-α plus CHX-induced degradation of survivin, cIAP1, and XIAP as well as apoptosis. A caspase inhibitor (z-VAD-fmk) suppressed TNF-α plus CHX-induced apoptosis, but allowed degradation of survivin, cIAP1 and XIAP. TNF-α receptor 1 and 2 were expressed on MKN28 cells. The magnitude of apoptosis induced by TNF-α plus BMS-345541 was much less than that induced by TNF-α plus CHX. These findings suggest that TNF-α plus CHX-induced apoptosis of gastric cancer MKN28 cells may be caused by accelerated degradation of the IAP family members (survivin, cIAP1, and XIAP), in addition to inhibition of NF-κB-dependent synthesis of anti-apoptotic molecules. PMID:25513960

  20. Concurrent Intervention With Exercises and Stabilized Tumor Necrosis Factor Inhibitor Therapy Reduced the Disease Activity in Patients With Ankylosing Spondylitis: A Meta-Analysis.

    PubMed

    Liang, Hui; Li, Wen-Rong; Zhang, Hua; Tian, Xu; Wei, Wei; Wang, Chun-Mei

    2015-12-01

    Since the use of tumor necrosis factor (TNF) inhibitor therapy is becoming wider, the effects of concurrent intervention with exercises and stabilized TNF inhibitors therapy in patients with ankylosing spondylitis (AS) are different. The study aimed to objectively evaluate whether concurrent intervention with exercises and stabilized TNF inhibitors can reduce the disease activity in patients with AS. A search from PubMed, Web of Science, EMBASE, and the Cochrane Library was electronically performed to collect studies which compared concurrent intervention with exercise and TNF inhibitor to conventional approach in terms of disease activity in patients with AS published from their inception to June 2015. Studies that measured the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), and chest expansion as outcomes were included. Two independent investigators screened the identified articles, extracted the data, and assessed the methodological quality of the included studies. Quantitative analysis was performed with Review Manager (RevMan) software (version 5.3.0). A total of 5 studies comprising 221 participants were included in the study. Meta-analyses showed that concurrent intervention with exercises and stabilized TNF inhibitors therapy significantly reduced the BASMI scores (MD, -0.99; 95% CI, -1.61 to -0.38) and BASDAI scores (MD, -0.58; 95% CI, -1.10 to -0.06), but the BASFI scores (MD, -0.31; 95% CI, -0.76 to 0.15) was not reduced, and chest expansion (MD, 0.80; 95% CI, -0.18 to 1.78) was not increased. Concurrent intervention with exercises and stabilized TNF inhibitors therapy can reduce the disease activity in patients with AS. More randomized controlled trials (RCTs) with high-quality, large-scale, and appropriate follow-up are warranted to further establish the benefit of concurrent intervention with exercises and TNF inhibitors for

  1. Association between tumour necrosis factorinhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study

    PubMed Central

    Pasternak, Björn; Friis-Møller, Nina; Andersson, Mikael; Jess, Tine

    2015-01-01

    Objective To investigate whether people with inflammatory bowel disease treated with tumour necrosis factor-α (TNF-α) inhibitors are at increased risk of serious infections. Design Nationwide register based propensity score matched cohort study. Setting Denmark, 2002-12. Participants The background cohort eligible for matching comprised 52 392 people with inflammatory bowel disease, aged 15 to 75 years, of whom 4300 were treated with TNF-α inhibitors. To limit confounding, a two stage matching method was applied; firstly matching on age, sex, disease duration, and inflammatory bowel disease subtype, and secondly matching on propensity scores (1:1 ratio); this yielded 1543 people treated with TNF-α inhibitors and 1543 untreated to be included in the analyses. Main outcome measures The main outcome was any serious infection, defined as a diagnosis of infection associated with hospital admission. Cox regression was used to estimate hazard ratios for two risk periods (90 and 365 days after the start of TNF-α inhibitor treatment). Hazard ratios of site specific serious infections were obtained solely for the 365 days risk period. Results Within the 90 days risk period, 51 cases of infection were observed in users of TNF-α inhibitors (incidence rate 14/100 person years), compared with 33 cases in non-users (9/100 person years), yielding a hazard ratio of 1.63 (95% confidence interval 1.01 to 2.63). Within the risk period of 365 days, the hazard ratio was 1.27 (0.92 to 1.75). In analyses of site specific infections, the hazard ratio was above 2 for several of the subgroups but only reached statistical significance for skin and soft tissue infections (2.51, 1.23 to 5.12). Conclusions This nationwide propensity score matched cohort study suggests an increased risk of serious infections associated with use of TNF-α inhibitors within the first 90 days of starting treatment and a subsequent decline in risk. This calls for increased clinical awareness of potential

  2. Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature including a series of six new patients.

    PubMed

    Wollina, Uwe; Hansel, Gesina; Koch, André; Schönlebe, Jaqueline; Köstler, Erich; Haroske, Gunter

    2008-01-01

    Tumor necrosis factor-alpha (TNFalpha) inhibition is effective in the treatment of moderate-to-severe psoriasis. We report on 120 patients from the literature including six new patients (three women and three men) who developed pustular lesions during treatment with TNFalpha inhibitors. We identified 72 women and 36 men (several papers did not specify the gender of patients) with an age range of 13-78 years (mean 42.3 years). The primary diagnoses were rheumatoid arthritis (n = 61), ankylosing spondylitis (n = 21), psoriasis (n = 10), Crohn disease (n = 8), SAPHO (synovitis acne pustulosis hyperostosis osteitis) syndrome (n = 3), psoriatic arthritis (n = 2), and other diagnoses (n = 15). Psoriasis (except palmoplantar pustular type) was the most common adverse effect during anti-TNFalpha treatment (n = 73), followed by palmoplantar pustular psoriasis (n = 37) and psoriasis of the nail (n = 6), sometimes combined in the same patient. Palmoplantar pustulosis and psoriasiform exanthema was the diagnosis in ten patients each. A positive personal history of psoriasis was recorded in 25 patients. A positive family history was noted in eight patients. No data about personal (n = 7) or family history (n = 46) were available in a number of patients. Newly induced psoriasis was diagnosed in 74 patients whereas an exacerbation or aggravation of a pre-existing psoriasis was noted in another 25 patients. All three TNFalpha inhibitors available on the market were involved: infliximab (63 patients), etanercept (37 patients), and adalimumab (26 patients). Several patients were treated with more than a single TFNalpha inhibitor. The timing of cutaneous adverse effects (psoriasis and psoriasiform rash) varied considerably among patients, ranging from after a single application to a delayed response of up to 63 months after initiation of treatment. The mean time to appearance of the cutaneous adverse effect for all TNFalpha inhibitors was 9.5 months. Cessation of the responsible

  3. Clinical Significance of Tumor Necrosis FactorInhibitors in the Treatment of Sciatica: A Systematic Review and Meta-Analysis

    PubMed Central

    Wang, Yun Fu; Chen, Ping You; Chang, Wei; Zhu, Fi Qi; Xu, Li Li; Wang, Song Lin; Chang, Li Ying; Luo, Jie; Liu, Guang Jian

    2014-01-01

    Background and Objective Currently, no satisfactory treatment is available for sciatica caused by herniated discs and/or spinal stenosis. The objective of this study is to assess the value of tumor necrosis factor (TNF)-α inhibitors in the treatment of sciatica. Methods Without language restrictions, we searched PubMed, OVID, EMBASE, the Web of Science, the Clinical Trials Registers, the Cochrane Central Register of Controlled Trials and the China Academic Library and Information System. We then performed a systematic review and meta-analysis on the enrolled trials that met the inclusion criteria. Results Nine prospective randomized controlled trials (RCTs) and two before-after controlled trials involving 531 patients met our inclusion criteria and were included in this study. Our systematic assessment and meta-analysis demonstrated that in terms of the natural course of the disease, compared with the control condition, TNF-α inhibitors neither significantly relieved lower back and leg pain (both p>0.05) nor enhanced the proportion of patients who felt overall satisfaction (global perceived effect (satisfaction)) or were able to return to work (return to work) (combined endpoint; p>0.05) at the short-term, medium-term and long-term follow-ups. In addition, compared with the control condition, TNF-α inhibitors could reduce the risk ratio (RR) of discectomy or radicular block (combined endpoint; RR = 0.51, 95% CI 0.26 to 1.00, p = 0.049) at medium-term follow-up, but did not decrease RR at the short-term (RR = 0.64, 95% CI 0.17 to 2.40, p = 0.508) and long-term follow-ups (RR = 0.64, 95% CI 0.40 to 1.03, p = 0.065). Conclusion The currently available evidence demonstrated that other than reducing the RR of discectomy or radicular block (combined endpoint) at medium-term follow-up, TNF-α inhibitors showed limited clinical value in the treatment of sciatica caused by herniated discs and/or spinal stenosis. PMID:25050851

  4. Synergistic Induction of Apoptosis in Primary B-CLL Cells after Treatment with Recombinant Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand and Histone Deacetylase Inhibitors

    PubMed Central

    Norian, Lyse A.; Kucaba, Tamara A.; Earel, James K.; Knutson, Tina; vanOosten, Rebecca L.; Griffith, Thomas S.

    2009-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently being investigated as a therapeutic agent for a variety of malignancies, as it triggers apoptosis specifically in transformed cells. However, TRAIL use as a stand alone therapeutic is hampered by the fact that many primary tumor cells are resistant to TRAIL-mediated apoptosis. Here, we investigated the extent to which pretreatment of TRAIL-resistant primary B-cell chronic lymphocytic leukemia (B-CLL) cells with histone deacetylase inhibitors (HDACis) could render them susceptible to killing by TRAIL. We found that HDAC inhibition in B-CLL cells led to increased TRAIL receptor expression, increased caspase activation, decreased expression of antiapoptotic regulators such as Bcl-2, and ultimately, enhanced TRAIL-induced apoptosis. Importantly, untransformed peripheral blood mononuclear cells remained largely resistant to TRAIL, even in the presence of HDACis. These results suggest that combination therapies using HDAC inhibition and TRAIL could prove beneficial for the treatment of B-CLL. PMID:19547714

  5. Tumor necrosis factor-α synthesis inhibitor, 3’6,dithiothalidomide, reverses behavioral impairments induced by minimal traumatic brain injury in mice

    PubMed Central

    Baratz, Renana; Tweedie, David; Rubovitch, Vardit; Luo, Weiming; Yoon, Jeong Seon; Hoffer, Barry J.; Greig, Nigel H.; Pick, Chaim G.

    2012-01-01

    Mild traumatic brain injury (mTBI) patients do not show clear structural brain defects and, in general, do not require hospitalization, but frequently suffer from long-lasting cognitive, behavioral and emotional difficulties. Although there is no current effective treatment or cure for mTBI, tumor necrosis factor-alpha (TNF-α), a cytokine fundamental in the systemic inflammatory process, represents a potential drug target. TNF-α levels increase after mTBI and may induce or exacerbate secondary damage to brain tissue. The present study evaluated the efficacy of the experimental TNF-α synthesis inhibitor, 3,6'-dithiothalidomide, on recovery of mice from mTBI in a closed head weight-drop model that induces an acute elevation in brain TNF-α and an impairment in cognitive performance, as assessed by the Y-maze, by novel object recognition and by passive avoidance paradigms at 72 hr and 7 days after injury. These impairments were fully ameliorated in mice that received a one time administration of 3,6'-dithiothalidomide at either a low (28 mg/kg) or high (56 mg/kg) dose provided either 1 hr prior to injury, or at 1 or 12 hr post injury. Together, these results implicate TNF-α as a drug target for mTBI and suggests that 3,6'-dithiothalidomide may act as a neuroprotective drug to minimize impairment. PMID:21740439

  6. NASPGHAN Clinical Report: Surveillance, Diagnosis, and Prevention of Infectious Diseases in Pediatric Patients With Inflammatory Bowel Disease Receiving Tumor Necrosis FactorInhibitors.

    PubMed

    Ardura, Monica I; Toussi, Sima S; Siegel, Jane D; Lu, Ying; Bousvaros, Athos; Crandall, Wallace

    2016-07-01

    Children and adolescents with inflammatory bowel disease (IBD) receiving therapy with tumor necrosis factor α inhibitors (anti-TNFα) pose a unique challenge to health care providers in regard to the associated risk of infection. Published experience in adult populations with distinct autoinflammatory and autoimmune diseases treated with anti-TNFα therapies demonstrates an increased risk of serious infections with intracellular bacteria, mycobacteria, fungi, and some viruses; however, there is a paucity of robust pediatric data. With a rising incidence of pediatric IBD and increasing use of biologic therapies, heightened knowledge and awareness of infections in this population is important for primary care pediatricians, pediatric gastroenterologists, and infectious disease (ID) physicians. This clinical report is the result of a consensus review performed by pediatric ID and gastroenterology physicians detailing relevant published literature regarding infections in pediatric patients with IBD receiving anti-TNFα therapies. The objective of this document is to provide comprehensive information for prevention, surveillance, and diagnosis of infections based on current knowledge, until additional pediatric data are available to inform evidence-based recommendations. PMID:27027903

  7. Induction of plasminogen activator inhibitor 1 gene expression in murine liver by lipopolysaccharide. Cellular localization and role of endogenous tumor necrosis factor-alpha.

    PubMed Central

    Fearns, C.; Loskutoff, D. J.

    1997-01-01

    We previously demonstrated that lipopolysaccharide (LPS) induces plasminogen activator inhibitor 1 (PAI-1) gene expression primarily in endothelial cells in most organs of the mouse, with maximal induction by 3 hours. Here we show that induction in the liver occurs in a distinctly different pattern. For example, the increase in PAI-1 mRNA in liver was biphasic with an initial peak at 1 to 2 hours and a second peak at 6 to 8 hours. Moreover, in situ hybridization experiments revealed that PAI-1 mRNA was induced in both endothelial cells and hepatocytes. The endothelial cell response was monophasic and maximal between 1 and 4 hours, whereas the hepatocyte response was biphasic, peaking at 2 hours and again at 6 to 8 hours. To determine possible mechanisms involved in the induction of PAI-1 by LPS, we analyzed the tissues for changes in tumor necrosis factor (TNF)-alpha LPS caused a rapid induction of TNF-alpha mRNA in Kupffer cells, detectable within 15 minutes. Pretreatment of mice with anti-TNF antiserum before challenge with LPS reduced the subsequent increase in plasma levels of PAI-1 by 50 to 70% and significantly reduced the level of induction of PAI-1 mRNA in the liver at both early and late times. Pretreatment appeared to inhibit induction primarily within hepatocytes. These results suggest that LPS may induce PAI-1 in endothelial cells and hepatocytes by different mechanisms. Images Figure 3 Figure 4 Figure 7 PMID:9033272

  8. Safety of Resuming Tumor Necrosis Factor Inhibitors in Ankylosing Spondylitis Patients Concomitant with the Treatment of Active Tuberculosis: A Retrospective Nationwide Registry of the Korean Society of Spondyloarthritis Research

    PubMed Central

    Kim, Hye Won; Kwon, Seong Ryul; Jung, Kyong-Hee; Kim, Seong-Kyu; Baek, Han Joo; Seo, Mi Ryung; Bang, So-Young; Lee, Hye-Soon; Suh, Chang-Hee; Jung, Ju Yang; Son, Chang-Nam; Shim, Seung Cheol; Lee, Sang-Hoon; Lee, Seung-Geun; Lee, Yeon-Ah; Lee, Eun Young; Kim, Tae-Hwan

    2016-01-01

    Backgrounds Patients who develop an active tuberculosis infection during tumor necrosis factor (TNF) inhibitor treatment typically discontinue TNF inhibitor and receive standard anti-tuberculosis treatment. However, there is currently insufficient information on patient outcomes following resumption of TNF inhibitor treatment during ongoing anti- tuberculosis treatment. Our study was designed to investigate the safety of resuming TNF inhibitors in ankylosing spondylitis (AS) patients who developed tuberculosis as a complication of the use of TNF inhibitors. Methods Through the nationwide registry of the Korean Society of Spondyloarthritis Research, 3929 AS patients who were prescribed TNF inhibitors were recruited between June 2003 and June 2014 at fourteen referral hospitals. Clinical information was analyzed about the patients who experienced tuberculosis after exposure to TNF inhibitors. The clinical features of resumers and non-resumers of TNF inhibitors were compared and the outcomes of tuberculosis were surveyed individually. Findings Fifty-six AS patients were treated for tuberculosis associated with TNF inhibitors. Among them, 23 patients resumed TNF inhibitors, and these patients were found to be exposed to TNF inhibitors for a longer period of time and experienced more frequent disease flare-up after discontinuation of TNF inhibitors compared with those who did not resume. Fifteen patients resumed TNF inhibitors during anti-tuberculosis treatment (early resumers) and 8 after completion of anti-tuberculosis treatment (late resumers). Median time to resuming TNF inhibitor from tuberculosis was 3.3 and 9.0 months in the early and late resumers, respectively. Tuberculosis was treated successfully in all resumers and did not relapse in any of them during follow-up (median 33.8 [IQR; 20.8–66.7] months). Conclusions Instances of tuberculosis were treated successfully in our AS patients, even when given concomitantly with TNF inhibitors. We suggest that early

  9. High levels of memory B cells are associated with response to a first tumor necrosis factor inhibitor in patients with rheumatoid arthritis in a longitudinal prospective study

    PubMed Central

    2014-01-01

    Introduction Tumor necrosis factor inhibitor (TNFi) therapy is effective for rheumatoid arthritis (RA). Some researchers have suggested that TNFi therapy affects B-cell homeostasis. We studied the effect of TNFi therapy on the distribution of peripheral B-cell subsets to elucidate B-cell–related biomarkers to predict the TNFi response. Methods Peripheral B cells were analyzed for expression of CD19, CD27, CD38 and immunoglobulin D in 31 healthy donors and 96 RA patients, including 21 patients who were followed 3 months after TNFi initiation. Results Treatment with steroids significantly altered the distribution of B-cell subsets. After we adjusted for age, sex and steroid dose, we found that patients with RA had B-cell subset proportions similar to controls. B-cell subset distributions did not differ upon use of TNFi at baseline or before or after TNFi introduction. TNFi responders (according to European League Against Rheumatism criteria) at 3 months had significantly higher proportions of CD27+ memory B cells at baseline, and ≥26% CD27+ cells at inclusion was associated with a relative risk of 4.9 (1.3 to 18.6) for response to TNFi treatment. CD27+ cells produced three times more TNFα than did TNFi-naïve B cells and were correlated with interferon γ produced from CD4+ cells in patients without TNFi treatment. Conclusions In patients with RA, high levels of baseline memory B cells were associated with response to TNFi, which may be related to TNFα-dependent activation of the T helper type 1 cell pathway. PMID:24735586

  10. Tumour necrosis factor-alpha-induced ICAM-1 expression in human vascular endothelial and lung epithelial cells: modulation by tyrosine kinase inhibitors.

    PubMed Central

    Burke-Gaffney, A.; Hellewell, P. G.

    1996-01-01

    1. Tumour necrosis factor-alpha (TNF alpha) increases the expression of the adhesion molecule intercellular adhesion molecule-1 (ICAM-1) on cultured endothelial and epithelial cells and modulation of this may be important in controlling inflammation. Activation of tyrosine kinase(s) is known to be involved in the signal transduction pathways of many cytokines. In this study we have investigated the effects of the tyrosine kinase inhibitors, ST638, tyrphostin AG 1288 and genistein, on TNF alpha-induced ICAM-1 expression in human alveolar epithelial (A549) and vascular endothelial (EAhy926) cell lines and also normal human lung microvascular endothelial cells (HLMVEC). 2. ICAM-1 expression on cultured cells was determined by a sensitive enzyme-linked immunosorbant assay (ELISA). Endothelial or epithelial monolayers were exposed to increasing doses of TNF-alpha (0.01-10 ng ml-1), in the presence or absence of either ST638 (3-100 microM), AG 1288 (3-100 microM) or genistein (100 microM) and ICAM-1 expression was measured at 4 and 24 h. Control experiments examined the effect of ST638 on phorbol 12-myristate 13-acetate (PMA, 20 ng ml-1, 4 h)-stimulated ICAM-1 and compared it to that of a specific protein kinase C inhibitor, R031-8220 (10 microM). Also, functional consequences of changes in ICAM-1 expression were assessed by measuring adhesion of 111 In-labelled human neutrophils to EAhy926 endothelial and A549 epithelial monolayers treated with TNF alpha, in the presence or absence of ST638. 3. ST638 caused a concentration-dependent reduction in TNF alpha- (0.1-10 ng ml-1)-induced ICAM-1 on EAhy926 endothelial (at 4 h) and A549 epithelial monolayers (at 4 and 24 h). In contrast, ST638 caused a concentration-dependent increase in TNF alpha- (0.1-10 ng ml-1)-induced ICAM-1 on EAhy926 endothelial cells at 24 h. Similar effects were seen with AG 1288 or genistein. ST638 (100 microM) significantly (P < 0.01) inhibited ICAM-1 expression on HLMVEC endothelial cells induced by

  11. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis

    PubMed Central

    Roubille, Camille; Richer, Vincent; Starnino, Tara; McCourt, Collette; McFarlane, Alexandra; Fleming, Patrick; Siu, Stephanie; Kraft, John; Lynde, Charles; Pope, Janet; Gulliver, Wayne; Keeling, Stephanie; Dutz, Jan; Bessette, Louis; Bissonnette, Robert; Haraoui, Boulos

    2015-01-01

    The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso). Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010–2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data. Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001). In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003). In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk. PMID:25561362

  12. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

    PubMed

    Roubille, Camille; Richer, Vincent; Starnino, Tara; McCourt, Collette; McFarlane, Alexandra; Fleming, Patrick; Siu, Stephanie; Kraft, John; Lynde, Charles; Pope, Janet; Gulliver, Wayne; Keeling, Stephanie; Dutz, Jan; Bessette, Louis; Bissonnette, Robert; Haraoui, Boulos

    2015-03-01

    The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso). Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010-2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data. Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001). In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003). In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk. PMID:25561362

  13. Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation.

    PubMed

    Martin, John; Midgley, Adam; Meran, Soma; Woods, Emma; Bowen, Timothy; Phillips, Aled O; Steadman, Robert

    2016-06-24

    Fibroblasts are central to wound healing and fibrosis through TGFβ1-triggered differentiation into contractile, α-smooth muscle actin (α-SMA)-positive myofibroblasts. This is mediated by accumulation of a pericellular matrix of hyaluronan (HA) and the HA-dependent co-localization of CD44 with the epidermal growth factor receptor (EGFR). Interactions of HA with hyaladherins, such as inter-α-inhibitor (IαI) and tumor necrosis factor-stimulated gene-6 (TSG-6), are also essential for differentiation. This study investigated the mechanisms involved. TSG-6 and α-SMA had different kinetics of induction by TGFβ1, with TSG-6 peaking before α-SMA Si CD44 or EGFR inhibition prevented differentiation but had no effect on TSG-6 expression. TSG-6 was essential for differentiation, and mAb A38 (preventing IαI heavy chain (HC) transfer), HA-oligosaccharides, cobalt, or Si bikunin prevented TSG-6 activity, preventing differentiation. A38 also prevented the EGFR/CD44 association. This suggested that TSG-6/IαI HC interaction was necessary for the effect of TSG-6 and that HC stabilization of HA initiated the CD44/EGFR association. The newly described HC5 was shown to be the principal HC expressed, and its cell surface expression was prevented by siRNA inhibition of TSG-6 or bikunin. HC5 was released by hyaluronidase treatment, confirming its association with cell surface HA. Finally, HC5 knockdown by siRNA confirmed its role in myofibroblast differentiation. The current study describes a novel mechanism linking the TSG-6 transfer of the newly described HC5 to the HA-dependent control of cell phenotype. The interaction of HC5 with cell surface HA was essential for TGFβ1-dependent differentiation of fibroblasts to myofibroblasts, highlighting its importance as a novel potential therapeutic target. PMID:27143355

  14. [Recommendations for the diagnosis and treatment of latent and active tuberculosis in patients with inflammatory joint diseases treated with tumour necrosis factor alpha inhibitors].

    PubMed

    Fonseca, João Eurico; Lucas, Helena; Canhão, Helena; Duarte, Raquel; Santos, Maria José; Villar, Miguel; Faustino, Augusto; Raymundo, Elena

    2006-01-01

    The Portuguese Society of Rheumatology (SPR) and the Portuguese Society of Pulmonology (SPP) have developed guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (AT) in patients with inflammatory joint diseases (IJD), namely rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, treated with tumour necrosis factor alpha (TNF-alpha) antagonists. Due to the high risk of tuberculosis (TB) in patients with IJD, LTBI and AT screening should be performed as soon as possible, ideally at the moment of IJD diagnosis. Even if TB screening was performed at the beginning of the disease, the evaluation should be repeated before starting anti-TNF-alpha therapy. When TB (LTBI orAT) treatment is indicated, it should be performed before the beginning of anti-TNF-alpha therapy. If the IJD activity requires urgent anti-TNF-alpha therapy, these drugs can be started after two months of antituberculosis therapy in AT cases, or after one month in LTBI cases. Chest X-ray is mandatory for all patients. If abnormal, e.g. Gohn complex, the patient should be treated as LTBI; residual lesions require the exclusion of AT and patients with history of untreated or incomplete TB treatment should be treated as LTBI. In cases of suspected active lesions, AT diagnosis should be confirmed and adequate therapy initiated. Tuberculin skin test (TST), with two units of RT23, should be performed in all patients. If induration is less than 5 mm, the test should be repeated after 1 to 2 weeks, on the opposite forearm, and should be considered negative if the result is again inferior to 5 mm. Positive TST implicates LTBI treatment. IfTST is performed in immunosupressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNFalpha therapy, even in the presence of a negative test. PMID:17094335

  15. Recommendations for the diagnosis and treatment of latent and active tuberculosis in inflammatory joint diseases candidates for therapy with tumor necrosis factor alpha inhibitors: March 2008 update.

    PubMed

    Fonseca, João Eurico; Lucas, Helena; Canhão, Helena; Duarte, Raquel; Santos, Maria José; Villar, Miguel; Faustino, Augusto; Raymundo, Elena

    2008-01-01

    The Portuguese Society of Rheumatology and the Portuguese Society of Pulmonology have updated the guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (ATB) in patients with inflammatory joint diseases (IJD) that are candidates to therapy with tumour necrosis factor alpha (TNFalpha) antagonists. In order to reduce the risk of tuberculosis (TB) reactivation and the incidence of new infections, TB screening is recommended to be done as soon as possible, ideally at the moment of IJD diagnosis, and patient assessment repeated before starting anti-TNFalpha therapy. Treatment for ATB and LTBI must be done under the care of a TB specialist. When TB treatment is indicated, it should be completed prior to starting anti-TNFalpha therapy. If the IJD activity justifies the need for immediate treatment, anti-TNFalpha therapy can be started two months after antituberculous therapy has been initiated, in the case of ATB, and one month after in the case of LTBI. Chest X-ray is mandatory for all patients. If Gohn s complex is present, the patient should be treated for LTBI; healed lesions require the exclusion of ATB. In cases of suspected active lesions ATB should be excluded/confirmed and adequate therapy initiated. Tuberculin skin test, with two units of RT23, should be performed in all patients. If the induration is <5 mm, the test should be repeated within 1 to 2 weeks, on the opposite forearm, and will be considered negative only if the result is again <5 mm. Positive TST implicates LTBI treatment, unless previous proper treatment was provided. If TST is performed in immunossuppressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNFalpha therapy, even in the presence of a negative test, after risk/benefit assessment. PMID:18344925

  16. Recommendations for the diagnosis and treatment of latent and active tuberculosis in inflammatory joint diseases candidates for therapy with tumor necrosis factor alpha inhibitors - March 2008 update.

    PubMed

    Fonseca, João Eurico; Lucas, Helena; Canhão, Helena; Duarte, Raquel; Santos, Maria José; Villar, Miguel; Faustino, Augusto; Raymundo, Elena

    2008-01-01

    The Portuguese Society of Rheumatology and the Portuguese Society of Pulmonology have updated the guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (ATB) in patients with inflammatory joint diseases (IJD) that are candidates to therapy with tumour necrosis factor alpha (TNFα) antagonists. In order to reduce the risk of tuberculosis (TB) reactivation and the incidence of new infections, TB screening is recommended to be done as soon as possible, ideally at the moment of IJD diagnosis, and patient assessment repeated before starting anti-TNFα therapy. Treatment for ATB and LTBI must be done under the care of a TB specialist. When TB treatment is indicated, it should be completed prior to starting anti-TNFα therapy. If the IJD activity justifies the need for immediate treatment, anti-TNFα therapy can be started two months after antituberculous therapy has been initiated, in the case of ATB, and one month after in the case of LTBI. Chest X-ray is mandatory for all patients. If Gohn's complex is present, the patient should be treated for LTBI; healed lesions require the exclusion of ATB. In cases of suspected active lesions, ATB should be excluded/confirmed and adequate therapy initiated. Tuberculin skin test, with two units of RT23, should be performed in all patients. If the induration is <5 mm, the test should be repeated within 1 to 2 weeks, on the opposite forearm, and will be considered negative only if the result is again <5 mm. Positive TST implicates LTBI treatment, unless previous proper treatment was provided. If TST is performed in immunossuppressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNF-α therapy, even in the presence of a negative test, after risk / benefit assessment. Rev Port Pneumol 2007; XIV (2): 271-283. PMID:25966834

  17. Dose reduction of recombinant human tumor necrosis factor inhibitors (etanercept) can be effective in ankylosing spondylitis patients with synovitis of the hip in a Chinese population.

    PubMed

    Li, Jitian; Wang, Xiaoqing; Han, Zongchang; Zhang, Yonghong; Wang, Yuli; Zhang, Yishan; Li, Wuyin

    2016-09-01

    Ankylosing spondylitis (AS) is an immune-mediated inflammatory arthritis and enthesitis involving the spine and peripheral joints. In recent years, specific antagonist of tumor necrosis factor (anti-TNFα, etanercept) 50 mg weekly therapy has rapidly gained popularity for the treatment of AS. However, the dose of etanercept has not been determined in Asian, particularly Chinese populations. The purpose of the study was to evaluate the efficacy and safety of dose reduction of etanercept (50 mg/week in 4 weeks followed by 25 mg/week in 8 weeks) in the treatment of AS with synovitis of the hip, as against the conventional dose (50 mg/week in 12 weeks) in a Chinese population. Forty-three Chinese AS patients with synovitis of the hip were involved in this study. Seventeen of them were randomized to receive conventional dose of etanercept treatment and 26 were given a dose reduction regimen for 12 weeks. The primary efficacy endpoint was disease activity of response for AS at week 12, including Bath AS Disease Activity Index (BASDAI), the serum erythrocyte sediment rate (ESR), C-reactive protein (CRP), and assessment of synovitis of the hip by ultrasonography. At 12 weeks, all of the patients had responses to some extent and the efficacy variables improved significantly over time, but not between treatment groups. Nine patients experienced at least one adverse event (generally, infections and injection site reactions), most of them mild or moderate. In sum, the dose reduction of etanercept regimen in the 12-week AS treatment was confirmed as a safe and effective therapy as the conventional dose was given. PMID:27381286

  18. Tumor Necrosis Factor-α-induced Proteolytic Activation of Pro-matrix Metalloproteinase-9 by Human Skin Is Controlled by Down-regulating Tissue Inhibitor of Metalloproteinase-1 and Mediated by Tissue-associated Chymotrypsin-like Proteinase*

    PubMed Central

    Han, Yuan-Ping; Nien, Yih-Dar; Garner, Warren L.

    2008-01-01

    The proteolytic activation of pro-matrix metalloproteinase (MMP)-9 by conversion of the 92-kDa precursor into an 82-kDa active form has been observed in chronic wounds, tumor metastasis, and many inflammation-associated diseases, yet the mechanistic pathway to control this process has not been identified. In this report, we show that the massive expression and activation of MMP-9 in skin tissue from patients with chronically unhealed wounds could be reconstituted in vitro with cultured normal human skin by stimulation with transforming growth factor-β and tumor necrosis factor (TNF)-α. We dissected the mechanistic pathway for TNF-α induced activation of pro-MMP-9 in human skin. We found that proteolytic activation of pro-MMP-9 was mediated by a tissue-associated chymotrypsin-like proteinase, designated here as pro-MMP-9 activator (pM9A). This unidentified activator specifically converted pro-MMP-9 but not pro-MMP-2, another member of the gelatinase family. The tissue-bound pM9A was steadily expressed and not regulated by TNF-α, which indicated that the cytokine-mediated activation of pro-MMP-9 might be regulated at the inhibitor level. Indeed, the skin constantly secreted tissue inhibitor of metalloproteinase-1 at the basal state. TNF-α, but not transforming growth factor-β, down-regulated this inhibitor. The TNF-α-mediated activation of pro-MMP-9 was tightly associated with down-regulation of tissue inhibitor of metalloproteinase-1 in a dose-dependent manner. To establish this linkage, we demonstrate that the recombinant tissue inhibitor of metalloproteinase-1 could block the activation of pro-MMP-9 by either the intact skin or skin fractions. Thus, these studies suggest a novel regulation for the proteolytic activation of MMP-9 in human tissue, which is mediated by tissue-bound activator and controlled by down-regulation of a specific inhibitor. PMID:12004062

  19. Indirect comparisons of the efficacy of subsequent biological agents in patients with psoriatic arthritis with an inadequate response to tumor necrosis factor inhibitors: a meta-analysis.

    PubMed

    Ungprasert, Patompong; Thongprayoon, Charat; Davis, John M

    2016-07-01

    Significant portion of patients with psoriatic arthritis (PsA) could not tolerate or do not have a satisfactory response to either non-steroidal anti-inflammatory drugs (NSAIDs), non-biologic disease-modifying anti-rheumatic drugs (DMARDs), or even TNF inhibitors. Non-TNF inhibitor biologic agents have emerged as second-line therapy in such situation. However, the comparative efficacy of these agents remains unknown as head-to-head randomized controlled trials (RCTs) are not available. RCTs examining the efficacy of non-TNF inhibitor biologic agents in patients with PsA who experienced inadequate response or intolerance of TNF inhibitors were identified. If more than one RCT was available for a given biologic agent, the pooled odds ratio (OR) and 95 % confidence interval (CI) of achieving 20 % improvement according to American College of Rheumatology criteria (ACR20) response across trials were calculated. The pooled OR for each biologic agent was then compared using the indirect comparison technique. Five RCTs of four non-TNF inhibitor biologic agents, including abatacept, secukinumab, ustekinumab, and apremilast, with 675 participants were identified and included in the data analyses. We found no significant difference in any comparisons, with the p values ranging from 0.14 to 0.98. Our study demonstrates that the likelihood of achieving the ACR20 response in patients with TNF inhibitor experience is not significantly different between the four non-TNF biologic agents. However, the interpretation of this analysis is limited by the small sample sizes. Head-to-head comparisons are still required to confirm the comparative efficacy. PMID:26852316

  20. Three Cases of Previous Smokers with Rheumatoid Arthritis Who Did Not Respond to Tumor Necrosis Factor Inhibitors Were Treated Successfully with an Anti-Interleukin-6 Receptor Antibody

    PubMed Central

    Iwata, Yasuo

    2015-01-01

    We report three cases of previous smokers who did not respond to TNF inhibitors but who responded successfully to an anti-interleukin-6 receptor antibody (tocilizumab (TCZ)). Case 1 is a 63-year-old woman whose smoking index was 200 and had been complaining of polyarthralgia since 1996. She started treatment with etanercept due to high disease activity, but her DAS28-CRP was 4.2. She was therefore switched to TCZ, which dramatically improved her symptoms; her DAS28-CRP had decreased to 2.1. Case 2 is a 64-year-old man whose smoking index was 1600 and had been complaining of polyarthralgia since 2006. Because his DAS28-CRP score increased over time to 5.9, etanercept and adalimumab were added sequentially, but he showed no response over the course of two years. The patient was therefore switched to TCZ, which dramatically improved his symptoms: his DAS28-CRP decreased to 2.7. Case 3 is a 48-year-old woman whose smoking index was 560 and had been complaining of pain in both knee joints since 2001. She was treated with adalimumab due to high disease activity but showed no response over the course of 1.5 years. The patient was therefore switched to TCZ, and her DAS28-CRP decreased to 1.8. An IL-6 blockade might be suitable for treating these 3 cases of previous smokers. PMID:25648415

  1. Novel histone deacetylase inhibitor MPT0G009 induces cell apoptosis and synergistic anticancer activity with tumor necrosis factor-related apoptosis-inducing ligand against human hepatocellular carcinoma.

    PubMed

    Chen, Mei-Chuan; Huang, Hui-Hsuan; Lai, Chin-Yu; Lin, Yi-Jyun; Liou, Jing-Ping; Lai, Mei-Jung; Li, Yu-Hsuan; Teng, Che-Ming; Yang, Chia-Ron

    2016-01-01

    Hepatocellular carcinoma (HCC) is a frequent cause of cancer-related death; therefore, more effective anticancer therapies for the treatment of HCC are needed. Histone deacetylase (HDAC) inhibitors serve as promising anticancer drugs because they can induce cell growth arrest and apoptosis. We previously reported that 3-[1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]-N-hydroxyacrylamide (MPT0G009)-a novel 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines compound-demonstrated potent pan-HDAC inhibition and anti-inflammatory effects. In this study, we evaluated the anti-HCC activity of MPT0G009 in vitro and in vivo. Growth inhibition, apoptosis, and inhibited HDAC activity induced by MPT0G009 were more potent than a marketed HDAC inhibitor SAHA (Vorinostat). Furthermore, MPT0G009-induced apoptosis of Hep3B cells was characterized by an increase in apoptotic (sub-G1) population, loss of mitochondrial membrane potential, activation of caspase cascade, increased levels of pro-apoptotic protein (Bim), and decreased levels of anti-apoptotic proteins (Bcl-2, Bcl-xL, and FLICE-inhibitory protein); the downregulation FLIP by MPT0G009 is mediated through proteasome-mediated degradation and transcriptional suppression. In addition, combinations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with lower concentrations (0.1 μM) of MPT0G009 were synergistic in cell growth inhibition and apoptosis in HCC cells. In the in vivo model, MPT0G009 markedly reduced Hep3B xenograft tumor volume, inhibited HDAC activities, and induced apoptosis in the Hep3B xenografts. Our results demonstrate that MPT0G009 is a potential new candidate drug for HCC therapy. PMID:26587975

  2. Novel histone deacetylase inhibitor MPT0G009 induces cell apoptosis and synergistic anticancer activity with tumor necrosis factor-related apoptosis-inducing ligand against human hepatocellular carcinoma

    PubMed Central

    Lai, Chin-Yu; Lin, Yi-Jyun; Liou, Jing-Ping; Lai, Mei-Jung; Li, Yu-Hsuan; Teng, Che-Ming; Yang, Chia-Ron

    2016-01-01

    Hepatocellular carcinoma (HCC) is a frequent cause of cancer-related death; therefore, more effective anticancer therapies for the treatment of HCC are needed. Histone deacetylase (HDAC) inhibitors serve as promising anticancer drugs because they can induce cell growth arrest and apoptosis. We previously reported that 3-[1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]-N-hydroxyacrylamide (MPT0G009)—a novel 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines compound—demonstrated potent pan-HDAC inhibition and anti-inflammatory effects. In this study, we evaluated the anti-HCC activity of MPT0G009 in vitro and in vivo. Growth inhibition, apoptosis, and inhibited HDAC activity induced by MPT0G009 were more potent than a marketed HDAC inhibitor SAHA (Vorinostat). Furthermore, MPT0G009-induced apoptosis of Hep3B cells was characterized by an increase in apoptotic (sub-G1) population, loss of mitochondrial membrane potential, activation of caspase cascade, increased levels of pro-apoptotic protein (Bim), and decreased levels of anti-apoptotic proteins (Bcl-2, Bcl-xL, and FLICE-inhibitory protein); the downregulation FLIP by MPT0G009 is mediated through proteasome-mediated degradation and transcriptional suppression. In addition, combinations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with lower concentrations (0.1 μM) of MPT0G009 were synergistic in cell growth inhibition and apoptosis in HCC cells. In the in vivo model, MPT0G009 markedly reduced Hep3B xenograft tumor volume, inhibited HDAC activities, and induced apoptosis in the Hep3B xenografts. Our results demonstrate that MPT0G009 is a potential new candidate drug for HCC therapy. PMID:26587975

  3. Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) Mutation and TRAP1 Inhibitor Gamitrinib-triphenylphosphonium (G-TPP) Induce a Forkhead Box O (FOXO)-dependent Cell Protective Signal from Mitochondria.

    PubMed

    Kim, Hyunjin; Yang, Jinsung; Kim, Min Ju; Choi, Sekyu; Chung, Ju-Ryung; Kim, Jong-Min; Yoo, Young Hyun; Chung, Jongkyeong; Koh, Hyongjong

    2016-01-22

    TRAP1 (tumor necrosis factor receptor-associated protein 1), a mitochondrial Hsp90 family chaperone, has been identified as a critical regulator of cell survival and bioenergetics in tumor cells. To discover novel signaling networks regulated by TRAP1, we generated Drosophila TRAP1 mutants. The mutants successfully developed into adults and produced fertile progeny, showing that TRAP1 is dispensable in development and reproduction. Surprisingly, mutation or knockdown of TRAP1 markedly enhanced Drosophila survival under oxidative stress. Moreover, TRAP1 mutation ameliorated mitochondrial dysfunction and dopaminergic (DA) neuron loss induced by deletion of a familial Parkinson disease gene PINK1 (Pten-induced kinase 1) in Drosophila. Gamitrinib-triphenylphosphonium, a mitochondria-targeted Hsp90 inhibitor that increases cell death in HeLa and MCF7 cells, consistently inhibited cell death induced by oxidative stress and mitochondrial dysfunction induced by PINK1 mutation in mouse embryonic fibroblast cells and DA cell models such as SH-SY5Y and SN4741 cells. Additionally, gamitrinib-triphenylphosphonium also suppressed the defective locomotive activity and DA neuron loss in Drosophila PINK1 null mutants. In further genetic analyses, we showed enhanced expression of Thor, a downstream target gene of transcription factor FOXO, in TRAP1 mutants. Furthermore, deletion of FOXO almost nullified the protective roles of TRAP1 mutation against oxidative stress and PINK1 mutation. These results strongly suggest that inhibition of the mitochondrial chaperone TRAP1 generates a retrograde cell protective signal from mitochondria to the nucleus in a FOXO-dependent manner. PMID:26631731

  4. Clinical studies with tumour necrosis factor.

    PubMed

    Spriggs, D R; Sherman, M L; Frei, E; Kufe, D W

    1987-01-01

    The mechanism of tumour necrosis factor (TNF) cytotoxicity remains unknown. The in vivo antitumour effects of TNF may be related to direct cytotoxicity, immunomodulatory effects or endothelial effects on tumour vasculature. Phase I and early Phase II clinical trials of human recombinant TNF are under way in Japan, the USA, the UK and Germany. The maximum Phase II dose for TNF has not been established. The clinical toxicity of TNF is generally similar to that of other biological agents. Systemic toxicity, including fever, chills, anorexia and nausea, has been seen in most patients treated with TNF and has not been clearly related to dose. Other toxicities have included liver function abnormalities, hypotension, transient neurological changes and haematological abnormalities. Few clinical responses have been reported but organized Phase II testing remains to be completed. Combination trials with interferons have recently been initiated. Phase II efficacy studies of TNF as a single agent and in combination are needed for an assessment of the value of this agent in cancer therapy. PMID:3330011

  5. Retention of the second-line biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis failing one tumor necrosis factor alpha inhibitor: data from the BioRx.si registry.

    PubMed

    Rotar, Ziga; Hočevar, Alojzija; Rebolj Kodre, Anamarija; Praprotnik, Sonja; Tomšič, Matija

    2015-10-01

    This study aimed to investigate the retention of the second-line biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis patients failing their first tumor necrosis factor alpha inhibitor (TNFi). Data was extracted from the Slovenian registry (BioRx.si) on December 15, 2012. Baseline patient characteristics were compared between second-line TNFi and non-TNFi, and potential confounders were identified by the means of binary logistic regression. Differential drug retention was assessed using the Kaplan-Meier method and crude and inverse probability-weighted Cox proportional hazards regression models (Cox model). Two hundred thirty-eight out of 688 patients who received a TNFi as the first biologic were switched to another biologic: 130 to a second-line TNFi and 108 to either rituximab (31.5 %) or tocilizumab (68.5 %) (non-TNFi). Disease activity at starting second-line bDMARD and stopping the first-line TNFi due to either lack of effectiveness or loss of effectiveness were identified as potential confounders. There appears to be a statistically significant retention advantage of the non-TNFi over the second-line TNFi (log rank test, p = 0.000). This advantage is retained even after taking into account the possible effect of confounders which was tested using the inverse probability-weighted Cox model [hazard ratio (HR) 4.39; 95 % confidence interval (CI) 2.62-8.01, p < 0.001]. After the first-line TNFi's failure, a second-line TNFi is more likely to fail earlier than non-TNFi. PMID:26345633

  6. A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis.

    PubMed

    Kung, G; Dai, P; Deng, L; Kitsis, R N

    2014-04-01

    TNFα signaling can promote apoptosis or a regulated form of necrosis. ARC (apoptosis repressor with CARD (caspase recruitment domain)) is an endogenous inhibitor of apoptosis that antagonizes both the extrinsic (death receptor) and intrinsic (mitochondrial/ER) apoptosis pathways. We discovered that ARC blocks not only apoptosis but also necrosis. TNFα-induced necrosis was abrogated by overexpression of wild-type ARC but not by a CARD mutant that is also defective for inhibition of apoptosis. Conversely, knockdown of ARC exacerbated TNFα-induced necrosis, an effect that was rescued by reconstitution with wild-type, but not CARD-defective, ARC. Similarly, depletion of ARC in vivo exacerbated necrosis caused by infection with vaccinia virus, which elicits severe tissue damage through this pathway, and sensitized mice to TNFα-induced systemic inflammatory response syndrome. The mechanism underlying these effects is an interaction of ARC with TNF receptor 1 that interferes with recruitment of RIP1, a critical mediator of TNFα-induced regulated necrosis. These findings extend the role of ARC from an apoptosis inhibitor to a regulator of the TNFα pathway and an inhibitor of TNFα-mediated regulated necrosis. PMID:24440909

  7. Effects of tumor necrosis factor α-857C/T polymorphism on the expression of tumor necrosis factor α.

    PubMed

    Kimura, Koji; Takayanagi, Risa; Yokoyama, Haruko; Yamada, Yasuhiko

    2016-08-01

    It was reported that homozygosity for a lymphotoxin α (LTA) 1-1-1-1 haplotype (LTA NcoI-TNFc-aa13L-aa26) may identify subgroups with a poor response to infliximab in Crohn's disease patients. Previously, we found a genetic polymorphism that linked with the LTA 1-1-1-1 haplotype and noted that it was a tumor necrosis factor (TNF) α-857 T allele. To investigate the effects of the -857C/T (rs1799724) polymorphism on the expression of TNFα, we compared levels of transcriptional activity of the gene, mRNA, and protein of the TNFα. The change in transcriptional activity of the -857T allele was higher than that of the -857C allele. Furthermore, the accumulated transcriptional activity of the -857T allele was 1.3-fold higher than that of the -857C allele up to 48 h. The levels of mRNA and protein of the TNFα after stimulation were also shown to be significantly higher in -857C/T as compared to the -857C/C genotype. Our results suggested that TNFα promoter -857T is higher than -857C in the levels of transcriptional activity of the gene, mRNA, and protein of the TNFα. The differences in therapeutic effect of TNF inhibitors among individuals can be explained in part by the induction ability of TNFα via the -857C/T polymorphism. PMID:27307133

  8. [Neurological complications during treatment of the tumor necrosis alpha inhibitors].

    PubMed

    Piusińska-Macoch, Renata

    2013-05-01

    Medications with TNF-alpha inhibitors family are successfully applicable in rheumatology, gastroenterology, dermatology and neurology. Still, the ongoing research on the safety assessment of their application, also due to neurological complications. The vast majority of these complications is associated with an increased risk of serious virus (Herpes simplex--JC) and bacterial (Listeria monocytogenes) neuroinfections. They can cause the occurrence of progressive multifocal leukoencephalopathy--PML with a severe clinical course and poor prognosis or herpes simplex encephalitis--HSE. Meta-analysis revealed a number of cases of PML and the HSE in the first 6 months of treatment with natalizumab, efalizumab, rituximab, abatacept and infliximab. Common complication occasionally turning on this biologics is chronic demyelinating polyneuropathy or Lewis-Sumner syndrome. Described are cases of central and peripheral demyelination typical of multiple sclerosis (MS). Are also reported cases of motor multifocal neuropathy with conduction block acute encephalithis with polyneuropathy or mononeuropathy in the form of anterior optic neuropathy Guillen-Barre' syndrome and its variant, Miller-Fisher syndrome have been confirmed as adverse events following treatment with infliximab. Also revealed several cases of myasthenia gravis after using etanercept. In the few cases of systemic lupus CNS involvement caused by treatment with TNF inhibitors, the mechanism of these disorders is still considered too vague. Due to the emerging reports on the number of neurological adverse events of TNF antagonists, significantly higher than those described in the literature, the safety of their use requires further monitoring and multicenter studies. PMID:23894783

  9. A GSK-3β Inhibitor Protects Against Radiation Necrosis in Mouse Brain

    SciTech Connect

    Jiang, Xiaoyu; Perez-Torres, Carlos J.; Thotala, Dinesh; Engelbach, John A.; Yuan, Liya; Cates, Jeremy; Gao, Feng; Drzymala, Robert E.; Rich, Keith M.; Schmidt, Robert E.; Ackerman, Joseph J.H.; Hallahan, Dennis E.; Garbow, Joel R.

    2014-07-15

    Purpose: To quantify the effectiveness of SB415286, a specific inhibitor of GSK-3β, as a neuroprotectant against radiation-induced central nervous system (brain) necrosis in a mouse model. Methods and Materials: Cohorts of mice were treated with SB415286 or dimethyl sulfoxide (DMSO) prior to irradiation with a single 45-Gy fraction targeted to the left hemisphere (brain) using a gamma knife machine. The onset and progression of radiation necrosis (RN) were monitored longitudinally by noninvasive in vivo small-animal magnetic resonance imaging (MRI) beginning 13 weeks postirradiation. MRI-derived necrotic volumes for SB415286- and DMSO-treated mice were compared. MRI results were supported by correlative histology. Results: Mice treated with SB415286 showed significant protection from radiation-induced necrosis, as determined by in vivo MRI with histologic validation. MRI-derived necrotic volumes were significantly smaller at all postirradiation time points in SB415286-treated animals. Although the irradiated hemispheres of the DMSO-treated mice demonstrated many of the classic histologic features of RN, including fibrinoid vascular necrosis, vascular telangiectasia, hemorrhage, and tissue loss, the irradiated hemispheres of the SB415286-treated mice consistently showed only minimal tissue damage. These studies confirmed that treatment with a GSK-3β inhibitor dramatically reduced delayed time-to-onset necrosis in irradiated brain. Conclusions: The unilateral cerebral hemispheric stereotactic radiation surgery mouse model in concert with longitudinal MRI monitoring provided a powerful platform for studying the onset and progression of RN and for developing and testing new neuroprotectants. Effectiveness of SB415286 as a neuroprotectant against necrosis motivates potential clinical trials of it or other GSK-3β inhibitors.

  10. Advances in the diagnosis and treatment of tumor necrosis factor receptor-associated periodic syndrome.

    PubMed

    Aguado-Gil, L; Irarrazaval-Armendáriz, I; Pretel-Irazabal, M

    2013-09-01

    Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant disease included in the group of autoinflammatory syndromes. It is characterized by recurrent episodes of fever and inflammation in different regions of the body. The main clinical manifestations are myalgia, migratory erythematous rash, periorbital edema, and abdominal pain. The diagnosis is reached using gene analysis and prognosis depends on the appearance of amyloidosis secondary to the recurrent episodes of inflammation. Tumor necrosis factor inhibitors and corticosteroids are the most widely used treatments. In recent years, significant advances have been made in the diagnosis and treatment of TRAPS, thanks to a better understanding of its pathogenesis. Dermatologists must be aware that the skin manifestations of TRAPS are particularly important, as they are often diagnostic. PMID:23891452

  11. The role of tumour necrosis factor alpha and soluble tumour necrosis factor alpha receptors in the symptomatology of schizophrenia.

    PubMed

    Turhan, Levent; Batmaz, Sedat; Kocbiyik, Sibel; Soygur, Arif Haldun

    2016-07-01

    Background Immunological mechanisms may be responsible for the development and maintenance of schizophrenia symptoms. Aim The aim of this study is to measure tumour necrosis factor-alpha (TNF-α), soluble tumour necrosis factor-alpha receptor I (sTNF-αRI), and soluble tumour necrosis factor-alpha receptor II (sTNF-αRII) levels in patients with schizophrenia and healthy individuals, and to determine their relationship with the symptoms of schizophrenia. Methods Serum TNF-α, sTNF-αRI and sTNF-αRII levels were measured. The Positive and Negative Syndrome Scale (PANSS) was administered for patients with schizophrenia (n = 35), and the results were compared with healthy controls (n = 30). Hierarchical regression analyses were undertaken to predict the levels of TNF-α, sTNF-αRI and sTNF-αRII. Results No significant difference was observed in TNF-α levels, but sTNF-αRI and sTNF-αRII levels were lower in patients with schizophrenia. Serum sTNF-αRI and sTNF-αRII levels were found to be negatively correlated with the negative subscale score of the PANSS, and sTNF-αRI levels were also negatively correlated with the total score of the PANSS. Smoking, gender, body mass index were not correlated with TNF-α and sTNF-α receptor levels. Conclusions These results suggest that there may be a change in anti-inflammatory response in patients with schizophrenia due to sTNF-αRI and sTNF-αRII levels. The study also supports low levels of TNF activity in schizophrenia patients with negative symptoms. PMID:26754110

  12. Potential roles for tumour necrosis factor alpha during embryonic development.

    PubMed

    Wride, M A; Sanders, E J

    1995-01-01

    This paper reviews the evidence indicating possible roles for tumour necrosis factor-alpha (TNF alpha) in development. It is proposed that TNF alpha may have essentially three major roles during embryonic development, which may be analogous to its roles in the immune system and during inflammation: a role in programmed cell death; a role as a cellular growth and differentiation factor; and also a role in the remodelling of extracellular matrix, and the regulation of cell adhesion molecules and integrins. The concept of the existence of a cytokine array during embryogenesis, analogous to that occurring in inflammation, is discussed, as well as potential roles for TNF alpha in the induction of ubiquitin; protective mechanisms embryonic cells may employ against TNF alpha-mediated cytotoxicity; and a consideration of the role TNF alpha may play in a "free radical theory of development". PMID:7717528

  13. Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: Inhibition of tumor angiogenesis with extensive tumor necrosis

    SciTech Connect

    Kang, Khong Bee . E-mail: dmskkb@nccs.com.sg; Wang, Ting Ting; Woon, Chow Thai; Cheah, Elizabeth S.; Moore, Xiao Lei; Zhu Congju; Wong, Meng Cheong

    2007-03-01

    Purpose: Toward improved glioblastoma multiforme treatment, we determined whether celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, could enhance glioblastoma radiosensitivity by inducing tumor necrosis and inhibiting tumor angiogenesis. Methods and Materials: U-87MG cells treated with celecoxib, irradiation, or both were assayed for clonogenic survival and angiogenic factor protein analysis (angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor [VEGF]). In vivo, survival of mice intracranially implanted with U-87MG cells and treated with celecoxib and/or irradiation was monitored. Isolated tumors were assessed for tumor necrosis and tumor microvascular density by von Williebrand's factor (vWF) immunohistochemical staining. Results: Celecoxib (4 and 30 {mu}M; 24, 48, and 72 h) enhanced U-87MG cell radiosensitivity by significantly reducing clonogenic survival of irradiated cells. Angiopoietin-1 and VEGF proteins were decreased, whereas angiopoietin-2 expression increased after 72 h of celecoxib alone and when combined with irradiation. In vivo, median survival of control mice intracranially implanted with U-87MG cells was 18 days. Celecoxib (100 mg/kg/day, 2 weeks) significantly extended median survival of irradiated mice (24 Gy total) from 34 to 41 days, with extensive tumor necrosis [24.5 {+-} 8.6% of tumor region, compared with irradiation alone (2.7 {+-} 1.8%)]. Tumor microvascular density was significantly reduced in combined celecoxib and irradiated tumors (52.5 {+-} 2.9 microvessels per mm{sup 2} tumor region), compared with irradiated tumors alone (65.4 {+-} 4.0 microvessels per mm{sup 2}). Conclusion: Celecoxib significantly enhanced glioblastoma radiosensitivity, reduced clonogenic survival, and prolonged survival of glioblastoma-implanted mice by inhibition of tumor angiogenesis with extensive tumor necr0010os.

  14. Pharmacokinetics and pharmacodynamics of DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)), a potent and selective inhibitor of tumor necrosis factor alpha-converting enzyme in rodents, dogs, chimpanzees, and humans.

    PubMed

    Qian, Mingxin; Bai, Stephen A; Brogdon, Bernice; Wu, Jing-Tao; Liu, Rui-Qin; Covington, Maryanne B; Vaddi, Kris; Newton, Robert C; Fossler, Michael J; Garner, C Edwin; Deng, Yuzhong; Maduskuie, Thomas; Trzaskos, James; Duan, James J-W; Decicco, Carl P; Christ, David D

    2007-10-01

    DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-alpha production in blood from rodents, chimpanzee, and human, with IC(50) values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 inhibited the production of TNF-alpha in a dose-dependent manner, with an oral ED(50) ranging from 1.1 to 6.1 mg/kg. Oral dosing of DPC 333 at 5.5 mg/kg daily for 2 weeks in a rat collagen antibody-induced arthritis model suppressed the maximal response by approximately 50%. DPC 333 was distributed widely to tissues including the synovium, the site of action for antiarthritic drugs. Pharmacokinetic and pharmacodynamic studies in chimpanzee revealed a systemic clearance of 0.4 l/h/kg, a V(ss) of 0.6 l/kg, an oral bioavailability of 17%, and an ex vivo IC(50) for the suppression of TNF-alpha production of 55 nM (n = 1). In a phase I clinical trial with male volunteers after single escalating doses of oral DPC 333, the terminal half-life was between 3 and 6 h and the ex vivo IC(50) for suppressing TNF-alpha production was 113 nM. Measurement of the suppression of TNF-alpha production ex vivo may serve as a good biomarker in evaluating the therapeutic efficacy of TACE inhibitors. Overall, the pharmacological profiles of DPC 333 support the notion that suppression of TNF-alpha with TACE inhibitors like DPC 333 may provide a novel approach in the treatment of various inflammatory diseases including rheumatoid arthritis, via control of excessive TNF-alpha production. PMID:17656469

  15. Anti-tumor necrosis factor-α therapy in uveitis.

    PubMed

    Cordero-Coma, Miguel; Sobrin, Lucia

    2015-01-01

    Since the first reported use in 2001 of an anti-tumor necrosis factor-alpha (TNF-α) agent, infliximab, for the treatment of uveitis, several new anti-TNF-α agents have emerged for the treatment of refractory noninfectious uveitides, although their use remains off-label in the US. These agents have demonstrated remarkable clinical antiinflammatory efficacy and a potential immunoregulatory role in selected uveitis patients, but it is currently unclear whether they can modify the natural history of disease. We review the rationale and clinical indications for this therapy, the differences between agents, how to manage dosing and intervals, and how to screen for and identify potential side effects. We also present a summary of the science behind the use of anti-TNF-α agents in ocular inflammation and the evidence for their efficacy. PMID:26164735

  16. Role of Tumor Necrosis Factor Superfamily in Neuroinflammation and Autoimmunity

    PubMed Central

    Sonar, Sandip; Lal, Girdhari

    2015-01-01

    Tumor necrosis factor superfamily (TNFSF) molecules play an important role in the activation, proliferation, differentiation, and migration of immune cells into the central nervous system (CNS). Several TNF superfamily molecules are known to control alloimmunity, autoimmunity, and immunity. Development of transgenic and gene knockout animals, and monoclonal antibodies against TNFSF molecules have increased our understanding of individual receptor–ligand interactions, and their intracellular signaling during homeostasis and neuroinflammation. A strong clinical association has been observed between TNFSF members and CNS autoimmunity such as multiple sclerosis and also in its animal model experimental autoimmune encephalomyelitis. Therefore, they are promising targets for alternative therapeutic options to control autoimmunity. Although, TNFSF ligands are widely distributed and have diverse functions, we have restricted the discussions in this review to TNFSF receptor–ligand interactions and their role in the pathogenesis of neuroinflammation and CNS autoimmunity. PMID:26257732

  17. Tumor necrosis factor alpha polymorphism in heart failure/cardiomyopathy.

    PubMed

    Vadlamani, Lou; Iyengar, Srinivas

    2004-01-01

    Tumor necrosis factor a (TNF-alpha) is a proinflammatory cytokine that is produced by activated macrophages. It has been shown to stimulate the release of endothelial cytokines and NO, increase vascular permeability, decrease contractility, and induce a prothrombotic state. The most studied TNF-a gene mutation in heart disease is a gamma to alpha substitution, which occurs when 308 nucleotides move upstream from the transcription initiation site in the TNF promoter and has been associated with elevated levels of TNF-alpha. The TNF1 allele (wild type) contains gamma at this site, while the TNF2 allele has an alpha substitution at the site. The TNF2 allele is a more powerful transcriptional activator, therefore leading to higher TNF-alpha levels. Most of the studies to date have failed to conclusively show any link between the polymorphism and heart disease, both coronary artery disease and cardiomyopathy/heart failure. PMID:15591843

  18. Predictors of Switching Anti-Tumor Necrosis Factor Therapy in Patients with Ankylosing Spondylitis

    PubMed Central

    Lee, Jeong-Won; Kang, Ji-Hyoun; Yim, Yi-Rang; Kim, Ji-Eun; Wen, Lihui; Lee, Kyung-Eun; Park, Dong-Jin; Kim, Tae-Jong; Park, Yong-Wook; Lee, Shin-Seok

    2015-01-01

    The aim of this study was to investigate the potential predictors of switching tumor necrosis factor (TNF)-α inhibitors in Korean patients with ankylosing spondylitis (AS). The patients who had been treated with TNF-α inhibitors were divided into two groups depending on whether they had switched TNF-α inhibitors. Demographic, clinical, laboratory, and treatment data at the time of initiation of TNF-α inhibitor treatment were compared between switchers and non-switchers, and within switchers according to the reasons for switching. Of the 269 patients, 70 (23%) had switched TNF-α inhibitors once; of these, 11 switched again. The median follow-up time was 52.7 months. Three- and five-year drug survival rates were 52%/48% for infliximab, 62%/42% for etanercept, and 71%/51% for adalimumab, respectively. Switchers were more likely to be prescribed disease-modifying anti-rheumatic drugs than non-switchers. A history of joint surgery and complete ankylosis of the sacroiliac joint was more frequent in switchers. Multivariate Cox’s proportional hazard analysis showed that the use of adalimumab as the first TNF-α inhibitor was less likely to lead to switching and complete ankylosis of the sacroiliac joints was more likely to lead to switching. The principal reasons for switching were drug inefficacy and adverse events, but the differences in the clinical data of these two groups of switchers were not significant. In AS patients who are candidates for TNF-α inhibitor therapy, switching may improve the therapeutic outcome based on clinical information. PMID:26176701

  19. TRIM32 protein sensitizes cells to tumor necrosis factor (TNFα)-induced apoptosis via its RING domain-dependent E3 ligase activity against X-linked inhibitor of apoptosis (XIAP).

    PubMed

    Ryu, Yeung Sook; Lee, Younglang; Lee, Keun Woo; Hwang, Chae Young; Maeng, Jin-Soo; Kim, Jeong-Hoon; Seo, Yeon-Soo; You, Kwan-Hee; Song, Byeongwoon; Kwon, Ki-Sun

    2011-07-22

    TRIM32, which belongs to the tripartite motif (TRIM) protein family, has the RING finger, B-box, and coiled-coil domain structures common to this protein family, along with an additional NHL domain at the C terminus. TRIM32 reportedly functions as an E3 ligase for actin, a protein inhibitor of activated STAT y (PIASy), dysbindin, and c-Myc, and it has been associated with diseases such as muscular dystrophy and epithelial carcinogenesis. Here, we identify a new substrate of TRIM32 and propose a mechanism through which TRIM32 might regulate apoptosis. Our overexpression and knockdown experiments demonstrate that TRIM32 sensitizes cells to TNFα-induced apoptosis. The RING domain is necessary for this pro-apoptotic function of TRM32 as well as being responsible for its E3 ligase activity. TRIM32 colocalizes and directly interacts with X-linked inhibitor of apoptosis (XIAP), a well known cancer therapeutic target, through its coiled-coil and NHL domains. TRIM32 overexpression enhances XIAP ubiquitination and subsequent proteasome-mediated degradation, whereas TRIM32 knockdown has the opposite effect, indicating that XIAP is a substrate of TRIM32. In vitro reconstitution assay reveals that XIAP is directly ubiquitinated by TRIM32. Our novel results collectively suggest that TRIM32 sensitizes TNFα-induced apoptosis by antagonizing XIAP, an anti-apoptotic downstream effector of TNFα signaling. This function may be associated with TRIM32-mediated tumor suppressive mechanism. PMID:21628460

  20. Tumor necrosis factor induced stimulation of granulopoiesis and radioprotection.

    PubMed

    Urbaschek, R; Männel, D N; Urbaschek, B

    1987-01-01

    Human recombinant tumor necrosis factor, TNF, was used to assess its ability to stimulate granulopoiesis and to protect mice against lethal irradiation, effects known to be inducable with TNF-rich postendotoxin serum from BCG infected mice (BCG/ET serum). Although the endotoxin contamination of this TNF preparation is extremely low its effects were compared in endotoxin low responder C3H/HeJ mice and susceptible NMRI mice. TNF is a potent inducer of serum colony stimulating activity, CSA, in both mouse strains. In peripheral blood a marked granulocytosis with a concomitant decrease in lymphocytes and monocytopenia occurs at 2 hours after injection of TNF. Moreover, TNF induces an increase in the number of splenic myelopoietic committed stem cells (GM-CFC, granulocyte-macrophage colony forming cells) determined five days after injection. The lethality rate, registered over 30 days after exposure to 660 cGy whole body X-irradiation is reduced to 40% in C3H/HeJ mice as compared to 75% in control animals. The reduction in lethality is observed both, when TNF was injected 24 hours before or after irradiation. In vitro, TNF significantly increases the number of colonies in the presence of CSA in bone marrow cultures. TNF per se does not effect colony growth. The studies reported here demonstrate that TNF is a myelopoiesis stimulating factor in mice which may be related to the reduction in lethality following whole body irradiation. PMID:3306175

  1. Tumour necrosis factor alpha antibody protects against lethal meningococcaemia.

    PubMed

    Nassif, X; Mathison, J C; Wolfson, E; Koziol, J A; Ulevitch, R J; So, M

    1992-03-01

    Tumour necrosis factor alpha (TNF-alpha) has been shown to be the principal mediator of Gram-negative bacterial endotoxin-induced shock. Nevertheless, evidence suggests that TNF-alpha plays a beneficial role in controlling bacterial infections when multiplication of the microorganism is required to kill the host. Using an infant rat model of Neisseria meningitidis infection, we found that blood TNF-alpha concentration reaches a peak three hours after intraperitoneal injection of 3 x 10(6) bacteria. Thereafter, the level of TNF-alpha decreased and was undetectable six to eight hours after infection. A correlation was observed between the magnitude of initial TNF-alpha response and a fatal outcome. Pretreatment of the animals with polyclonal anti-TNF antiserum significantly reduced mortality relative to animals pretreated with control serum. However, pretreatment of animals with anti-TNF antibody did not alter the bacterial invasion of the cerebrospinal fluid. Injection of heat-killed bacteria did not cause death and induced lower TNF-alpha levels than the same number of live bacteria. This excludes the possibility that the role of TNF-alpha is to mediate a shock induced by the endotoxin component of the bacterial inoculum. These results indicate that TNF-alpha has a deleterious effect in this model of bacteraemia. Identification of the critical factors that determine the action of TNF-alpha during lethal bacteraemia will lead to a better understanding of these diseases and the development of appropriate therapeutic intervention. PMID:1552859

  2. Tumour necrosis factor-alpha gene polymorphisms and Alzheimer's disease.

    PubMed

    Culpan, Doris; MacGowan, Sian H; Ford, Julia M; Nicoll, James A R; Griffin, W Sue; Dewar, Deborah; Cairns, Nigel J; Hughes, Anthony; Kehoe, Patrick G; Wilcock, Gordon K

    2003-10-16

    Recent findings suggest that production of pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), is increased in the brains of people with Alzheimer's disease (AD). We used direct sequencing methods on a section of the enhancer/promoter region and on a smaller fragment located 10.5 kb upstream of the TNF-alpha gene to respectively examine TNF-alpha polymorphisms and TNF-a and -b microsatellite alleles in a cohort of 235 post-mortem confirmed AD and 130 control cases. None of the TNF-alpha point mutations or microsatellite alleles investigated proved to be independent risk factors for AD. However, when -308/A, -238/G and TNF-a2 were examined as a 2-1-2 haplotype, we observed that the absence of that haplotype was significantly associated with AD (P = 0.014, Fisher's exact test) suggesting that the 2-1-2 haplotype may be protective against AD. PMID:12962917

  3. Tumor necrosis factor and cancer, buddies or foes?*

    PubMed Central

    WANG, Xia; LIN, Yong

    2008-01-01

    Tumor necrosis factor (TNF) is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory cytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation-associated carcinogenesis. TNF exerts its biological functions through activating distinct signaling pathways such as nuclear factor κB (NF-κB) and c-Jun N-terminal kinase (JNK). NF-κB is a major cell survival signal that is anti-apoptotic while sustained JNK activation contributes to cell death. The crosstalk between the NF-κB and JNK is involved in determining cellular outcomes in response to TNF. In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates cancer cells’ growth, proliferation, invasion and metastasis, and tumor angiogenesis. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-κB, by combined therapy. In this article we provide an overview of the roles of TNF-induced signaling pathways in cancer biology with specific emphasis on carcinogenesis and cancer therapy. PMID:18954521

  4. Tumor necrosis factor inhibitors added to nonbiological immunosuppressants vs. nonbiological immunosuppressants alone: a different signal of cancer risk according to the condition. A disproportionality analysis in a nationwide pharmacovigilance database.

    PubMed

    Saliba, Layla; Moulis, Guillaume; Abou Taam, Malak; Rousseau, Vanessa; Chebane, Leila; Petitpain, Nadine; Baldin, Bernadette; Pugnet, Grégory; Montastruc, Jean-Louis; Bagheri, Haleh

    2016-04-01

    We aimed at detecting a signal of an increased risk of cancer in patients treated with TNF inhibitor (TNFi) and nonbiological immunosuppressant (NBIS), compared with NBIS alone for autoimmune diseases. Secondly, we aimed at comparing this risk between the different TNFis. We conducted a disproportionality analysis (case/noncase study) from the French National PharmacoVigilance Database. We selected all the reports of serious adverse drug reactions from 2000 to 2010 in patients treated with NBIS for labeled indications of TNFi. Cases were all the reports of cancer that occurred after a minimal 3-month exposure to NBIS. Noncases were all the other reports. We searched for exposure to TNFi and calculated reporting odds ratios (RORs), stratified by condition and type of cancer and adjusted by age, gender, history of cancer, type of NBIS and year of reporting. Of the 1918 reports included in the study population, 217 were cases (135 solid and 82 blood cancers). A safety signal was found in rheumatoid arthritis (RA) (ROR: 5.43, 95% CI[3.52-8.38]) particularly for nonmelanoma skin cancer (NMSC) (20.17[2.49-163.36]), and in psoriasis/psoriatic arthritis (3.45[1.09-10.92]). No signal was found in inflammatory bowel diseases (IBD) and ankylosing spondylitis, whatever the type of cancer. There was no difference between TNFis. This study puts the argument of an increased risk of cancer (particularly NMSC) in patients with rheumatoid arthritis exposed to TNFi and NBIS compared with NBIS alone, but not in IBD and ankylosing spondylitis patients. No signal was detected for melanoma potentially related to the lack of power. The signal seems similar whatever the TNFi. PMID:26604187

  5. Tumor necrosis factor-alpha antagonists and neuropathy.

    PubMed

    Stübgen, Joerg-Patrick

    2008-03-01

    Tumor necrosis factor (TNF)-alpha plays an important role in many aspects of immune system development, immune-response regulation, and T-cell-mediated tissue injury. The evidence that TNF-alpha, released by autoreactive T cells and macrophages, may contribute to the pathogenesis of immune-mediated demyelinating neuropathies is reviewed. TNF-alpha antagonists (infliximab, etanercept, adalimumab) are indicated for the treatment of advanced inflammatory rheumatic and bowel disease, but these drugs can induce a range of autoimmune diseases that also attack the central and peripheral nervous systems. Case histories and series report on the association between anti-TNF-alpha treatment and various disorders of peripheral nerve such as Guillain-Barré syndrome, Miller Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy with conduction block, mononeuropathy multiplex, and axonal sensorimotor polyneuropathies. The proposed pathogeneses of TNF-alpha-associated neuropathies include both a T-cell and humoral immune attack against peripheral nerve myelin, vasculitis-induced nerve ischemia, and inhibition of signaling support for axons. Most neuropathies improve over a period of months by withdrawal of the TNF-alpha antagonist, with or without additional immune-modulating treatment. Preliminary observations suggest that TNF-alpha antagonists may be useful as an antigen-nonspecific treatment approach to immune-mediated neuropathies in patients with a poor response to, or intolerance of, standard therapies, but further studies are required. PMID:18041052

  6. Colchicine prevents tumor necrosis factor-induced toxicity in vivo.

    PubMed Central

    Tiegs, G; Freudenberg, M A; Galanos, C; Wendel, A

    1992-01-01

    Tumor necrosis factor (TNF) toxicity was induced in vivo by intravenous administration of 15 micrograms of recombinant murine TNF-alpha per kg to galactosamine-sensitized mice. Within 8 h, the animals developed a fulminant hepatitis. Intravenous administration of 0.5 mg of colchicine per kg at 19 and 4 h prior to TNF challenge protected the animals against hepatitis. Lipopolysaccharide (LPS)-stimulated, bone marrow-derived macrophages from C3H/HeN mice released significant amounts of TNF in vitro. When such macrophages were intravenously given to LPS-resistant galactosamine-sensitized C3H/HeJ mice, these animals died within 24 h. Preincubation of these transferred macrophages with colchicine did not suppress the LPS-inducible TNF release from these cells. Concordantly, administration of macrophages exposed to colchicine in vitro resulted in full lethality. However, in vivo pretreatment of C3H/HeJ mice with colchicine 19 and 4 h prior to the transfer of LPS-stimulated macrophages prevented lethality. In LPS-responsive NMRI mice which had been protected against galactosamine-LPS-induced hepatitis by pretreatment with colchicine, TNF was still released into the blood. We conclude from our findings that the in vivo protection by colchicine is mediated by blocking TNF action on target cells while the effector cells of LPS toxicity, i.e., the macrophages, remain responsive. PMID:1563785

  7. Expression of Tumor Necrosis Factor in Human Acute Cardiac Rejection

    PubMed Central

    Arbustini, Eloisa; Grasso, Maurizia; Diegoli, Marta; Bramerio, Manuela; Foglieni, Andrea Scotti; Albertario, Marco; Martinelli, Luigi; Gavazzi, Antonello; Goggi, Claudio; Campana, Carlo; Vigano, Mario

    1991-01-01

    The authors performed an immunohistochemical study on expression of tumor necrosis factor alpha (TNFα) in endomyocardial biopsies from human cardiac allografts. TNFα immunoreactivity was found in 45% biopsies with mild acute rejection, in 83% biopsies with focal moderate rejection, in 80% biopsies with diffuse moderate rejection. Biopsies with absent rejection did not show immunoreactive cells. In mild rejection, positive cells were few and scanty monocytes and macrophages (MAC-387 and LN5 positive cells) and T lymphocytes (UCHL-1/CD45 RO positive cells) (up to 20% of all infiltrating cells). Expression of major histocompatibility complex (MHC) class II antigens on infiltrating and endothelial cells occurred earlier and independent of TNFα reactivity. Number of immunoreactive cells increased in moderate rejection (up to 50%). Immunoreactivity was also present in nonpigmented macrophages in part of the biopsies with resolving rejection (45%). The authors conclude that TNFα is expressed in acute cardiac rejection by immunologically activated inflammatory cells. Immunoreactive cells increase in number with increasing severity of the reaction. ImagesFigure 1Figure 2Figure 3Figure 4 PMID:1928295

  8. Constitutive synthesis of tumor necrosis factor in the thymus.

    PubMed Central

    Giroir, B P; Brown, T; Beutler, B

    1992-01-01

    Although tumor necrosis factor (TNF) is a major mediator of endotoxic shock, the normal function of TNF that has preserved this protein throughout mammalian evolution remains unknown. If the protein serves a role in normal development or homeostasis, it must be produced under physiologic conditions. To determine whether TNF secretion occurs in normal animals, and to define the tissue sources of the protein, we prepared a reporter construct in which the TNF coding sequence and introns are replaced by the chloramphenicol acetyltransferase (CAT) coding sequence. This construct was inserted into the murine genome, yielding 13 transgenic founders. Macrophages harvested from 4 of the transgenic lines expressed CAT activity after stimulation with Escherichia coli lipopolysaccharide in vitro. Each of these 4 transgenic lines also constitutively expressed CAT activity in the thymus but in no other tissue examined. Cultured thymocytes secrete TNF, as demonstrated both by cytotoxicity assays and by immunoprecipitation of radiolabeled thymic culture medium. CAT activity was associated with the thymic lymphocyte population and not with thymic macrophages or dendritic cells. CAT activity was present in thymic lymphocytes irrespective of CD4 or CD8 expression; T cells from the spleen, however, had no detectable CAT activity. The biosynthesis of TNF in the thymus of normal animals implies a role for this protein in the development or regulation of the immune response. Images PMID:1594585

  9. Tumor Necrosis Factor Superfamily in Innate Immunity and Inflammation

    PubMed Central

    Šedý, John; Bekiaris, Vasileios; Ware, Carl F.

    2015-01-01

    The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor–ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes), lymphotoxin-β receptor (LT-βR), and HVEM are used by embryonic and adult innate lymphocytes to promote the development and homeostasis of lymphoid organs. Lymphotoxin-expressing innate-acting B cells construct microenvironments in lymphoid organs that restrict pathogen spread and initiate interferon defenses. Recent results illustrate how the communication networks formed among these cytokines and the coreceptors B and T lymphocyte attenuator (BTLA) and CD160 both inhibit and activate innate lymphoid cells (ILCs), innate γδ T cells, and natural killer (NK) cells. Understanding the role of TNFSF/TNFRSF and interacting proteins in innate cells will likely reveal avenues for future therapeutics for human disease. PMID:25524549

  10. Tumor necrosis factor superfamily in innate immunity and inflammation.

    PubMed

    Šedý, John; Bekiaris, Vasileios; Ware, Carl F

    2015-04-01

    The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor-ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes), lymphotoxin-β receptor (LT-βR), and HVEM are used by embryonic and adult innate lymphocytes to promote the development and homeostasis of lymphoid organs. Lymphotoxin-expressing innate-acting B cells construct microenvironments in lymphoid organs that restrict pathogen spread and initiate interferon defenses. Recent results illustrate how the communication networks formed among these cytokines and the coreceptors B and T lymphocyte attenuator (BTLA) and CD160 both inhibit and activate innate lymphoid cells (ILCs), innate γδ T cells, and natural killer (NK) cells. Understanding the role of TNFSF/TNFRSF and interacting proteins in innate cells will likely reveal avenues for future therapeutics for human disease. PMID:25524549

  11. Targeted Cancer Therapy with Tumor Necrosis Factor-Alpha

    PubMed Central

    Cai, Weibo; Kerner, Zachary J.; Hong, Hao; Sun, Jiangtao

    2013-01-01

    Tumor necrosis factor-alpha (TNF-α), a member of the TNF superfamily, was the first cytokine to be evaluated for cancer biotherapy. However, the clinical use of TNF-α is severely limited by its toxicity. Currently, TNF-α is administered only through locoregional drug delivery systems such as isolated limb perfusion and isolated hepatic perfusion. To reduce the systemic toxicity of TNF-α, various strategies have been explored over the last several decades. This review summarizes current state-of-the-art targeted cancer therapy using TNF-α. Passive targeting, cell-based therapy, gene therapy with inducible or tissue-specific promoters, targeted polymer-DNA complexes, tumor pre-targeting, antibody-TNF-α conjugate, scFv/TNF-α fusion proteins, and peptide/TNF-α fusion proteins have all been investigated to combat cancer. Many of these agents are already in advanced clinical trials. Molecular imaging, which can significantly speed up the drug development process, and nanomedicine, which can integrate both imaging and therapeutic components, has the potential to revolutionize future cancer patient management. Cooperative efforts from scientists within multiple disciplines, as well as close partnerships among many organizations/entities, are needed to quickly translate novel TNF-α-based therapeutics into clinical investigation. PMID:24115841

  12. Tumor necrosis factor drives increased splenic monopoiesis in old mice.

    PubMed

    Loukov, Dessi; Naidoo, Avee; Puchta, Alicja; Marin, Jorge L Arredondo; Bowdish, Dawn M E

    2016-07-01

    Aging is accompanied by changes in hematopoiesis and consequently in leukocyte phenotype and function. Although age-related changes in bone marrow hematopoiesis are fairly well documented, changes in extramedullary hematopoiesis are less well described. We observed that 18-22-mo-old mice had larger spleens than young controls and found that the enlargement was caused by increased monopoiesis. Because extramedullary hematopoiesis is often driven by inflammation, we hypothesized that the chronic, low-level inflammation that occurs with age is a causal agent in splenomegaly. To test this theory, we compared the number of monocytes in 18-mo-old tumor necrosis factor-knockout mice, which are protected from age-associated inflammation, and found that they did not have increased extramedullary monopoiesis. To determine whether increased splenic monopoiesis is caused by intrinsic changes in the myeloid precursors that occur with age or by the aging microenvironment, we created heterochronic bone marrow chimeras. Increased splenic monopoiesis occurred in old recipient mice, regardless of the age of the donor mouse, but not in young recipient mice, demonstrating that these cells respond to signals from the microenvironment. These data suggest that decreasing the inflammatory microenvironment with age would be an effective strategy for reducing inflammatory diseases propagated by cells of myeloid lineage, which increase in number with age. PMID:27037197

  13. Early embryonic and endometrial regulation of tumor necrosis factor and tumor necrosis factor receptor 2 in the cattle uterus.

    PubMed

    Correia-Álvarez, E; Gómez, E; Martín, D; Carrocera, S; Pérez, S; Peynot, N; Giraud-Delville, C; Caamaño, J N; Balseiro, A; Sandra, O; Duranthon, V; Muñoz, M

    2015-04-01

    Tumor necrosis factor (TNF) alpha likely mediates embryomaternal communication in mammals. In bovine, we have previously found that the uterine fluid of heifers that carried early embryos shows downregulation in the TNF and nuclear factor κB system. In this work, we assessed the expression of TNF and its receptor TNFR2 in the bovine endometrium and embryos during blastocyst development. Moreover, to explore the endometrial immune response to early embryos, we analyzed the number of CD45 leukocytes in the bovine endometrium. Day 8 endometrium and blastocyst recovered from animals after transfer of Day 5 embryos showed TNF and TNFR2 mRNA transcription and protein colocalization. The presence of embryos increased endometrial TNF and TNFR2 protein, whereas endometrial leukocytes decreased. Blastocysts exposed to the uterine tract had undetectable levels of TNF and lower levels of TNFR2 mRNA. These results suggest that the endometrium might lower the TNF concentration in the blastocyst by (1) regulating TNF secretion into the uterine fluid and (2) inducing decreased TNF and TNFR2 mRNA transcription in the embryo. Thus, TNF and TNFR2 might participate in early embryomaternal communication. PMID:25589228

  14. Bilirubin release induced by tumor necrosis factor in combination with galactosamine is toxic to mice.

    PubMed

    Van Molle, W; Libert, C

    2003-08-01

    Application of tumor necrosis factor (TNF) in combination with galactosamine (GalN) in mice causes severe apoptosis of hepatocytes, resulting in complete destruction of the liver. Administration of high levels of unconjugated bilirubin and abnormally high production of unconjugated bilirubin have been reported to cause liver damage and are associated with several human pathologies. Serum alanine aminotransferase as well as total and direct bilirubin levels in mice were determined. Bilirubin levels are shown to significantly increase after a challenge with TNF/GalN in mice. Pretreatment with a heme oxygenase-1 inhibitor significantly prevents this release in bilirubin and offers significant protection against TNF/GalN-induced lethality. A correlation between the release of unconjugated bilirubin and the toxicity accompanied with this release is provided. PMID:12906872

  15. Tumor necrosis factor inhibition increases the revascularization of ischemic hind-limbs in diabetic mice.

    PubMed

    Assiri, Adel M A; El-Baz, Hatim A; Amin, Ali H

    2015-10-01

    Tumor necrosis factor (TNF) is first identified as a mediator of lethal endotoxin poisoning. The anti-TNF therapy in the treatment of rheumatoid arthritis is based on the recognition of the role of TNF as the master regulator. Type II diabetes is characterized with altered stem cells and reduced vasculogenesis. Therefore, we aimed to determine if TNF inhibitor would improve vasculogenesis in ischemic hind-limbs of diabetic mice. Fifty male type 2 diabetic and their control (8-10 weeks old mice) were used, and ischemia was induced in the hind-limbs of all mice for 28 days. Vessel density was assessed by high-definition microangiography at the end of the treatment period. After 4 weeks, vessel density displayed no difference between the ischemic and the non-ischemic legs in control mice. However, in diabetic mice, the ischemic hind-limb vessel density was significantly decreased. Interestingly, diabetic mice displayed a significant improved vasculogenesis when treated with TNF inhibitor. Moreover, this data was confirmed by capillary density determined by immunostaining. TNF inhibitors are able to improve the formation of microvessels in response to ischemia in type 2 diabetes. PMID:26026701

  16. Induction of manganese superoxide dismutase by tumour necrosis factor-alpha in human endometrial stromal cells.

    PubMed

    Karube-Harada, A; Sugino, N; Kashida, S; Takiguchi, S; Takayama, H; Yamagata, Y; Nakamura, Y; Kato, H

    2001-11-01

    The present study was undertaken to investigate the effect of tumour necrosis factor-alpha (TNFalpha) on superoxide dismutase (SOD) expression in human endometrial stromal cells (ESC) and to determine whether there is a difference in responsiveness to TNFalpha between ESC and decidualized ESC. TNFalpha increased manganese-SOD (Mn-SOD) mRNA level and Mn-SOD activity in a dose-dependent manner in ESC. The concentration of TNFalpha required for an effect was lower for decidualized ESC than for non-decidualized ESC. TNFalpha had no effect on copper-zinc-SOD (Cu,Zn-SOD) expression in either type of cell. Incubation of ESC with actinomycin D, an RNA synthesis inhibitor, blocked TNFalpha-induced Mn-SOD mRNA expression, but cycloheximide, a protein synthesis inhibitor, had no effect. H7, an inhibitor of protein kinase C (PKC), also inhibited TNFalpha-stimulated Mn-SOD mRNA expression in both types of cells. These findings suggest that TNFalpha-induced Mn-SOD expression is regulated at the transcription level and mediated by PKC-dependent phosphorylation and that de-novo protein synthesis is not required for the TNFalpha effect. In summary, TNFalpha induces Mn-SOD expression in human ESC. This phenomenon may be important for protection of ESC from cytokine-mediated oxidative stress. PMID:11675473

  17. Regulation of bitter taste responses by tumor necrosis factor.

    PubMed

    Feng, Pu; Jyotaki, Masafumi; Kim, Agnes; Chai, Jinghua; Simon, Nirvine; Zhou, Minliang; Bachmanov, Alexander A; Huang, Liquan; Wang, Hong

    2015-10-01

    Inflammatory cytokines are important regulators of metabolism and food intake. Over production of inflammatory cytokines during bacterial and viral infections leads to anorexia and reduced food intake. However, it remains unclear whether any inflammatory cytokines are involved in the regulation of taste reception, the sensory mechanism governing food intake. Previously, we showed that tumor necrosis factor (TNF), a potent proinflammatory cytokine, is preferentially expressed in a subset of taste bud cells. The level of TNF in taste cells can be further induced by inflammatory stimuli. To investigate whether TNF plays a role in regulating taste responses, in this study, we performed taste behavioral tests and gustatory nerve recordings in TNF knockout mice. Behavioral tests showed that TNF-deficient mice are significantly less sensitive to the bitter compound quinine than wild-type mice, while their responses to sweet, umami, salty, and sour compounds are comparable to those of wild-type controls. Furthermore, nerve recording experiments showed that the chorda tympani nerve in TNF knockout mice is much less responsive to bitter compounds than that in wild-type mice. Chorda tympani nerve responses to sweet, umami, salty, and sour compounds are similar between TNF knockout and wild-type mice, consistent with the results from behavioral tests. We further showed that taste bud cells express the two known TNF receptors TNFR1 and TNFR2 and, therefore, are potential targets of TNF. Together, our results suggest that TNF signaling preferentially modulates bitter taste responses. This mechanism may contribute to taste dysfunction, particularly taste distortion, associated with infections and some chronic inflammatory diseases. PMID:25911043

  18. Tumor necrosis factor-beta in human pregnancy and labor.

    PubMed

    Laham, N; Van Dunné, F; Abraham, L J; Farrugia, W; Bendtzen, K; Brennecke, S P; Rice, G E

    1997-04-01

    The aims of this study were to determine tumor necrosis factor-beta (TNF-beta) concentration profiles in peripheral venous plasma and amniotic fluid during pregnancy and at the time of labor and to characterise TNF-beta mRNA expression and TNF-beta release from human gestational tissues. In addition, we investigated the expression of TNF-beta binding protein, lymphotoxin-beta (LT-beta), in human gestational tissues. The mean (+/-S.E.M.) TNF-beta concentrations in maternal plasma (TIL, 78 +/- 12 pg/ml, n = 7 vs. TNIL, 304 +/- 88 pg/ml, n = 7) and amniotic fluid (TIL, 8 +/- 5 pg/ml, n = 6 vs. TNIL, 73 +/- 20 pg/ml, n = 20) were significantly (P < 0.05) decreased in association with term labor-onset (TIL) compared to term not-in-labor (TNIL). TNF-beta concentration in maternal plasma and amniotic fluid did not change significantly either with preterm labor (PIL), or during pregnancy. Group-matched comparison of maternal plasma and amniotic fluid TNF-beta concentrations demonstrated that amniotic fluid TNF-beta concentrations were 6-8 fold lower than maternal plasma TNF-beta concentrations. Furthermore, no detectable TNF-beta was secreted from cultured human amniotic, choriodecidual and placental explants. Although, TNF-beta mRNA was detected in amnion, choriodecidual and placenta, LT-beta was similarly expressed in these tissues, suggesting that TNF-beta may be cell membrane bound. These data demonstrate that TNF-beta is present at low levels within the intrauterine environment and may suggest that TNF-beta is specifically inhibited at the maternal-fetal interface. PMID:9185077

  19. A third distinct tumor necrosis factor receptor of orthopoxviruses.

    PubMed

    Loparev, V N; Parsons, J M; Knight, J C; Panus, J F; Ray, C A; Buller, R M; Pickup, D J; Esposito, J J

    1998-03-31

    Cowpox virus Brighton red strain (CPV) contains a gene, crmD, which encodes a 320-aa tumor necrosis factor receptor (TNFR) of 44% and 22% identity, respectively, to the CPV TNFR-like proteins, cytokine response modifiers (crm) CrmB and CrmC. The crmD gene was interrupted in three other cowpox strains examined and absent in various other orthopoxviruses; however, four strains of ectromelia virus (ECT) examined contained an intact crmD (97% identity to CPV crmD) and lacked cognates of crmB and crmC. The protein, CrmD, contains a transport signal; a 151-aa cysteine-rich region with 21 cysteines that align with human TNFRII ligand-binding region cysteines; and C-terminal region sequences that are highly diverged from cellular TNFR C-terminal region sequences involved in signal transduction. Bacterial maltose-binding proteins containing the CPV or ECT CrmD cysteine-rich region bound TNF and lymphotoxin-alpha (LTalpha) and blocked their in vitro cytolytic activity. Secreted viral CrmD bound TNF and LTalpha and was detectable after the early stage of replication, using nonreducing conditions, as 60- to 70-kDa predominant and 90- to 250-kDa minor disulfide-linked complexes that were able to be reduced to a 46-kDa form and deglycosylated to a 38-kDa protein. Cells infected with CPV produced extremely low amounts of CrmD compared with ECT. Possessing up to three TNFRs, including CrmD, which is secreted as disulfide-linked complexes in varied amounts by CPV and ECT, likely enhances the dynamics of the immune modulating mechanisms of orthopoxviruses. PMID:9520445

  20. Mitochondria mediate tumor necrosis factor-alpha/NF-kappaB signaling in skeletal muscle myotubes

    NASA Technical Reports Server (NTRS)

    Li, Y. P.; Atkins, C. M.; Sweatt, J. D.; Reid, M. B.; Hamilton, S. L. (Principal Investigator)

    1999-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is implicated in muscle atrophy and weakness associated with a variety of chronic diseases. Recently, we reported that TNF-alpha directly induces muscle protein degradation in differentiated skeletal muscle myotubes, where it rapidly activates nuclear factor kappaB (NF-kappaB). We also have found that protein loss induced by TNF-alpha is NF-kappaB dependent. In the present study, we analyzed the signaling pathway by which TNF-alpha activates NF-kappaB in myotubes differentiated from C2C12 and rat primary myoblasts. We found that activation of NF-kappaB by TNF-alpha was blocked by rotenone or amytal, inhibitors of complex I of the mitochondrial respiratory chain. On the other hand, antimycin A, an inhibitor of complex III, enhanced TNF-alpha activation of NK-kappaB. These results suggest a key role of mitochondria-derived reactive oxygen species (ROS) in mediating NF-kappaB activation in muscle. In addition, we found that TNF-alpha stimulated protein kinase C (PKC) activity. However, other signal transduction mediators including ceramide, Ca2+, phospholipase A2 (PLA2), and nitric oxide (NO) do not appear to be involved in the activation of NF-kappaB.

  1. Tumor Necrosis Factor-alpha Converting Enzyme: Implications for Ocular Inflammatory Diseases

    PubMed Central

    Ramana, Kota V

    2010-01-01

    Tumor necrosis factor-alpha (TNF-α) –converting enzyme (TACE), a member of the family of metalloproteinase disintegrin proteins, is responsible for the conversion of inactive TNF-α precursor from to active mature form. TNF-α is a pleiotropic cytokine that contributes to cellular immunity and inflammatory response in wide range of inflammatory pathologies. Although a large number of studies indicate the use of TACE inhibitors, which prevents processing of TNF-α as potential therapeutic drugs for the treatment of inflammatory diseases including rheumatoid arthritis, Crohn’s disease and cancer, very few studies indicate its use in ocular pathologies. It is still not clearly understood how the TACE-mediated shedding of cytokines and growth factors in various ocular tissues plays a critical role in the cytotoxic signals causing tissue dysfunction and damage leading to blindness. Regulation of TACE activity is likely to have wide implications for ocular immunology and inflammatory diseases. Specifically, since anti-TNF-α therapies have been used to prevent ocular inflammatory complications, the use of TACE inhibitors could be a novel therapeutic approach for ocular inflammatory diseases especially uveitis. PMID:20303413

  2. Effect of mycobacteria on sensitivity to the cytotoxic effects of tumor necrosis factor.

    PubMed Central

    Filley, E A; Rook, G A

    1991-01-01

    Unlike Mycobacterium leprae, Mycobacterium tuberculosis is not found inside cells other than macrophages and polymorphonuclear cells in vivo, yet previous work has revealed that in vitro it readily enters all cell lines tested. Moreover, these cells are not killed by the intracellular mycobacteria. We report here that when fibroblasts take up live (but not killed) M. tuberculosis H37Rv, they develop greatly increased sensitivity to the toxic effects of tumor necrosis factor (TNF) whether the cell line is inherently sensitive to TNF or not. Ultrasonically disrupted M. tuberculosis also has this property. The increased sensitivity is seen in the absence of metabolic inhibitors, although addition of emetine, an inhibitor of protein synthesis, causes the effect to manifest itself earlier and at a lower concentration of TNF. In contrast, infection with Mycobacterium bovis bacillus Calmette-Guérin induces little or no increased sensitivity to TNF, whereas Mycobacterium avium and M. tuberculosis H37Ra have intermediate sensitivities. We discuss the possibility that virulent tuberculosis strains produce a factor which distorts the normal protective function of TNF, rendering it toxic to host tissues and leading to the classical immunopathology of tuberculous lesions. PMID:1906841

  3. BRAF inhibitor and stereotactic radiosurgery is associated with an increased risk of radiation necrosis

    PubMed Central

    Patel, Kirtesh R.; Chowdhary, Mudit; Switchenko, Jeffrey M.; Kudchadkar, Ragini; Lawson, David H.; Cassidy, Richard J.; Prabhu, Roshan S.; Khan, Mohammad K.

    2016-01-01

    We retrospectively compared the outcomes and toxicities of melanoma brain metastases (MBM) patients treated with BRAF inhibitors (BRAFi) and stereotactic radiosurgery (SRS) with SRS alone. We identified 87 patients with 157 MBM treated with SRS alone from 2005 to 2013. Of these, 15 (17.2%) patients with 32 MBM (21.4%) received BRAFi therapy: three (20.0%) before SRS, two (13.3%) concurrent, and 10 (66.7%) after SRS. Overall survival (OS) was compared between cohorts using the product limit method. Intracranial outcomes were compared using cumulative incidence with competing risk for death. Baseline patient characteristics were similar between groups, except for the SRS cohort, which had higher rates of chemotherapy and more recent year of diagnosis. Radiation characteristics, including dose per fraction, total dose, gross tumor volume size, and prescription isodose, were also similar between cohorts. One-year outcomes – OS (64.3 vs. 40.4%, P =0.205), local failure (3.3 vs. 9.6%, P =0.423), and distant intracranial failure (63.9 vs. 65.1%, P =0.450) were not statistically different between the SRS + BRAFi and SRS-alone groups, respectively. The SRS + BRAFi group showed higher rates of radiographic radiation necrosis (RN) (22.2 vs. 11.0% at 1 year, P <0.001) and symptomatic radiation necrosis (SRN) (28.2 vs. 11.1% at 1 year, P <0.001). Multivariable analysis showed that BRAFi predicted an increased risk of both radiographic and SRN. SRS and BRAFi predicted for an increased risk of radiographic and SRN compared with SRS alone. Approaches to mitigate RN for patients receiving SRS and BRAFi should be considered until the clinical trial (http//:www.clinicaltrials.gov: NCT01721603) evaluating this treatment regimen is completed. PMID:27223498

  4. BRAF inhibitor and stereotactic radiosurgery is associated with an increased risk of radiation necrosis.

    PubMed

    Patel, Kirtesh R; Chowdhary, Mudit; Switchenko, Jeffrey M; Kudchadkar, Ragini; Lawson, David H; Cassidy, Richard J; Prabhu, Roshan S; Khan, Mohammad K

    2016-08-01

    We retrospectively compared the outcomes and toxicities of melanoma brain metastases (MBM) patients treated with BRAF inhibitors (BRAFi) and stereotactic radiosurgery (SRS) with SRS alone. We identified 87 patients with 157 MBM treated with SRS alone from 2005 to 2013. Of these, 15 (17.2%) patients with 32 MBM (21.4%) received BRAFi therapy: three (20.0%) before SRS, two (13.3%) concurrent, and 10 (66.7%) after SRS. Overall survival (OS) was compared between cohorts using the product limit method. Intracranial outcomes were compared using cumulative incidence with competing risk for death. Baseline patient characteristics were similar between groups, except for the SRS cohort, which had higher rates of chemotherapy and more recent year of diagnosis. Radiation characteristics, including dose per fraction, total dose, gross tumor volume size, and prescription isodose, were also similar between cohorts. One-year outcomes - OS (64.3 vs. 40.4%, P=0.205), local failure (3.3 vs. 9.6%, P=0.423), and distant intracranial failure (63.9 vs. 65.1%, P=0.450) were not statistically different between the SRS+BRAFi and SRS-alone groups, respectively. The SRS+BRAFi group showed higher rates of radiographic radiation necrosis (RN) (22.2 vs. 11.0% at 1 year, P<0.001) and symptomatic radiation necrosis (SRN) (28.2 vs. 11.1% at 1 year, P<0.001). Multivariable analysis showed that BRAFi predicted an increased risk of both radiographic and SRN. SRS and BRAFi predicted for an increased risk of radiographic and SRN compared with SRS alone. Approaches to mitigate RN for patients receiving SRS and BRAFi should be considered until the clinical trial (http//:www.clinicaltrials.gov: NCT01721603) evaluating this treatment regimen is completed. PMID:27223498

  5. Cannabinoids act as necrosis-inducing factors in Cannabis sativa

    PubMed Central

    Shoyama, Yoshinari; Sugawa, Chitomi; Tanaka, Hiroyuki

    2008-01-01

    Cannabis sativa is well known to produce unique secondary metabolites called cannabinoids. We recently discovered that Cannabis leaves induce cell death by secreting tetrahydrocannabinolic acid (THCA) into leaf tissues. Examinations using isolated Cannabis mitochondria demonstrated that THCA causes mitochondrial permeability transition (MPT) though opening of MPT pores, resulting in mitochondrial dysfunction (the important feature of necrosis). Although Ca2+ is known to cause opening of animal MPT pores, THCA directly opened Cannabis MPT pores in the absence of Ca2+. Based on these results, we conclude that THCA has the ability to induce necrosis though MPT in Cannabis leaves, independently of Ca2+. We confirmed that other cannabinoids (cannabidiolic acid and cannabigerolic acid) also have MPT-inducing activity similar to that of THCA. Moreover, mitochondria of plants which do not produce cannabinoids were shown to induce MPT by THCA treatment, thus suggesting that many higher plants may have systems to cause THCA-dependent necrosis. PMID:19704450

  6. Cannabinoids act as necrosis-inducing factors in Cannabis sativa.

    PubMed

    Shoyama, Yoshinari; Sugawa, Chitomi; Tanaka, Hiroyuki; Morimoto, Satoshi

    2008-12-01

    Cannabis sativa is well known to produce unique secondary metabolites called cannabinoids. We recently discovered that Cannabis leaves induce cell death by secreting tetrahydrocannabinolic acid (THCA) into leaf tissues. Examinations using isolated Cannabis mitochondria demonstrated that THCA causes mitochondrial permeability transition (MPT) though opening of MPT pores, resulting in mitochondrial dysfunction (the important feature of necrosis). Although Ca(2+) is known to cause opening of animal MPT pores, THCA directly opened Cannabis MPT pores in the absence of Ca(2+). Based on these results, we conclude that THCA has the ability to induce necrosis though MPT in Cannabis leaves, independently of Ca(2+). We confirmed that other cannabinoids (cannabidiolic acid and cannabigerolic acid) also have MPT-inducing activity similar to that of THCA. Moreover, mitochondria of plants which do not produce cannabinoids were shown to induce MPT by THCA treatment, thus suggesting that many higher plants may have systems to cause THCA-dependent necrosis. PMID:19704450

  7. Increased concentrations of tumour necrosis factor in "cachectic" patients with severe chronic heart failure.

    PubMed Central

    McMurray, J; Abdullah, I; Dargie, H J; Shapiro, D

    1991-01-01

    OBJECTIVE--To ascertain whether patients with cardiac failure and reduced body weight ("cardiac cachexia") have increased circulating concentrations of tumour necrosis factor (cachectin). DESIGN--Patients with cardiac failure were prospectively identified as "cachectic" (body fat less than 27% in men and less than 29% in women measured by skinfold thickness callipers) or "non-cachectic". Tumour necrosis factor was assayed blind to patient group. SETTING--Cardiology unit in a tertiary referral centre. PATIENTS--26 consecutive patients (10 women) (mean age 61) admitted for investigation or treatment of chronic heart failure. All were in New York Heart Association class III or IV. RESULTS--In nine of the 16 cachectic patients the concentration of tumour necrosis factor was increased (mean (SEM) 74 (20) pg/ml) compared with one of the 10 "non-cachectic" patients (22 pg/ml, p less than 0.001). Patients with a raised circulating concentration of tumour necrosis factor weighed significantly less (55.6 (3.5) kg) than those in whom the concentration of tumour necrosis factor was normal (69.0 (4.1) kg) (p = 0.02). CONCLUSIONS--Circulating concentrations of tumour necrosis factor were increased in a significant proportion of patients with chronic heart failure and low body weight. Tumour necrosis factor stimulates catabolism experimentally and it may be a factor in the weight loss seen in patients with "cardiac cachexia". PMID:1747295

  8. Tumor necrosis factor induces glomerular damage in the rabbit.

    PubMed Central

    Bertani, T.; Abbate, M.; Zoja, C.; Corna, D.; Perico, N.; Ghezzi, P.; Remuzzi, G.

    1989-01-01

    Tumor necrosis factor (TNF) is a polypeptide hormone produced by activated macrophages detectable in the circulation of experimental animals given endotoxin. Recent evidence strongly suggests that many of the deleterious effects of endotoxin in experimental animals are mediated by TNF. Because endotoxemia in experimental animals and humans is associated with glomerular damage the present investigation was designed to establish whether TNF directly induces glomerular functional and structural changes. Twenty-three rabbits were given human recombinant TNF at the doses of 0.08, 0.8, and 8.0 micrograms/kg/h as a continuous 5-hour intravenous infusion. Animals were killed at the end of the infusion. All rabbits given 0.8 and 8.0 micrograms/kg/h TNF developed anemia (Ht value decrease at 5 hours: 0.8 microgram/kg/h, 15%; 8.0 micrograms/kg/h, 16%); leukopenia (leukocyte count decrease at 5 hours: 0.8 micrograms/kg/h, 47%; 8.0 micrograms/kg/h, 59%); thrombocytopenia (platelet count decrease at 5 hours; 0.8 micrograms/kg/h, 45%; 8.0 micrograms/kg/h, 57%). Rabbits given 8.0 micrograms/kg/h also had renal failure (serum creatinine from 1.02 +/- 0.15 to 1.64 +/- 0.34 mg/dl). By light microscopy only occasional polymorphonuclear leukocytes in the glomerular capillaries were detectable in rabbits infused with 0.08 micrograms/kg/h TNF, whereas with 0.8 micrograms/kg/h TNF the presence of inflammatory cells in the glomerular capillaries was the prominent finding. With 8.0 micrograms/kg/h TNF beside leukocyte accumulation, fibrin was detected in the glomerular capillary lumens of two of eight animals. Electron microscopy found dose-dependent glomerular endothelial cell damage in animals given TNF with fibrinlike material in the capillary lumens. Glomerular changes induced by TNF were remarkably similar to those previously found in animals given endotoxin. Thus, TNF is likely to be the mediator of endotoxin-induced glomerular damage and can be regarded as a new mediator of

  9. Myocardial steatosis and necrosis in atria and ventricles of rats given pyruvate dehydrogenase kinase inhibitors.

    PubMed

    Jones, Huw Bowen; Reens, Jaimini; Johnson, Elizabeth; Brocklehurst, Simon; Slater, Ian

    2014-12-01

    Pharmaceutical therapies for non-insulin-dependent diabetes mellitus (NIDDM) include plasma glucose lowering by enhancing glucose utilization. The mitochondrial pyruvate dehydrogenase (PDH) complex is important in controlling the balance between glucose and fatty acid substrate oxidation. Administration of pyruvate dehydrogenase kinase inhibitors (PDHKIs) to rats effectively lowers plasma glucose but results in myocardial steatosis that in some instances is associated primarily with atrial and to a lesser degree with ventricular pathology. Induction of myocardial steatosis is not dose-dependent, varies from minimal to moderate severity, and is either of multifocal or diffuse distribution. Ventricular histopathology was restricted to few myocardial degenerative fibers, while that in the atrium/atria was of either acute or chronic appearance with the former showing myocardial degeneration/necrosis, acute myocarditis, edema, endothelial activation (rounding up), endocarditis, and thrombosis associated with moderate myocardial steatosis and the latter with myocardial loss, replacement fibrosis, and no apparent or minimal association with steatosis. The evidence from these evaluations indicate that excessive intramyocardial accumulation of lipid may be either primarily adverse or represents an indicator of other adversely affected cellular processes. PMID:24742628

  10. Tumor necrosis factor-alpha gene is not associated with obsessive-compulsive disorder.

    PubMed

    Zai, Gwyneth; Arnold, Paul D; Burroughs, Eliza; Richter, Margaret A; Kennedy, James L

    2006-02-01

    Dysregulation of the immune system has been suggested to play a role in the complex etiology of obsessive-compulsive disorder. In this context, tumor necrosis factor-alpha is considered an interesting candidate for genetic studies as overproduction of tumor necrosis factor-alpha, which may be genetically modulated, can exert neurotoxic effects and influence neural cell growth and proliferation. Moreover, the tumor necrosis factor-alpha gene is located on chromosome 6p21.3, a region that has been found to be weakly associated with obsessive-compulsive disorder in linkage studies. One functional polymorphism, G-308A, has been found within the gene. PMID:16395130

  11. Superior Orbital Fissure Syndrome and Ophthalmoplegia Caused by Varicella Zoster Virus with No Skin Eruption in a Patient Treated with Tumor Necrosis Alpha Inhibitor.

    PubMed

    Jensen, Helene; Thomsen, Sidsel Thorup; Hansen, Stine Scott; Munksgaard, Signe Bruun; Lindelof, Mette

    2015-01-01

    Varicella zoster virus lies dormant in the dorsal root ganglia after symptomatic chicken pox infection, usually in childhood. If the virus reactivates in the trigeminal ganglia, it can cause varicella zoster ophthalmicus, which can have severe ocular complications. We report a case of a 73-year-old woman in severe immunosuppression due to treatment with mycophenolate mofetil, glucocorticosteroids and a tumor necrosis factor alpha inhibitor. The reactivation caused superior orbital fissure syndrome, which has only rarely been described in relation to varicella zoster virus reactivation. In our case, the syndrome was seen along with severe encephalitis. PMID:26600786

  12. Superior Orbital Fissure Syndrome and Ophthalmoplegia Caused by Varicella Zoster Virus with No Skin Eruption in a Patient Treated with Tumor Necrosis Alpha Inhibitor

    PubMed Central

    Jensen, Helene; Thomsen, Sidsel Thorup; Hansen, Stine Scott; Munksgaard, Signe Bruun; Lindelof, Mette

    2015-01-01

    Varicella zoster virus lies dormant in the dorsal root ganglia after symptomatic chicken pox infection, usually in childhood. If the virus reactivates in the trigeminal ganglia, it can cause varicella zoster ophthalmicus, which can have severe ocular complications. We report a case of a 73-year-old woman in severe immunosuppression due to treatment with mycophenolate mofetil, glucocorticosteroids and a tumor necrosis factor alpha inhibitor. The reactivation caused superior orbital fissure syndrome, which has only rarely been described in relation to varicella zoster virus reactivation. In our case, the syndrome was seen along with severe encephalitis. PMID:26600786

  13. Erythropoietin protects myocardin-expressing cardiac stem cells against cytotoxicity of tumor necrosis factor-{alpha}

    SciTech Connect

    Madonna, Rosalinda; Shelat, Harnath; Xue, Qun; Willerson, James T.; De Caterina, Raffaele; Geng, Yong-Jian

    2009-10-15

    Cardiac stem cells are vulnerable to inflammation caused by infarction or ischemic injury. The growth factor, erythropoietin (Epo), ameliorates the inflammatory response of the myocardium to ischemic injury. This study was designed to assess the role of Epo in regulation of expression and activation of the cell death-associated intracellular signaling components in cardiac myoblasts stimulated with the proinflammatory cytokine tumor necrosis factor (TNF)-{alpha}. Cardiac myoblasts isolated from canine embryonic hearts characterized by expression of myocardin A, a promyogenic transcription factor for cardiovascular muscle development were pretreated with Epo and then exposed to TNF-{alpha}. Compared to untreated cells, the Epo-treated cardiac myoblasts exhibited better morphology and viability. Immunoblotting revealed lower levels of active caspase-3 and reductions in iNOS expression and NO production in Epo-treated cells. Furthermore, Epo pretreatment reduced nuclear translocation of NF-{kappa}B and inhibited phosphorylation of inhibitor of kappa B (I{kappa}B) in TNF-{alpha}-stimulated cardiac myoblasts. Thus, Epo protects cardiac myocyte progenitors or myoblasts against the cytotoxic effects of TNF-{alpha} by inhibiting NF-{kappa}B-mediated iNOS expression and NO production and by preventing caspase-3 activation.

  14. Involvement of specific matrix metalloproteinases during tumor necrosis factor/IFNgamma-based cancer therapy in mice.

    PubMed

    Van Roy, Maarten; Van Lint, Philippe; Van Laere, Ineke; Wielockx, Ben; Wilson, Carole; López-Otin, Carlos; Shapiro, Stephen; Libert, Claude

    2007-09-01

    The potent antitumor activity of tumor necrosis factor (TNF) in combination with IFN-gamma can only be applied in local regimens due to their strong proinflammatory properties. It has been shown that the broad-spectrum matrix metalloproteinase (MMP) inhibitor BB-94 protects against TNF/IFNgamma-induced toxicity without blocking the antitumor effect. Here, we tried to explain this protective role of BB-94 and sought to assign roles to specific MMPs in TNF/IFNgamma-induced toxicity. By studying the expression of MMP genes in different organs and in the tumor, we observed that the expression levels of MMP-7, MMP-8, MMP-9, and MMP-12 and tissue inhibitor of metalloproteinase-4 are clearly up-regulated in the liver during therapy. MMP-8 and MMP-9 are also up-regulated in the lung and kidney, respectively. In the tumor, most MMP genes are expressed, but only MMP-3 is up-regulated during TNF/IFNgamma treatment. Using MMP-deficient or double-deficient mice, we have shown a mediating role for MMP-3 during TNF/IFNgamma treatment in tumor-free and B16BL6 melanoma-bearing mice. By contrast, MMP-12 seemed to have some protective role in both models. However, because most phenotypes were not extremely outspoken, we have to conclude, based on the set of MMP-deficient mice we have studied, that inhibition of a single MMP will probably not increase the therapeutic value of TNF/IFNgamma, but that rather, broad-spectrum MMP inhibitors will be required. PMID:17876053

  15. Glioma-secreted soluble factors stimulate microglial activation: The role of interleukin-1β and tumor necrosis factor-α.

    PubMed

    Hwang, Ji-Sun; Jung, Eun-Hye; Kwon, Mi-Youn; Han, Inn-Oc

    2016-09-15

    We aimed to elucidate the effect of soluble factors secreted by glioma on microglial activation. Conditioned medium (CM) from glioma cells, CRT-MG and C6, significantly induced nitric oxide (NO) production and stimulated the mRNA expression of inducible NO synthase (iNOS), interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-α) and cyclooxygenase 2 (COX-2) in BV2 cells. Glioma CM stimulated p38 mitogen-activated protein kinase (MAPK) phosphorylation, and a p38 MAPK inhibitor, SB203580, suppressed CM-induced NO production in BV2 cells. In addition, CM stimulated nuclear factor-kappaB (NF-κB) DNA binding and transcriptional activity, which was repressed by SB203580. Gliomas displayed higher mRNA expression and release of TNF-α and IL-1β than primary astrocyte cells. Neutralization of TNF-α and IL-1β in C6-CM using a neutralizing antibody inhibited NO/iNOS expression in BV-2 cells. These results indicate potential contribution of diffusible tumor-derived factors to regulate microglial activation and subsequent tumor microenvironment. PMID:27609291

  16. Media effects in modulating the conformational equilibrium of a model compound for tumor necrosis factor converting enzyme inhibition

    NASA Astrophysics Data System (ADS)

    Banchelli, Martina; Guardiani, Carlo; Sandberg, Robert B.; Menichetti, Stefano; Procacci, Piero; Caminati, Gabriella

    2015-07-01

    Small-molecule inhibitors of Tumor Necrosis Factor α Converting Enzyme (TACE) are a promising therapeutic tool for Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. Here we report on an extensive chemical-physical analysis of the media effects in modulating the conformational landscape of MBET306, the common scaffold and a synthetic precursor of a family of recently discovered tartrate-based TACE inhibitors. The structural features of this molecule with potential pharmaceutical applications have been disclosed by interpreting extensive photophysical measurements in various solvents with the aid of enhanced sampling molecular dynamics simulations and time dependent density functional calculations. Using a combination of experimental and computational techniques, the paper provides a general protocol for studying the structure in solution of molecular systems characterized by the existence of conformational metastable states.

  17. Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF

    PubMed Central

    Olleros, Maria L.; Chavez-Galan, Leslie; Segueni, Noria; Bourigault, Marie L.; Vesin, Dominique; Kruglov, Andrey A.; Drutskaya, Marina S.; Bisig, Ruth; Ehlers, Stefan; Aly, Sahar; Walter, Kerstin; Kuprash, Dmitry V.; Chouchkova, Miliana; Kozlov, Sergei V.; Erard, François; Ryffel, Bernard; Quesniaux, Valérie F. J.; Nedospasov, Sergei A.

    2015-01-01

    Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-κB activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF. PMID:26123801

  18. Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF.

    PubMed

    Olleros, Maria L; Chavez-Galan, Leslie; Segueni, Noria; Bourigault, Marie L; Vesin, Dominique; Kruglov, Andrey A; Drutskaya, Marina S; Bisig, Ruth; Ehlers, Stefan; Aly, Sahar; Walter, Kerstin; Kuprash, Dmitry V; Chouchkova, Miliana; Kozlov, Sergei V; Erard, François; Ryffel, Bernard; Quesniaux, Valérie F J; Nedospasov, Sergei A; Garcia, Irene

    2015-09-01

    Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-κB activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF. PMID:26123801

  19. Tumor necrosis factor gene expression is mediated by protein kinase C following activation by ionizing radiation.

    SciTech Connect

    Hallahan, D. E.; Virudachalam, S.; Sherman, M. L.; Huberman, E.; Kufe, D. W.; Weichselbaum, R. R.; Univ. of Chicago; Dana-Farber Cancer Inst.; Univ. of Chicago

    1991-01-01

    Tumor necrosis factor (TNF) production following X-irradiation has been implicated in the biological response to ionizing radiation. Protein kinase C (PKC) is suggested to participate in TNF transcriptional induction and X-ray-mediated gene expression. We therefore studied radiation-mediated TNF expression in HL-60 cells with diminished PKC activity produced by either pretreatment with protein kinase inhibitors or prolonged 12-O-tetradecanoylphorbol-13-acetate treatment. Both treatments resulted in attenuation of radiation-mediated TNF induction. Consistent with these results, we found no detectable induction of TNF expression following X-irradiation in the HL-60 variant deficient in PKC-mediated signal transduction. The rapid activation of PKC following {gamma}-irradiation was established using an in vitro assay measuring phosphorylation of a PKC specific substrate. A 4.5-fold increase in PKC activity occurred 15 to 30 s following irradiation, which declined to baseline at 60 s. Two-dimensional gel electrophoresis of phosphoproteins extracted from irradiated cells demonstrated in vivo phosphorylation of the PKC specific substrate Mr 80,000 protein at 45 s following X-irradiation. These findings indicate that signal transduction via the PKC pathway is required for the induction of TNF gene expression by ionizing radiation.

  20. Enhancement of tumor necrosis factor-induced endothelial cell injury by cycloheximide

    SciTech Connect

    Nolop, K.B.; Ryan, U.S. )

    1990-08-01

    Tumor necrosis factor (TNF), a potent polypeptide mediator released by activated monocytes and macrophages, has a number of proinflammatory effects on endothelial cells. TNF is cytotoxic to tumor cells in vivo and in vitro, but TNF-induced toxicity to endothelial cells is less well established. We now report that cycloheximide (CHX), an inhibitor of protein synthesis, renders endothelial cells highly susceptible to TNF-induced lysis. TNF alone did not change the overall rate of protein synthesis by endothelial cells, whereas the addition of CHX completely abolished protein synthesis. Endothelial cells incubated in TNF alone in high concentrations (up to 1,000 U/ml) showed minimal rounding up and release of 51Cr. Likewise, CHX alone (5 micrograms/ml) had no significant effect on endothelial cell morphology and release of 51Cr. However, incubation of endothelial cells in both CHX and TNF caused injury in a dose-dependent manner. Morphological evidence of cell retraction, rounding, and detachment began within 2 h, but specific 51Cr release did not begin to rise until after 4 h. These changes were not observed when endothelial cells were incubated with TNF/CHX at 4 degrees C. The combination of TNF/CHX was lethal to all endothelial cells tested (bovine pulmonary artery, human umbilical vein, and human aorta), with human aortic cells showing the most pronounced changes. We conclude that healthy endothelial cells are resistant to TNF-induced lysis, but inhibition of their ability to make protein renders them highly susceptible.

  1. Renal Tumor Necrosis Factor α Contributes to Hypertension in Dahl Salt-Sensitive Rats

    PubMed Central

    Huang, Baorui; Cheng, Yuan; Usa, Kristie; Liu, Yong; Baker, Maria Angeles; Mattson, David L.; He, Yongcheng; Wang, Niansong; Liang, Mingyu

    2016-01-01

    Tumor necrosis factor α (TNFα) is a major proinflammatory cytokine and its level is elevated in hypertensive states. Inflammation occurs in the kidneys during the development of hypertension. We hypothesized that TNFα specifically in the kidney contributes to the development of hypertension and renal injury in Dahl salt-sensitive (SS) rats, a widely used model of human salt-sensitive hypertension and renal injury. SS rats were chronically instrumented for renal interstitial infusion and blood pressure measurement in conscious, freely moving state. Gene expression was measured using real-time PCR and renal injury assessed with histological analysis. The abundance of TNFα in the renal medulla of SS rats, but not the salt-insensitive congenic SS.13BN26 rats, was significantly increased when rats had been fed a high-salt diet for 7 days (n = 6 or 9, p < 0.01). The abundance of TNFα receptors in the renal medulla was significantly higher in SS rats than SS.13BN26 rats. Renal interstitial administration of Etanercept, an inhibitor of TNFα, significantly attenuated the development of hypertension in SS rats on a high-salt diet (n = 7–8, p < 0.05). Glomerulosclerosis and interstitial fibrosis were also significantly ameliorated. These findings indicate intrarenal TNFα contributes to the development of hypertension and renal injury in SS rats. PMID:26916681

  2. Renal Tumor Necrosis Factor α Contributes to Hypertension in Dahl Salt-Sensitive Rats.

    PubMed

    Huang, Baorui; Cheng, Yuan; Usa, Kristie; Liu, Yong; Baker, Maria Angeles; Mattson, David L; He, Yongcheng; Wang, Niansong; Liang, Mingyu

    2016-01-01

    Tumor necrosis factor α (TNFα) is a major proinflammatory cytokine and its level is elevated in hypertensive states. Inflammation occurs in the kidneys during the development of hypertension. We hypothesized that TNFα specifically in the kidney contributes to the development of hypertension and renal injury in Dahl salt-sensitive (SS) rats, a widely used model of human salt-sensitive hypertension and renal injury. SS rats were chronically instrumented for renal interstitial infusion and blood pressure measurement in conscious, freely moving state. Gene expression was measured using real-time PCR and renal injury assessed with histological analysis. The abundance of TNFα in the renal medulla of SS rats, but not the salt-insensitive congenic SS.13(BN26) rats, was significantly increased when rats had been fed a high-salt diet for 7 days (n = 6 or 9, p < 0.01). The abundance of TNFα receptors in the renal medulla was significantly higher in SS rats than SS.13(BN26) rats. Renal interstitial administration of Etanercept, an inhibitor of TNFα, significantly attenuated the development of hypertension in SS rats on a high-salt diet (n = 7-8, p < 0.05). Glomerulosclerosis and interstitial fibrosis were also significantly ameliorated. These findings indicate intrarenal TNFα contributes to the development of hypertension and renal injury in SS rats. PMID:26916681

  3. A comparison of the intoxication pathways of tumor necrosis factor and diphtheria toxin

    SciTech Connect

    Chang, M.P.

    1988-01-01

    The mechanism by which tumor necrosis factor-alpha (TNF) initiates tumor cell destruction is unknown. We have approached this problem by comparing the biological properties of TNF with diphtheria toxin (DTx), a well-characterized cytotoxin. Initial studies with human U937 cells revealed that a transient exposure to low pH enhances the cytotoxic activity of TNF. Detailed studies on the interaction of TNF with pure lipid vesicles revealed that the acid-enhanced cytolytic activity of this cytokine is correlated with the acquisition of membrane binding and insertion properties. Significantly, an increase in target membrane stabilization was observed in the presence of TNF; hence, TNF is not directly lytic for membranes. In susceptible target cells, DTx induces the release of {sup 51}Cr- and {sup 75}Se-labeled proteins within 7 h. Although DTx-triggered cell death has generally been accepted as a straightforward effect of translation inhibition, little or no cell lysis was observed over a 20-30 h period when target cells were exposed to cycloheximide, amino acid deficient medium or metabolic poisons even though protein synthesis was inhibited to levels observed with DTx. The protein synthesis inhibition and cytolytic activities of DTx showed similar dose-dependencies, target cell specificities, and sensitivities to NH{sub 4}Cl inhibition. DTx-induced DNA fragmentation preceded cells lysis and did not occur in cells that were treated with the other protein synthesis inhibitors.

  4. Mitochondria-targeted antioxidants do not prevent tumour necrosis factor-induced necrosis of L929 cells.

    PubMed

    Jarvis, Reagan M; Göttert, Jana; Murphy, Michael P; Ledgerwood, Elizabeth C

    2007-09-01

    Mitochondrial production of reactive oxygen species (ROS) is widely reported as a central effector during TNF-induced necrosis. The effect of a family of mitochondria-targeted antioxidants on TNF-induced necrosis of L929 cells was studied. While the commonly used lipid-soluble antioxidant BHA effectively protected cells from TNF-induced necrosis, the mitochondria-targeted antioxidants MitoQ(3), MitoQ(5), MitoQ(10) and MitoPBN had no effect on TNF-induced necrosis. Since BHA also acts as an uncoupler of mitochondrial membrane potential, two additional uncouplers were tested. FCCP and CCCP both provided dose-dependent inhibition of TNF-induced necrosis. In conclusion, the generation of mitochondrial ROS may not be necessary for TNF-induced necrosis. Instead, these results suggest alternative mitochondrial functions, such as a respiration-dependent process, are critical for necrotic death. PMID:17729122

  5. Relationships between tumour necrosis factor, eicosanoids and platelet-activating factor as mediators of endotoxin-induced shock in mice.

    PubMed Central

    Myers, A. K.; Robey, J. W.; Price, R. M.

    1990-01-01

    1. The toxicity of intravenous recombinant human tumour necrosis factor (rhTNF), a TNF fragment (TNF114-130), endotoxin and combinations of rhTNF or TNF114-130 were tested in mice. Neither rhTNF nor TNF114-130 was lethal alone, but when combined with a non-lethal dose of endotoxin, rhTNF provoked dose-dependent mortality, as did higher doses of endotoxin alone. 2. Both the toxicity and the vasopermeability changes induced by endotoxin alone were blocked by the platelet-activating factor (PAF) antagonist BN52021, indomethacin or the dual cyclo-oxygenase/lipoxygenase inhibitor BW755C. 3. The lethality of the combined low dose endotoxin/rhTNF challenge was unaffected by pretreatment with BN52021, indomethacin or BW755C, or by treatment at 6 h intervals with BN52021 or BW755C. 4. The results of these studies suggest that TNF, a putative, early mediator of septic or endotoxin shock, cannot by itself mimic all of the effects of bacterial endotoxin in the model used in this study. Apparently, TNF works synergistically with other mediators whose release is stimulated by endotoxin. 5. The results also suggest that the mechanism of shock production by the rhTNF/endotoxin combination in mice is not dependent on the early stimulation of eicosanoid or PAF synthesis by rhTNF. PMID:2110016

  6. Vertical Transmission of Histoplasmosis Associated With Anti-Tumor Necrosis Factor Therapy.

    PubMed

    Carlucci, James G; Halasa, Natasha; Creech, C Buddy; Dulek, Daniel E; Gómez-Duarte, Oscar G; Nelson, George E; Talbot, H Keipp; Scalise, Melissa L; Scott, Patricia L; Mahadevan, Uma; Beaulieu, Dawn B

    2016-06-01

    Therapeutics blocking the activity of tumor necrosis factor (anti-TNF) are a risk factor for invasive fungal infections; however, infectious risks to infants born to mothers receiving anti-TNF therapy are not well defined. We report a case of vertical transmission of disseminated histoplasmosis in a mother-infant pair exposed to anti-TNF therapy. PMID:27012275

  7. Tumor Necrosis Factor Inhibition and Head and Neck Cancer Recurrence and Death in Rheumatoid Arthritis

    PubMed Central

    Phillips, Christopher; Zeringue, Angelique L.; McDonald, Jay R.; Eisen, Seth A.; Ranganathan, Prabha

    2015-01-01

    The objective of this retrospective cohort study was to determine the effect of tumor necrosis factor inhibitor (TNFi) therapy on the risk of head and neck cancer (HNC) recurrence or HNC-attributable death in patients with rheumatoid arthritis (RA). RA patients with HNC were assembled from the US national Veterans’ Affairs (VA) administrative databases, and diagnoses confirmed and data collected by electronic medical record review. The cohort was divided into those treated with non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs) versus TNF inhibitors (TNFi) after a diagnosis of HNC. Likelihood of a composite endpoint of recurrence or HNC-attributable death was determined by Cox proportional hazards regression. Of 180 patients with RA and HNC, 31 were treated with TNFi and 149 with nbDMARDs after the diagnosis of HNC. Recurrence or HNC-attributable death occurred in 5/31 (16.1%) patients in the TNFi group and 44/149 (29.5%) patients in the nbDMARD group (p = 0.17); it occurred in 2/16 (13%) patients who received TNFi in the year prior to HNC diagnosis but not after. Overall stage at diagnosis (p = 0.03) and stage 4 HNC (HR 2.49 [CI 1.06–5.89]; p = 0.04) were risk factors for recurrence or HNC-attributable death; treatment with radiation or surgery was associated with a lower risk (HR 0.35 [CI 0.17–0.74]; p = 0.01 and HR 0.39 [CI 0.20–0.76]; p = 0.01 respectively). Treatment with TNFi was not a risk factor for recurrence or HNC-attributable death (HR 0.75; CI 0.31–1.85; p = 0.54). We conclude that treatment with TNFi may be safe in patients with RA and HNC, especially as the time interval between HNC treatment and non-recurrence increases. In this study, TNF inhibition was not associated with an increase in recurrence or HNC-attributable death. PMID:26599370

  8. Unilamellar liposomes modulate secretion of tumor necrosis factor by lipopolysaccharide-stimulated macrophages.

    PubMed Central

    Brisseau, G F; Kresta, A; Schouten, D; Bohnen, J M; Shek, P N; Fok, E; Rotstein, O D

    1994-01-01

    Liposomal encapsulation of antimicrobial agents has been used to improve drug delivery, particularly against intracellular pathogens. The effect of unilamellar liposomes on macrophage activation in response to Escherichia coli lipopolysaccharide was examined. Liposomes caused a dose- and time-dependent inhibition of tumor necrosis factor release by lipopolysaccharide-treated cells. The accumulation of tumor necrosis factor mRNA transcripts was unaffected, suggesting a posttranscriptional mechanism for this effect. However, induction of macrophage procoagulant activity was unaffected by liposomes, indicating a selective rather than a global inhibition. These data suggest that liposomes used for drug delivery may modulate the host response to infection. Images PMID:7872768

  9. Dissecting Cellulitis of the Scalp Responding to Intravenous Tumor Necrosis Factor-alpha Antagonist.

    PubMed

    Wollina, Uwe; Gemmeke, Astrid; Koch, André

    2012-04-01

    The authors present the case of a 30-year-old male patient with a severe and long-standing dissecting cellulitis of the scalp. The disease did not respond to conventional treatment, including oral antibiotics, isotretinoin, and prednisolone. Quality of life was significantly impaired. After introduction of anti-tumor necrosis factor-alpha treatment (infliximab), the malodorous discharge stopped, inflammation was reduced significantly, nodules became flat, and pain decreased. The treatment was well tolerated although he developed a temporary psoriasiform rash after the second intravenous infusion. In conclusion, anti-tumor necrosis factor-alpha treatment is a new therapeutic option in this severe and recalcitrant disorder. PMID:22708007

  10. Predisposing Factors of Liver Necrosis after Transcatheter Arterial Chemoembolization in Liver Metastases from Neuroendocrine Tumor

    SciTech Connect

    Joskin, Julien Baere, Thierry de; Auperin, Anne; Tselikas, Lambros Guiu, Boris Farouil, Geoffroy; Boige, Valérie Malka, David; Leboulleux, Sophie; Ducreux, Michel; Baudin, Eric; Deschamps, Frédéric

    2015-04-15

    PurposeTo investigate predictive factors for liver necrosis after transcatheter arterial chemoembolization (TACE) of neuroendocrine liver metastases.MethodsA total of 164 patients receiving 374 TACE were reviewed retrospectively to analyze predictive factors of liver necrosis. We analyzed patient age and sex; metastasis number and location; percentage of liver involvement; baseline liver function test; and pretreatment imaging abnormalities such as bile duct dilatation (BDD), portal vein narrowing (PVN), and portal vein thrombosis (PVT). We analyzed TACE technique such as Lipiodol or drug-eluting beads (DEB) as the drug’s vector; dose of chemotherapy; diameter of DEB; and number, frequency, and selectivity of TACE.ResultsLiver necrosis developed after 23 (6.1 %) of 374 TACE. In multivariate analysis, DEB > 300 μm in size induced more liver necrosis compared to Lipiodol (odds ratio [OR] 35.20; p < 0.0001) or with DEB < 300 μm in size (OR 19.95; p < 0.010). Pretreatment BDD (OR 119.64; p < 0.0001) and PVT (OR 9.83; p = 0.030) were predictive of liver necrosis. BDD or PVT responsible for liver necrosis were present before TACE in 59 % (13 of 22) and were induced by a previous TACE in 41 % (9 of 22) of cases.ConclusionDEB > 300 μm in size, BDD, and PVT are responsible for increased rate of liver necrosis after TACE. Careful analysis of BDD or PVT on pretreatment images as well as images taken between two courses can help avoid TACE complications.

  11. Avascular necrosis of bone after allogeneic bone marrow transplantation: clinical findings, incidence and risk factors.

    PubMed

    Socié, G; Sélimi, F; Sedel, L; Frija, J; Devergie, A; Esperou Bourdeau, H; Ribaud, P; Gluckman, E

    1994-03-01

    In the present study we describe the incidence, clinical course, and management of avascular necrosis of bone following allogeneic bone marrow transplantation, and identify risk factors related to its development. All patients developing avascular necrosis of bone after allogeneic bone marrow transplantation between January 1974 and September 1992 were included in the analysis and were studied using the Hôpital Saint Louis Bone Marrow Transplant Database and hospital records. 27/727 allogeneic transplant recipients developed avascular necrosis leading to an 8.1% incidence at 5 years, by product limit estimate, ranging from 5% to 11.2%. Symptoms developed 119-1747 d (median 398 d) after transplantation. In these 27 patients a total of 52 joints were affected (mean 1.92 per patient, range 1-7). The hip joint was most often affected (69% of patients). All patients had joint pain that led to diagnosis by means of standard radiographs with or without the help of technetium-99 scans and/or magnetic resonance imaging. All but three patients received steroid therapy for acute graft-versus-host disease. Among 10 factors tested, three were shown to be significantly linked to an increased risk for developing avascular necrosis by multivariate analysis: male gender (relative risk (RR) 4.72, P = 0.002), age older than 16 (RR = 3.87, P = 0.004), and acute graft-versus-host disease requiring steroid therapy (RR = 6.30, P = 0.0002). 10 patients (37%) required joint replacement within 19 months (range 2-42) following diagnosis of avascular necrosis. In conclusion, avascular necrosis of bone is a frequent late complication of allogeneic bone marrow transplantation causing significant morbidity and requiring replacement surgery in one-third of affected patients. In this 18-year single-centre survey, older age, male gender and steroid therapy given for acute graft-versus-host disease were shown to independently increase the risk of avascular necrosis of bone. PMID:8043445

  12. Phenyltriazolinones as potent factor Xa inhibitors.

    PubMed

    Quan, Mimi L; Pinto, Donald J P; Rossi, Karen A; Sheriff, Steven; Alexander, Richard S; Amparo, Eugene; Kish, Kevin; Knabb, Robert M; Luettgen, Joseph M; Morin, Paul; Smallwood, Angela; Woerner, Francis J; Wexler, Ruth R

    2010-02-15

    We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate. PMID:20100660

  13. Risk factors for mastectomy flap necrosis following immediate tissue expander breast reconstruction.

    PubMed

    Mlodinow, Alexei S; Fine, Neil A; Khavanin, Nima; Kim, John Y S

    2014-10-01

    Tissue expander placement is a mainstay of reconstructive surgery in the post-mastectomy patient. Necrosis of the native breast tissue is one of the most significant concerns in their post-operative care. The goal of this study is to elucidate factors that confer risk of this outcome. Chart review was conducted for a consecutive series of immediate tissue expander reconstructions by the two senior authors. Data was collected for several preoperative and intraoperative variables, as well as the outcome of mastectomy flap necrosis. Of the 1566 breasts that were examined, 135 (8.6%) experienced flap necrosis. The cohorts with and without flap necrosis were well matched. Those with the outcome of interest had significantly higher rates of switching to an autologous method of reconstruction (31.9% vs 6.2%, p < 0.001). Regression analysis revealed smoking status, increased age, tumescent mastectomy technique, and high (>66.67%) intraoperative tissue expander fill to confer increased risk of mastectomy flap necrosis. While smoking and older age are well-supported by the literature, tumescent technique and tissue expander fill are more novel points of discussion, which may serve as proxies for other issues. Awareness of these risk factors and their interplay will aid in clinical judgement and postoperative care of these patients. PMID:24495186

  14. Inverse regulation of human ERBB2 and epidermal growth factor receptors by tumor necrosis factor alpha.

    PubMed Central

    Kalthoff, H; Roeder, C; Gieseking, J; Humburg, I; Schmiegel, W

    1993-01-01

    Recombinant human tumor necrosis factor (TNF) alpha decreased the expression of ERBB2 mRNA by stimulating p55 TNF receptors of pancreatic tumor cells. This decrease contrasts with an increase in epidermal growth factor receptor (EGFR) mRNA. Both effects were selectively achieved by TNF-alpha or -beta, whereas interferon alpha or gamma or transforming growth factor beta showed no such effects. The inverse regulatory effects of TNF on ERBB2 and EGFR mRNA levels were evoked by different signaling pathways of p55 TNF receptors. The TNF-mediated ERBB2 mRNA decrease was followed by a reduction in protein. Four of five pancreatic tumor cell lines exhibited this down-regulation. This decrease of ERBB2 is a singular example of a modulation of this growth factor receptor by TNF. Overexpression of ERBB2 has been reported to cause resistance to TNF and other cytotoxic cytokines. In our study we show that the TNF-mediated down-regulation of ERBB2 in pancreatic tumor cells is accompanied by an increase in growth inhibition at low doses of TNF. The simultaneous alteration of the ERBB2/EGFR balance by TNF represents a striking model of cytokine receptor transregulation in the growth control of malignant pancreatic epithelial cells. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8105469

  15. Genetics Home Reference: tumor necrosis factor receptor-associated periodic syndrome

    MedlinePlus

    ... Tumor necrosis factor receptor-associated periodic syndrome (TRAPS): definition, semiology, prognosis, pathogenesis, treatment, and place relative to other periodic joint diseases. Joint Bone Spine. 2004 Jul;71(4):284-90. Review. Citation on PubMed Pettersson T, Kantonen J, Matikainen S, ...

  16. Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes.

    PubMed Central

    Held, W; MacDonald, H R; Weissman, I L; Hess, M W; Mueller, C

    1990-01-01

    Progressive destruction of the insulin-producing beta cells in nonobese diabetic mice is observed after infiltration of the pancreas with lymphocytes [Makino, S., Kunimoto, K., Muraoka, Y., Mizushima, Y., Katagiri, K. & Tochino, Y. (1980) Exp. Anim. (Tokyo) 29, 1-13]. We show that the genes for tumor necrosis factor alpha and granzyme A, a serine protease associated with cytoplasmic granules of cytotoxic cells, are expressed during the development of spontaneous diabetes mellitus in the nonobese diabetic mouse. Granzyme A-positive cells are found both in and surrounding the islets, implying induction prior to islet infiltration. Tumor necrosis factor alpha expression is exclusively observed in the intra-islet infiltrate, predominantly in lymphocytes adjacent to insulin-producing beta cells, the targets of the autoimmune destruction, implying that tumor necrosis factor alpha expression is induced locally--i.e., in the islet. A considerable portion of cells expressing tumor necrosis factor alpha appear to be CD4+ T cells. This T-cell subset was previously shown to be necessary for development of the disease. Thus, these findings may be important for understanding the pathogenesis of autoimmune diabetes mellitus and potentially also for that of other T-cell-mediated autoimmune diseases. Images PMID:2179951

  17. Functional Characterization of Tumor Necrosis Factor Superfamily 15(TNFSF15) Induced by Lipopolysaccharides and Eimeria Infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A full-length cDNA encoding chicken tumor necrosis factor superfamily 15 (TNFSF15) was isolated and its functional role was investigated. TNFSF15 transcripts were primarily expressed in spleen, liver, intestinal intraepithelial lymphocytes (IEL), peripheral blood lymphocytes and bursa. In vitro inf...

  18. Structural Biology of Tumor Necrosis Factor Demonstrated for Undergraduates Instruction by Computer Simulation

    ERIC Educational Resources Information Center

    Roy, Urmi

    2016-01-01

    This work presents a three-dimensional (3D) modeling exercise for undergraduate students in chemistry and health sciences disciplines, focusing on a protein-group linked to immune system regulation. Specifically, the exercise involves molecular modeling and structural analysis of tumor necrosis factor (TNF) proteins, both wild type and mutant. The…

  19. Phosphorylation of tumor necrosis factor receptor 1 (p55) protects macrophages from silica-induced apoptosis.

    PubMed

    Gambelli, Federica; Di, Peter; Niu, Xiaomei; Friedman, Mitchell; Hammond, Timothy; Riches, David W H; Ortiz, Luis A

    2004-01-16

    Macrophages play a fundamental role in silicosis in part by removing silica particles and producing inflammatory mediators in response to silica. Tumor necrosis factor alpha (TNFalpha) is a prominent mediator in silicosis. Silica induction of apoptosis in macrophages might be mediated by TNFalpha. However, TNFalpha also activates signal transduction pathways (NF-kappaB and AP-1) that rescue cells from apoptosis. Therefore, we studied the TNFalpha-mediated mechanisms that confer macrophage protection against the pro-apoptotic effects of silica. We will show that exposure to silica induced TNFalpha production by RAW 264.7 cells, but not by IC-21. Silica-induced activation of NF-kappaB and AP-1 was only observed in RAW 264.7 macrophages. ERK activation in response to silica exposure was only observed in RAW 264.7 macrophages, whereas activation of p38 phosphorylation was predominantly observed in IC-21 macrophages. No changes in JNK activity were observed in either cell line in response to silica exposure. Silica induced apoptosis in both macrophage cell lines, but the induction of apoptosis was significantly larger in IC-21 cells. Protection against apoptosis in RAW 264.7 cells in response to silica was mediated by enhanced NF-kappaB activation and ERK-mediated phosphorylation of the p55 TNFalpha receptor. Inhibition of these two protective mechanisms by specific pharmacological inhibitors or transfection of dominant negative mutants that inhibit IkappaBalpha or ERK phosphorylation significantly increased silica-induced apoptosis in RAW 264.7 macrophages. These data suggest that NF-kappaB activation and ERK-mediated phosphorylation of the p55 TNF receptor are important cell survival mechanisms in the macrophage response to silica exposure. PMID:14570868

  20. Tumor Necrosis Factor, but Not Neutrophils, Alters the Metabolic Profile in Acute Experimental Arthritis.

    PubMed

    Oliveira, Marina C; Tavares, Luciana P; Vago, Juliana P; Batista, Nathália V; Queiroz-Junior, Celso M; Vieira, Angelica T; Menezes, Gustavo B; Sousa, Lirlândia P; van de Loo, Fons A J; Teixeira, Mauro M; Amaral, Flávio A; Ferreira, Adaliene V M

    2016-01-01

    Metabolic alterations are associated with arthritis apart from obesity. However, it is still unclear which is the underlying process behind these metabolic changes. Here, we investigate the role of tumor necrosis factor (TNF) in this process in an acute model of antigen-induced arthritis (AIA). Immunized male BALB/c mice received an intra-articular injection of PBS (control) or methylated bovine serum albumin (mBSA) into their knees, and were also pre-treated with different drugs: Etanercept, an anti-TNF drug, DF2156A, a CXCR1/2 receptor antagonist, or a monoclonal antibody RB6-8C5 to deplete neutrophils. Local challenge with mBSA evoked an acute neutrophil influx into the knee joint, and enhanced the joint nociception, along with a transient systemic metabolic alteration (higher levels of glucose and lipids, and altered adipocytokines). Pre-treatment with the conventional biological Etanercept, an inhibitor of TNF action, ameliorated the nociception and the acute joint inflammation dominated by neutrophils, and markedly improved many of the altered systemic metabolites (glucose and lipids), adipocytokines and PTX3. However, the lessening of metabolic changes was not due to diminished accumulation of neutrophils in the joint by Etanercept. Reduction of neutrophil recruitment by pre-treating AIA mice with DF2156A, or even the depletion of these cells by using RB6-8C5 reduced all of the inflammatory parameters and hypernociception developed after AIA challenge, but could not prevent the metabolic changes. Therefore, the induction of joint inflammation provoked acute metabolic alterations which were involved with TNF. We suggest that the role of TNF in arthritis-associated metabolic changes is not due to local neutrophils, which are the major cells present in this model, but rather due to cytokines. PMID:26742100

  1. Analysis of Tumor Necrosis Factor Function Using the Resonant Recognition Model.

    PubMed

    Cosic, Irena; Cosic, Drasko; Lazar, Katarina

    2016-06-01

    The tumor necrosis factor (TNF) is a complex protein that plays a very important role in a number of biological functions including apoptotic cell death, tumor regression, cachexia, inflammation inhibition of tumorigenesis and viral replication. Its most interesting function is that it is an inhibitor of tumorigenesis and inductor of apoptosis. Thus, the TNF could be a good candidate for cancer therapy. However, the TNF has also inflammatory and toxic effects. Therefore, it would be very important to understand complex functions of the TNF and consequently be able to predict mutations or even design the new TNF-related proteins that will have only a tumor inhibition function, but not other side effects. This can be achieved by applying the resonant recognition model (RRM), a unique computational model of analysing macromolecular sequences of proteins, DNA and RNA. The RRM is based on finding that certain periodicities in distribution of free electron energies along protein, DNA and RNA are strongly correlated to the biological function of these macromolecules. Thus, based on these findings, the RRM has capabilities of protein function identification, prediction of bioactive amino acids and protein design with desired biological function. Using the RRM, we separate different functions of TNF as different periodicities (frequencies) within the distribution of free energy electrons along TNF protein. Interestingly, these characteristic TNF frequencies are related to previously identified characteristics of proto-oncogene and oncogene proteins describing TNF involvement in oncogenesis. Consequently, we identify the key amino acids related to the crucial TNF function, i.e. receptor recognition. We have also designed the peptide which will have the ability to recognise the receptor without side effects. PMID:27286856

  2. Anti-tumour necrosis factor agent and liver injury: Literature review, recommendations for management

    PubMed Central

    Rossi, Roberta Elisa; Parisi, Ioanna; Despott, Edward John; Burroughs, Andrew Kenneth; O'Beirne, James; Conte, Dario; Hamilton, Mark Ian; Murray, Charles Daniel

    2014-01-01

    Abnormalities in liver function tests, including transient and self-limiting hypertransaminasemia, cholestatic disease and hepatitis, can develop during treatment with anti-tumour-necrosis-factor (TNF) therapy. The optimal management of liver injury related to anti-TNF therapy is still a matter of debate. Although some authors recommend discontinuing treatment in case of both a rise of alanine aminotransferase more than 5 times the upper limit of normal, or the occurrence of jaundice, there are no standard guidelines for the management of anti-TNF-related liver injury. Bibliographical searches were performed in PubMed, using the following key words: inflammatory bowel disease (IBD); TNF inhibitors; hypertransaminasemia; drug-related liver injury; infliximab. According to published data, elevation of transaminases in patients with IBD treated with anti-TNF is a common finding, but resolution appears to be the usual outcome. Anti-TNF agents seem to be safe with a low risk of causing severe drug-related liver injury. According to our centre experience, we found that hypertransaminasemia was a common, mainly self-limiting finding in our IBD cohort and was not correlated to infliximab treatment on both univariate and multivariate analyses. An algorithm for the management of liver impairment occurring during anti-TNF treatment is also proposed and this highlights the need of a multidisciplinary approach and suggests liver biopsy as a key-point in the management decision in case of severe rise of transaminases. However, hepatic injury is generally self-limiting and drug withdrawal seems to be an exception. PMID:25516646

  3. Vpr Enhances Tumor Necrosis Factor Production by HIV-1-Infected T Cells

    PubMed Central

    Roesch, Ferdinand; Richard, Léa; Rua, Réjane; Porrot, Françoise; Casartelli, Nicoletta

    2015-01-01

    ABSTRACT The HIV-1 accessory protein Vpr displays different activities potentially impacting viral replication, including the arrest of the cell cycle in the G2 phase and the stimulation of apoptosis and DNA damage response pathways. Vpr also modulates cytokine production by infected cells, but this property remains partly characterized. Here, we investigated the effect of Vpr on the production of the proinflammatory cytokine tumor necrosis factor (TNF). We report that Vpr significantly increases TNF secretion by infected lymphocytes. De novo production of Vpr is required for this effect. Vpr mutants known to be defective for G2 cell cycle arrest induce lower levels of TNF secretion, suggesting a link between these two functions. Silencing experiments and the use of chemical inhibitors further implicated the cellular proteins DDB1 and TAK1 in this activity of Vpr. TNF secreted by HIV-1-infected cells triggers NF-κB activity in bystander cells and allows viral reactivation in a model of latently infected cells. Thus, the stimulation of the proinflammatory pathway by Vpr may impact HIV-1 replication in vivo. IMPORTANCE The role of the HIV-1 accessory protein Vpr remains only partially characterized. This protein is important for viral pathogenesis in infected individuals but is dispensable for viral replication in most cell culture systems. Some of the functions described for Vpr remain controversial. In particular, it remains unclear whether Vpr promotes or instead prevents proinflammatory and antiviral immune responses. In this report, we show that Vpr promotes the release of TNF, a proinflammatory cytokine associated with rapid disease progression. Using Vpr mutants or inhibiting selected cellular genes, we show that the cellular proteins DDB1 and TAK1 are involved in the release of TNF by HIV-infected cells. This report provides novel insights into how Vpr manipulates TNF production and helps clarify the role of Vpr in innate immune responses and inflammation

  4. Tumor Necrosis Factor, but Not Neutrophils, Alters the Metabolic Profile in Acute Experimental Arthritis

    PubMed Central

    Oliveira, Marina C.; Tavares, Luciana P.; Vago, Juliana P.; Batista, Nathália V.; Queiroz-Junior, Celso M.; Vieira, Angelica T.; Menezes, Gustavo B.; Sousa, Lirlândia P.; van de Loo, Fons A. J.; Teixeira, Mauro M.; Amaral, Flávio A.; Ferreira, Adaliene V. M.

    2016-01-01

    Metabolic alterations are associated with arthritis apart from obesity. However, it is still unclear which is the underlying process behind these metabolic changes. Here, we investigate the role of tumor necrosis factor (TNF) in this process in an acute model of antigen-induced arthritis (AIA). Immunized male BALB/c mice received an intra-articular injection of PBS (control) or methylated bovine serum albumin (mBSA) into their knees, and were also pre-treated with different drugs: Etanercept, an anti-TNF drug, DF2156A, a CXCR1/2 receptor antagonist, or a monoclonal antibody RB6-8C5 to deplete neutrophils. Local challenge with mBSA evoked an acute neutrophil influx into the knee joint, and enhanced the joint nociception, along with a transient systemic metabolic alteration (higher levels of glucose and lipids, and altered adipocytokines). Pre-treatment with the conventional biological Etanercept, an inhibitor of TNF action, ameliorated the nociception and the acute joint inflammation dominated by neutrophils, and markedly improved many of the altered systemic metabolites (glucose and lipids), adipocytokines and PTX3. However, the lessening of metabolic changes was not due to diminished accumulation of neutrophils in the joint by Etanercept. Reduction of neutrophil recruitment by pre-treating AIA mice with DF2156A, or even the depletion of these cells by using RB6-8C5 reduced all of the inflammatory parameters and hypernociception developed after AIA challenge, but could not prevent the metabolic changes. Therefore, the induction of joint inflammation provoked acute metabolic alterations which were involved with TNF. We suggest that the role of TNF in arthritis-associated metabolic changes is not due to local neutrophils, which are the major cells present in this model, but rather due to cytokines. PMID:26742100

  5. Targeting Tumor Necrosis Factor-α with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion

    PubMed Central

    Oberoi, Raghav; Schuett, Jutta; Schuett, Harald; Koch, Ann-Kathrin; Luchtefeld, Maren

    2016-01-01

    Objective It is well known that atherosclerotic inflammatory vascular disease is critically driven by oxidized lipids and cytokines. In this regard, tumor necrosis factor (TNF)-α is known as a crucial mediator of early pro-atherosclerotic events. Epidemiologic data suggest that blockade of TNF-α has beneficial effects on vascular outcomes in patients with rheumatoid arthritis, however, detailed mechanistic studies are still lacking. This study aims to elucidate effects of TNF-α blockade by adalimumab–which is approved for several inflammatory disorders–on endothelial activation and monocyte adhesion under pro-atherosclerotic conditions. Methods and Results Phorbol myristate acetate (PMA) differentiated THP-1 macrophages were stimulated with oxidized low density lipoprotein and subsequent analysis of this conditioned media (oxLDL CM) revealed a strong release of TNF-α. The TNF-α rich supernatant led to activation of human umbilical vein endothelial cells (HUVEC) as shown by enhanced expression of major adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin which was suppressed by the TNF-α inhibitor adalimumab. Accordingly, adalimumab effectively prevented THP-1 monocyte adhesion to endothelial cells under static as well as under flow conditions. Furthermore, adalimumab suppressed endothelial leakage as shown by Evan's blue diffusion across a confluent endothelial monolayer. Of note, after intraperitoneal injection we detected abundant deposition of fluorophore-labelled adalimumab in atherosclerotic plaques of hypercholesterolemic mice. Conclusion Our results show that adalimumab prevents major inflammatory effects of TNF-α on endothelial activation, endothelial monocyte adhesion, endothelial leakage and therefore extends the therapeutic options of adalimumab to limit vascular inflammation. PMID:27467817

  6. Histamine receptor antagonists, cyclooxygenase blockade, and tumor necrosis factor during acute septic insult.

    PubMed

    Leeper-Woodford, S K; Carey, D; Byrne, K; Walsh, C; Fisher, B; Sugerman, H J; Fowler, A A

    1998-02-01

    Tumor necrosis factor (TNF) may be a major endogenous mediator of sepsis-induced acute organ injury. We proposed that treatment of septic pigs with the combined agents ibuprofen, a cyclooxygenase inhibitor, and histamine receptor antagonists, cimetidine (H2 antagonist) and diphenhydramine (H1 antagonist) would result in lower circulating levels of TNF and decreased parameters of sepsis-induced injury in these animals. To test this, plasma TNF activity, cardiac index, systemic and pulmonary arterial pressures, arterial PO2 and bronchoalveolar lavage protein content were monitored for 300 min in four groups of anesthetized pigs: saline-infused control pigs (n = 4); pigs infused for 60 min with Pseudomonas aeruginosa (5 x 10(8) organisms/mL, .3 mL/20 kg/min) (n = 5) and pigs infused for 60 min with P. aeruginosa plus ibuprofen (12.5 mg/kg) alone (n = 4) or ibuprofen plus cimetidine (150 mg) and diphenhydramine (30 mg/kg) at 0 and 120 min (CID, n = 4). Within 60 min, pigs infused with P. aeruginosa exhibited increased plasma TNF activity (>8-fold increase in ng/mL TNF; L929 cytolysis assay) and showed alterations in all hemodynamic and pulmonary parameters. Ibuprofen or CID administration in the septic pigs decreased peak TNF activity by 4.6 and 10.2 ng/mL, respectively, and CID treatment was correlated with better attenuation of certain sepsis-induced alterations. These results show that CID treatment attenuates sepsis-induced injury and that this is correlated with reduced plasma TNF activity in a porcine model of sepsis-induced acute organ injury. PMID:9488252

  7. Pharmacologic reduction in tumor necrosis factor activity of pulmonary alveolar macrophages.

    PubMed

    Leeper-Woodford, S K; Fisher, B J; Sugerman, H J; Fowler, A A

    1993-02-01

    Tumor necrosis factor-alpha (TNF), an inflammatory cytokine released by macrophages, may be a mediator of lung injury during septicemia. We previously reported that the cyclooxygenase inhibitor ibuprofen and histamine receptor antagonists cimetidine (H2 antagonist) and diphenhydramine (H1 antagonist) attenuate lung injury and reduce circulating TNF surges during porcine sepsis. Since pulmonary alveolar macrophages (PAM) may participate in early sepsis by producing TNF, we hypothesized that the TNF activity of PAM is reduced by ibuprofen, cimetidine, and diphenhydramine. To test this, we examined changes in PAM-derived TNF bioactivity and cell viability of freshly isolated porcine PAM during exposure to bacterial endotoxin (LPS), ibuprofen, cimetidine, and diphenhydramine. The TNF activity (% L929 cytotoxicity of PAM conditioned medium) was elevated in LPS-stimulated PAM cultures (15 to 25% increase at 1 to 6 h and 40 to 43% increase at 6 to 48 h, compared with non-LPS-stimulated cultures), and ibuprofen (150 micrograms/ml) added with LPS decreased the TNF activity for 24 h (20 to 28% reduction at 1 to 24 h). Ibuprofen added 1 h after LPS was less effective in reducing the PAM-derived TNF activity (20 to 22% reduction at 2 to 6 h). Cimetidine (112 micrograms/ml) reduced the TNF activity of LPS-stimulated PAM cultures during the first 4 h of LPS exposure (15 to 24% decrease at 1 to 4 h). Diphenhydramine (150 micrograms/ml) attenuated the PAM-derived TNF activity but also decreased viability of PAM, indicating a toxic effect of this agent on PAM.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8093999

  8. Inhibitors of the Metalloproteinase Anthrax Lethal Factor.

    PubMed

    Goldberg, Allison B; Turk, Benjamin E

    2016-01-01

    Bacillus anthracis, a rod shaped, spore forming, gram positive bacteria, is the etiological agent of anthrax. B. anthracis virulence is partly attributable to two secreted bipartite protein toxins, which act inside host cells to disrupt signaling pathways important for host defense against infection. These toxins may also directly contribute to mortality in late stage infection. The zinc-dependent metalloproteinase anthrax lethal factor (LF) is a critical component of one of these protein toxins and a prime target for inhibitor development to produce anthrax therapeutics. Here, we describe recent efforts to identify specific and potent LF inhibitors. Derivatization of peptide substrate analogs bearing zinc-binding groups has produced potent and specific LF inhibitors, and X-ray crystallography of LFinhibitor complexes has provided insight into features required for high affinity binding. Novel inhibitor scaffolds have been identified through several approaches, including fragment-based drug discovery, virtual screening, and highthroughput screening of diverse compound libraries. Lastly, efforts to discover LF inhibitors have led to the development of new screening strategies, such as the use of full-length proteins as substrates, that may prove useful for other proteases as well. Overall, these efforts have led to a collection of chemically and mechanistically diverse molecules capable of inhibiting LF activity in vitro and in cells, as well as in animal models of anthrax infection. PMID:27072692

  9. Optogenetic Inhibitor of the Transcription Factor CREB.

    PubMed

    Ali, Ahmed M; Reis, Jakeb M; Xia, Yan; Rashid, Asim J; Mercaldo, Valentina; Walters, Brandon J; Brechun, Katherine E; Borisenko, Vitali; Josselyn, Sheena A; Karanicolas, John; Woolley, G Andrew

    2015-11-19

    Current approaches for optogenetic control of transcription do not mimic the activity of endogenous transcription factors, which act at numerous sites in the genome in a complex interplay with other factors. Optogenetic control of dominant negative versions of endogenous transcription factors provides a mechanism for mimicking the natural regulation of gene expression. Here we describe opto-DN-CREB, a blue-light-controlled inhibitor of the transcription factor CREB created by fusing the dominant negative inhibitor A-CREB to photoactive yellow protein (PYP). A light-driven conformational change in PYP prevents coiled-coil formation between A-CREB and CREB, thereby activating CREB. Optogenetic control of CREB function was characterized in vitro, in HEK293T cells, and in neurons where blue light enabled control of expression of the CREB targets NR4A2 and c-Fos. Dominant negative inhibitors exist for numerous transcription factors; linking these to optogenetic domains offers a general approach for spatiotemporal control of native transcriptional events. PMID:26590638

  10. Inhibition of Hageman factor (factor XII) by popcorn inhibitor.

    PubMed

    Kambhu, S A; Ratnoff, O D; Everson, B

    1985-05-01

    A protein derived from sweet corn or popcorn inhibits the enzymatic activity of the carboxy-terminal fragment of Hageman factor (HFf) and of ellagic acid-activated Hageman factor (HF, factor XII). Not clarified is whether the inhibitor is directed at the active site of HF. Filtration of normal plasma or purified HF through columns of popcorn inhibitor bound to agarose gels demonstrated that HF was bound to these gels and could then be eluted by buffers containing 2.0 mol/L sodium chloride. The eluted HF was in the precursor form. Thus, popcorn inhibitor appeared to attach to a point on the carboxy-terminal HFf that was distinct from the enzymatically active site of this clotting factor. PMID:3989356

  11. A Nonpolar Blueberry Fraction Blunts NADPH Oxidase Activation in Neuronal Cells Exposed to Tumor Necrosis Factor

    PubMed Central

    Gustafson, Sally J.; Dunlap, Kriya L.; McGill, Colin M.; Kuhn, Thomas B.

    2012-01-01

    Inflammation and oxidative stress are key to the progressive neuronal degeneration common to chronic pathologies, traumatic injuries, and aging processes in the CNS. The proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) orchestrates cellular stress by stimulating the production and release of neurotoxic mediators including reactive oxygen species (ROS). NADPH oxidases (NOX), ubiquitously expressed in all cells, have recently emerged as pivotal ROS sources in aging and disease. We demonstrated the presence of potent NOX inhibitors in wild Alaska bog blueberries partitioning discretely into a nonpolar fraction with minimal antioxidant capacity and largely devoid of polyphenols. Incubation of SH-SY5Y human neuroblastoma cells with nonpolar blueberry fractions obstructed the coalescing of lipid rafts into large domains disrupting NOX assembly therein and abolishing ROS production characteristic for TNF-α exposure. These findings illuminate nutrition-derived lipid raft modulation as a novel therapeutic approach to blunt inflammatory and oxidative stress in the aging or diseased CNS. PMID:22530077

  12. Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-alpha converting enzyme.

    PubMed Central

    Slack, B E; Ma, L K; Seah, C C

    2001-01-01

    The amyloid precursor protein (APP) of Alzheimer's disease is a transmembrane protein that is cleaved within its extracellular domain, liberating a soluble N-terminal fragment (sAPP alpha). Putative mediators of this process include three members of the ADAM (a disintegrin and metalloprotease) family, ADAM9, ADAM10 and ADAM17/TACE (tumour necrosis factor-alpha converting enzyme). Tumour necrosis factor-alpha protease inhibitor (TAPI-1), an inhibitor of ADAMs, reduced constitutive and muscarinic receptor-stimulated sAPP alpha release in HEK-293 cells stably expressing M3 muscarinic receptors. However, the former was less sensitive to TAPI-1 (IC(50)=8.09 microM) than the latter (IC(50)=3.61 microM), suggesting that these processes may be mediated by different metalloproteases. Constitutive sAPP alpha release was increased several-fold in cells transiently transfected with TACE, and this increase was proportional to TACE expression. In contrast, muscarinic-receptor-activated sAPP alpha release was not altered in TACE transfectants. TACE-dependent constitutive release of co-transfected APP(695) was inhibited by TAPI-1 with an IC(50) of 0.92 microm, a value significantly lower than the IC(50)s for inhibition of either constitutive or receptor-regulated sAPP alpha shedding mediated by endogenous secretases. The results indicate that TACE is capable of catalysing constitutive alpha-secretory cleavage of APP, but it is likely that additional members of the ADAM family mediate endogenous constitutive and receptor-coupled release of sAPP alpha in HEK-293 cells. PMID:11463349

  13. Monocyte Tumor Necrosis Factor-α–Converting Enzyme Catalytic Activity and Substrate Shedding in Sepsis and Noninfectious Systemic Inflammation*

    PubMed Central

    O’Callaghan, David J. P.; O’Dea, Kieran P.; Scott, Alasdair J.; Takata, Masao

    2015-01-01

    Objectives: To determine the effect of severe sepsis on monocyte tumor necrosis factor-α–converting enzyme baseline and inducible activity profiles. Design: Observational clinical study. Setting: Mixed surgical/medical teaching hospital ICU. Patients: Sixteen patients with severe sepsis, 15 healthy volunteers, and eight critically ill patients with noninfectious systemic inflammatory response syndrome. Interventions: None. Measurements and Main Results: Monocyte expression of human leukocyte antigen-D-related peptide, sol-tumor necrosis factor production, tumor necrosis factor-α–converting enzyme expression and catalytic activity, tumor necrosis factor receptor 1 and 2 expression, and shedding at 48-hour intervals from day 0 to day 4, as well as p38-mitogen activated protein kinase expression. Compared with healthy volunteers, both sepsis and systemic inflammatory response syndrome patients’ monocytes expressed reduced levels of human leukocyte antigen-D-related peptide and released less sol-tumor necrosis factor on in vitro lipopolysaccharide stimulation, consistent with the term monocyte deactivation. However, patients with sepsis had substantially elevated levels of basal tumor necrosis factor-α–converting enzyme activity that were refractory to lipopolysaccharide stimulation and this was accompanied by similar changes in p38-mitogen activated protein kinase signaling. In patients with systemic inflammatory response syndrome, monocyte basal tumor necrosis factor-α–converting enzyme, and its induction by lipopolysaccharide, appeared similar to healthy controls. Changes in basal tumor necrosis factor-α–converting enzyme activity at day 0 for sepsis patients correlated with Acute Physiology and Chronic Health Evaluation II score and the attenuated tumor necrosis factor-α–converting enzyme response to lipopolysaccharide was associated with increased mortality. Similar changes in monocyte tumor necrosis factor-α–converting enzyme activity could

  14. Tumor necrosis factor α is a risk factor for infection in peritoneal dialysis patients

    PubMed Central

    Kang, Eunjung; Kim, Seihran; Lee, Hwa Jung; Park, Inhwee; Kim, Heungsoo; Shin, Gyu-Tae

    2016-01-01

    Background/Aims: It has been shown that circulating tumor necrosis factor α (TNF-α) is elevated in end stage renal disease patients; however, the relationship between TNF-α and the development of infection in these patients is unknown. In this study, we investigated the association of plasma TNF-α and interleukin 6 (IL-6) with infection in peritoneal dialysis (PD) patients. We also evaluated the association of their plasma levels with the production by peripheral blood mononuclear cells (PBMC), and with various clinical parameters. Methods: We enrolled 32 patients on maintenance PD and 10 healthy controls. Plasma and PBMC were isolated from blood. PBMC were stimulated with lipopolysaccharide in vitro. Results: Mean follow-up duration was 775 days. Six patients developed organ infections (five pneumonia and one liver abscess), and six patients developed PD peritonitis and eight developed exit site infection. Plasma TNF-α and IL-6 levels were significantly elevated in organ infections but not in peritonitis or in exit site infection. Plasma TNF-α was the only significant risk factor for organ infections and pneumonia in multivariate regression analysis. Patients with high plasma TNF-α levels showed a significantly greater cumulative hazard rate for organ infections compared to those with low TNF-α levels. Plasma TNF-α levels correlated with TNF-α production by PBMC and showed an inverse association with Kt/V. Conclusions: This is the first study showing that plasma TNF-α is a significant risk factor for infection in PD patients. PMID:27000486

  15. Tumor Necrosis Factor Receptor 2: Its Contribution to Acute Cellular Rejection and Clear Cell Renal Carcinoma

    PubMed Central

    Wang, Jun; Al-Lamki, Rafia S.

    2013-01-01

    Tumor necrosis factor receptor 2 (TNFR2) is a type I transmembrane glycoprotein and one of the two receptors that orchestrate the complex biological functions of tumor necrosis factor (TNF, also designed TNF-α). Accumulating experimental evidence suggests that TNFR2 plays an important role in renal disorders associated with acute cellular rejection and clear cell renal carcinoma but its exact role in these settings is still not completely understood. This papers reviews the factors that may mediate TNFR2 induction in acute cellular rejection and clear cell renal carcinoma and its contribution to these conditions and discusses its therapeutic implications. A greater understanding of the function of TNFR2 may lead to the development of new anti-TNF drugs. PMID:24350291

  16. Structural biology of tumor necrosis factor demonstrated for undergraduates instruction by computer simulation.

    PubMed

    Roy, Urmi

    2016-05-01

    This work presents a three-dimensional (3D) modeling exercise for undergraduate students in chemistry and health sciences disciplines, focusing on a protein-group linked to immune system regulation. Specifically, the exercise involves molecular modeling and structural analysis of tumor necrosis factor (TNF) proteins, both wild type and mutant. The structure of the tumor necrosis factor type 1 receptor (TNF-R1) is also briefly explored. TNF and TNF-R1 play major roles in maintaining human immune-system homeostasis. Upon binding with TNFR-1, the TNF can activate the nuclear factor kappa B (NF-κB), eventually resulting in apoptosis or cell death. These essential features of the clinically relevant TNF family is explored within the frame work of a readily adaptable tutorial. © 2015 by The International Union of Biochemistry and Molecular Biology, 44:246-255, 2016. PMID:26638199

  17. Tumor necrosis factor-alpha genetic predisposing factors can influence clinical severity in nephropathia epidemica.

    PubMed

    Maes, Piet; Clement, Jan; Groeneveld, Paul H P; Colson, Paul; Huizinga, Tom W J; Van Ranst, Marc

    2006-01-01

    Severe human infection with Hantavirus is characterized by high fever, cold chills, thrombocytopenia, arterial hypotension, acute renal failure, and/or adult respiratory distress syndrome (ARDS)-like pulmonary involvement, but the clinical course varies greatly between individuals. We investigated whether genetically determined differences in tumor necrosis factor (TNF)-alpha production can influence the severity of Hantavirus disease. We studied a TNF-alpha single-nucleotide promoter polymorphism (SNP) at position -238 (a guanine [G]-to-adenine [A] transition) and ex vivo TNF-alpha production in a recall study of 36 Belgian patients who had a serologically proven form of Puumala virus-induced Hantavirus infection with the kidney as main target organ. In our study, the highest creatinine levels were found in patients with the lowest ex vivo TNF-alpha production. Creatinine levels correlated inversely with TNF-alpha production (R = -0.35, p < 0.05). The number of thrombocytes was significantly lower in patients with the GA-238 genotype (low TNF-alpha producers) compared with patients with the GG-238 genotype. In our study, genetically determined low production of TNF-alpha was associated with some parameters indicating a more severe clinical course of Puumala Hantavirus infection in humans, possibly by impaired activation of TNF-alpha-dependent antiviral mechanisms, which could in turn result in decreased clearance of Hantavirus. PMID:16987073

  18. Polyphenol Compound as a Transcription Factor Inhibitor.

    PubMed

    Park, Seyeon

    2015-11-01

    A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor-DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein-protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)). PMID:26529010

  19. Arsenite enhances tumor necrosis factor-{alpha}-induced expression of vascular cell adhesion molecule-1

    SciTech Connect

    Tsou, T.-C. . E-mail: tctsou@nhri.org.tw; Yeh, Szu Ching; Tsai, E.-M.; Tsai, F.-Y.; Chao, H.-R.; Chang, Louis W.

    2005-11-15

    Epidemiological studies demonstrated a high association of vascular diseases with arsenite exposure. We hypothesize that arsenite potentiates the effect of proinflammatory cytokines on vascular endothelial cells, and hence contributes to atherosclerosis. In this study, we investigated the effect of arsenite and its induction of glutathione (GSH) on vascular cell adhesion molecule-1 (VCAM-1) protein expression in human umbilical vein endothelial cells (HUVECs) in response to tumor necrosis factor-{alpha} (TNF-{alpha}), a typical proinflammatory cytokine. Our study demonstrated that arsenite pretreatment potentiated the TNF-{alpha}-induced VCAM-1 expression with up-regulations of both activator protein-1 (AP-1) and nuclear factor-{kappa}B (NF-{kappa}B). To elucidate the role of GSH in regulation of AP-1, NF-{kappa}B, and VCAM-1 expression, we employed L-buthionine (S,R)-sulfoximine (BSO), a specific {gamma}-glutamylcysteine synthetase ({gamma}-GCS) inhibitor, to block intracellular GSH synthesis. Our investigation revealed that, by depleting GSH, arsenite attenuated the TNF-{alpha}-induced VCAM-1 expression as well as a potentiation of AP-1 and an attenuation of NF-{kappa}B activations by TNF-{alpha}. Moreover, we found that depletion of GSH would also attenuate the TNF-{alpha}-induced VCAM-1 expression with a down-regulation of the TNF-{alpha}-induced NF-{kappa}B activation and without significant effect on AP-1. On the other hand, the TNF-{alpha}-induced VCAM-1 expression could be completely abolished by inhibition of AP-1 or NF-{kappa}B activity, suggesting that activation of both AP-1 and NF-{kappa}B was necessary for VCAM-1 expression. In summary, we demonstrate that arsenite enhances the TNF-{alpha}-induced VCAM-1 expression in HUVECs via regulation of AP-1 and NF-{kappa}B activities in a GSH-sensitive manner. Our present study suggested a potential mechanism for arsenite in the induction of vascular inflammation and vascular diseases via modulating the actions

  20. Tumor necrosis factor-induced contraction of cultured rat mesangial cells: interaction with angiotensin II.

    PubMed

    Medina, J; Baud, L; Garcia Escribano, C; Gila, J A; Rodriguez Puyol, D; Rodriguez Puyol, M

    1993-08-01

    The role of tumor necrosis factor alpha in the regulation of renal function, particularly glomerular filtration rate, has not been completely defined. This study was designed to assess the intrinsic role of this cytokine on glomerular filtration rate by analyzing its short-term effect on the degree of contraction in cultured rat mesangial cells, not only directly but also in the presence of angiotensin II. Contraction was evaluated both morphologically--by measuring planar cell surface area of cultured rat mesangial cells and glomerular cross-sectional area of isolated rat glomeruli--and biochemically--by analyzing myosin light-chain phosphorylation in cells. Tumor necrosis factor alpha significantly decreased planar cell surface area in a dose-dependent and time-dependent manner, an effect completely abolished by preincubation of the cells with platelet-activating factor receptor antagonists BN 52021 and alprazolam. This effect was also observed in the presence of angiotensin II, whether tumor necrosis factor alpha was added before or after angiotensin II, increasing the reduction in planar cell surface area induced by angiotensin II in both cases. Changes in planar cell surface area were evident not only when the absolute values of this parameter were considered but also when the percentage of contracted cells (cells with a planar cell surface area reduction > 10%) was analyzed. Tumor necrosis factor alpha also induced a significant reduction of glomerular cross-sectional area in isolated rat glomeruli. The results of the morphologic studies were supported by myosin light-chain phosphorylation experiments.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8340701

  1. Tumor necrosis factor alpha gene expression in human monocytic THP-1 cells exposed to beryllium.

    PubMed

    Galbraith, G M; Pandey, J P; Schmidt, M G; Arnaud, P; Goust, J M

    1996-01-01

    Chronic beryllium disease, which results from occupational exposure to particulate beryllium, is characterized by the development of lung granulomas and progressive pulmonary fibrosis. Increased production of proinflammatory cytokines (e.g., tumor necrosis factor alpha and interleukin-1 beta) by pulmonary alveolar macrophages occurs in many chronic fibrotic lung diseases and is thought to contribute to the disease process. The purpose of the present study was to investigate cytokine production by human monocytic cells exposed to beryllium in vitro. The results indicated that such cells respond to beryllium ions in the presence of fluoride by accumulation of messenger ribonucleic acid for both tumor necrosis factor alpha and interleukin-1 beta. These findings suggest that inhaled beryllium may directly stimulate the production of these cytokines by alveolar macrophages in vitro. PMID:8629860

  2. Key facts and hot spots on tumor necrosis factor receptor-associated periodic syndrome.

    PubMed

    Rigante, Donato; Lopalco, Giuseppe; Vitale, Antonio; Lucherini, Orso Maria; De Clemente, Caterina; Caso, Francesco; Emmi, Giacomo; Costa, Luisa; Silvestri, Elena; Andreozzi, Laura; Iannone, Florenzo; Galeazzi, Mauro; Cantarini, Luca

    2014-09-01

    Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), formerly known as familial Hibernian fever, is the most common autosomal dominant autoinflammatory disease, resulting from mutations in the TNFRSF1A gene, encoding the 55-kD tumor necrosis factor receptor. The pathophysiologic mechanism of TRAPS remains ambiguous and only partially explained. The onset age of the syndrome is variable and the clinical scenery is characterized by recurrent episodes of high-grade fever that typically lasts 1-3 weeks, associated with migrating myalgia, pseudocellulitis, diffuse abdominal pain, appendicitis-like findings, ocular inflammatory signs, and risk of long-term amyloidosis. Fever episodes are responsive to high-dose corticosteroids, but different classes of drugs have been reported to be ineffective. The use of etanercept is unable to control systemic inflammation, while interleukin-1 blockade has been shown as effective in the control of disease activity in many patients reported so far. PMID:24935411

  3. Tumour Necrosis Factor Superfamily Members in the Pathogenesis of Inflammatory Bowel Disease

    PubMed Central

    Ślebioda, Tomasz J.; Kmieć, Zbigniew

    2014-01-01

    Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the gastrointestinal tract of unclear aetiology of which two major forms are Crohn's disease (CD) and ulcerative colitis (UC). CD and UC are immunologically distinct, although they both result from hyperactivation of proinflammatory pathways in intestines and disruption of intestinal epithelial barrier. Members of the tumour necrosis factor superfamily (TNFSF) are molecules of broad spectrum of activity, including direct disruption of intestinal epithelial barrier integrity and costimulation of proinflammatory functions of lymphocytes. Tumour necrosis factor (TNF) has a well-established pathological role in IBD which also serves as a target in IBD treatment. In this review we discuss the role of TNF and other TNFSF members, notably, TL1A, FasL, LIGHT, TRAIL, and TWEAK, in the pathogenesis of IBD. PMID:25045210

  4. Myeloid Growth Factors Promote Resistance to Mycobacterial Infection by Curtailing Granuloma Necrosis through Macrophage Replenishment.

    PubMed

    Pagán, Antonio J; Yang, Chao-Tsung; Cameron, James; Swaim, Laura E; Ellett, Felix; Lieschke, Graham J; Ramakrishnan, Lalita

    2015-07-01

    The mycobacterial ESX-1 virulence locus accelerates macrophage recruitment to the forming tuberculous granuloma. Newly recruited macrophages phagocytose previously infected apoptotic macrophages to become new bacterial growth niches. Granuloma macrophages can then necrose, releasing mycobacteria into the extracellular milieu, which potentiates their growth even further. Using zebrafish with genetic or pharmacologically induced macrophage deficiencies, we find that global macrophage deficits increase susceptibility to mycobacterial infection by accelerating granuloma necrosis. This is because reduction in the macrophage supply below a critical threshold decreases granuloma macrophage replenishment to the point where apoptotic infected macrophages, failing to get engulfed, necrose. Reducing macrophage demand by removing bacterial ESX-1 offsets the susceptibility of macrophage deficits. Conversely, increasing macrophage supply in wild-type fish by overexpressing myeloid growth factors induces resistance by curtailing necrosis. These findings may explain the susceptibility of humans with mononuclear cytopenias to mycobacterial infections and highlight the therapeutic potential of myeloid growth factors in tuberculosis. PMID:26159717

  5. Polyphenol Compound as a Transcription Factor Inhibitor

    PubMed Central

    Park, Seyeon

    2015-01-01

    A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor–DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein–protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)). PMID:26529010

  6. Gemella morbillorum Bacteremia after Anti-Tumor Necrosis Factor Alpha as Acne Inversa Therapy

    PubMed Central

    Vossen, Matthias G.; Gattringer, Klaus B.; Khalifeh, Neda; Koreny, Maria; Spertini, Verena; Mallouhi, Ammar; Willeit, Markus; Volc-Platzer, Beatrix; Asboth, Friederike; Graninger, Wolfgang; Thalhammer, Florian

    2012-01-01

    We present a case of fever, brain abscesses, and Gemella morbillorum bacteremia after anti-tumor necrosis factor alpha (TNF-α) therapy in a 21-year-old acne inversa patient currently taking long-term dapsone. To the best of our knowledge, this is the first report describing such a case. During antimicrobial therapy, the patient developed systemic varicella infection with severe thrombocytopenia. PMID:22189120

  7. Impedance-Based Monitoring of Ongoing Cardiomyocyte Death Induced by Tumor Necrosis Factor

    PubMed Central

    Qiu, Yiling; Liao, Ronglih; Zhang, Xin

    2009-01-01

    Deregulated cardiomyocyte death is a critical risk factor in a variety of cardiovascular diseases. Although various assays have been developed to detect cell responses during cell death, the capability of monitoring cell detachment will enhance the understanding of death processes by providing instant information at its early phase. In this work, we developed an impedance-sensing assay for real-time monitoring of cardiomyocyte death induced by tumor necrosis factor-α based on recording the change in cardiomyocyte adhesion to extracellular matrix. Electrochemical impedance spectroscopy was employed in impedance data processing, followed by calibration with the electrical cell-substrate impedance-sensing technique. The adhesion profile of cardiomyocytes undergoing cell death processes was recorded as the time course of equivalent cell-substrate distance. The cell detachment was detected with our assay and proved related to cell death in the following experiments, indicating its advantage against the conventional assays, such as Trypan blue exclusion. An optimal concentration of tumor necrosis factor-α (20 ng/mL) was determined to induce cardiomyocyte apoptosis rather than the combinative cell death of necrosis and apoptosis by comparing the concentration-related adhesion profiles. The cardiomyocytes undergoing apoptosis experienced an increase of cell-substrate distance from 59.1 to 89.2 nm within 24 h. The early change of cell adhesion was proved related to cardiomyocyte apoptosis in the following TUNEL test at t = 24 h, which suggested the possibility of early and noninvasive detection of cardiomyocyte apoptosis. PMID:19254558

  8. Okadaic acid mimics multiple changes in early protein phosphorylation and gene expression induced by tumor necrosis factor or interleukin-1.

    PubMed

    Guy, G R; Cao, X; Chua, S P; Tan, Y H

    1992-01-25

    Okadaic acid, a phosphatase inhibitor from a marine organism, mimics tumor necrosis factor/interleukin-1 (TNF/IL-1) in inducing changes in early cellular protein phosphorylation. A total of approximately 116 proteins exhibit significant and concordant changes in phosphorylation or dephosphorylation within 15 min in human fibroblasts activated by either okadaic acid, TNF, or IL-1. The fidelity of this mimicry by okadaic acid extends to the phosphorylation of the 27 hsp complex, stathmin, eIF-4E, myosin light chain, nucleolin, epidermal growth factor receptor, and other cdc2-kinase substrates (c-abl, RB, and p53). The okadaic acid-induced pattern of protein phosphorylation is distinct from that observed in cells treated with phorbol 12-myristate 13-acetate or with ligands like epidermal growth factor, cyclic AMP agonists, bradykinin, or interferons. Like TNF, okadaic acid also induces the transcription of immediate early response genes like c-jun and Egr-1 as well as the interleukin-6 genes. The overall early effects of okadaic acid uniquely parallel those of TNF/IL-1 and not those of other cytokines or ligands. Regulation of protein phosphatase inhibition is discussed as a mechanism for TNF/IL-1 signal transduction. PMID:1370482

  9. RXFP1 is Targeted by Complement C1q Tumor Necrosis Factor-Related Factor 8 in Brain Cancer

    PubMed Central

    Thanasupawat, Thatchawan; Glogowska, Aleksandra; Burg, Maxwell; Wong, G. William; Hoang-Vu, Cuong; Hombach-Klonisch, Sabine; Klonisch, Thomas

    2015-01-01

    The relaxin-like RXFP1 ligand–receptor system has important functions in tumor growth and tissue invasion. Recently, we have identified the secreted protein, CTRP8, a member of the C1q/tumor necrosis factor-related protein (CTRP) family, as a novel ligand of the relaxin receptor, RXFP1, with functions in brain cancer. Here, we review the role of CTRP members in cancers cells with particular emphasis on CTRP8 in glioblastoma. PMID:26322020

  10. RXFP1 is Targeted by Complement C1q Tumor Necrosis Factor-Related Factor 8 in Brain Cancer.

    PubMed

    Thanasupawat, Thatchawan; Glogowska, Aleksandra; Burg, Maxwell; Wong, G William; Hoang-Vu, Cuong; Hombach-Klonisch, Sabine; Klonisch, Thomas

    2015-01-01

    The relaxin-like RXFP1 ligand-receptor system has important functions in tumor growth and tissue invasion. Recently, we have identified the secreted protein, CTRP8, a member of the C1q/tumor necrosis factor-related protein (CTRP) family, as a novel ligand of the relaxin receptor, RXFP1, with functions in brain cancer. Here, we review the role of CTRP members in cancers cells with particular emphasis on CTRP8 in glioblastoma. PMID:26322020

  11. Novel inhibitors of Anthrax edema factor

    PubMed Central

    Chen, Deliang; Misra, Milind; Sower, Laurie; Peterson, Johnny W.; Kellogg, Glen E.; Schein, Catherine H.

    2008-01-01

    Several pathogenic bacteria produce adenylyl cyclase toxins, such as the edema factor (EF) of Bacillus anthracis. These disturb cellular metabolism by catalyzing production of excessive amounts of the regulatory molecule cAMP. Here, a structure-based method, where a 3D- pharmacophore that fit the active site of EF was constructed from fragments, was used to identify non-nucleotide inhibitors of EF. A library of small molecule fragments was docked to the EF- active site in existing crystal structures and those with the highest HINT scores were assembled into a 3D-pharmacophore. About 10,000 compounds, from over 2.7 million compounds in the ZINC database, had a similar molecular framework. These were ranked according to their docking scores, using methodology that was shown to achieve maximum accuracy (i.e., how well the docked position matched the experimentally determined site for ATP analogues in crystal structures of the complex). Finally, 19 diverse compounds with the best AutoDock binding/docking scores were assayed in a cell based assay for their ability to reduce cAMP secretion induced by EF. Four of the test compounds, from different structural groups, inhibited in the low micromolar range. One of these has a core structure common to phosphatase inhibitors previously identified by high-throughput assays of a diversity library. Thus, the fragment based pharmacophore identified a small number of diverse compounds for assay, and greatly enhanced the selection process of advanced lead compounds for combinatorial design. PMID:18620864

  12. A tumour necrosis factor alpha polymorphism is not associated with rheumatoid arthritis.

    PubMed Central

    Wilson, A G; de Vries, N; van de Putte, L B; Duff, G W

    1995-01-01

    OBJECTIVE--To determine whether a polymorphism within the tumour necrosis factor alpha (TNF alpha) gene is associated with susceptibility to, or severity of, rheumatoid arthritis (RA). METHODS--Consecutive patients with recent onset RA were enrolled in a prospective trial. DNA was collected, disease activity was measured at presentation, and radiographic progression at three years was assessed. Typing of TNF alpha was by polymerase chain reaction and single stranded conformation polymorphism analysis. RESULTS--No association of TNF alpha alleles and susceptibility to, or severity of, RA was demonstrated. CONCLUSIONS--These results indicate that this TNF alpha polymorphism does not play a part in the genetic background of RA. PMID:7668906

  13. Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance

    NASA Astrophysics Data System (ADS)

    Hotamisligil, Gokhan S.; Shargill, Narinder S.; Spiegelman, Bruce M.

    1993-01-01

    Tumor necrosis factor-α (TNF-α) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-α messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-α protein was also elevated locally and systemically. Neutralization of TNF-α in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-α in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

  14. Effects of interferon-gamma and tumor necrosis factor-alpha on macrophage enzyme levels

    NASA Technical Reports Server (NTRS)

    Pierangeli, Silvia S.; Sonnenfeld, Gerald

    1989-01-01

    Murine peritoneal macrophages were treated with interferon-gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF). Measurements of changes in acid phosphatase and beta-glucuronidase levels were made as an indication of activation by cytokine treatment. IFN-gamma or TNF-gamma treatment resulted in a significant increase in the activities of both enzymes measured in the cell lysates. This increase was observable after 6 h of incubation, but reached its maximum level after 24 h of incubation. The effect of the treatment of the cell with both cytokines together was additive. No synergistic effect of addition of both cytokines on the enzyme levels was observed.

  15. Multiple roles of tumor necrosis factor-alpha in fracture healing.

    PubMed

    Karnes, Jonathan M; Daffner, Scott D; Watkins, Colleen M

    2015-09-01

    This review presents a summary of basic science evidence examining the influence of tumor necrosis factor-alpha (TNF-α) on secondary fracture healing. Multiple studies suggest that TNF-α, in combination with the host reservoir of peri-fracture mesenchymal stem cells, is a main determinant in the success of bone healing. Disease states associated with poor bone healing commonly have inappropriate TNF-α responses, which likely contributes to the higher incidence of delayed and nonunions in these patient populations. Appreciation of TNF-α in fracture healing may lead to new therapies to augment recovery and reduce the incidence of complications. PMID:25959413

  16. Synthesis of tumor necrosis factor α for use as a mirror-image phage display target.

    PubMed

    Petersen, Mark E; Jacobsen, Michael T; Kay, Michael S

    2016-06-21

    Tumor Necrosis Factor alpha (TNFα) is an inflammatory cytokine that plays a central role in the pathogenesis of chronic inflammatory disease. Here we describe the chemical synthesis of l-TNFα along with the mirror-image d-protein for use as a phage display target. The synthetic strategy utilized native chemical ligation and desulfurization to unite three peptide segments, followed by oxidative folding to assemble the 52 kDa homotrimeric protein. This synthesis represents the foundational step for discovering an inhibitory d-peptide with the potential to improve current anti-TNFα therapeutic strategies. PMID:27211891

  17. Coexistent tumor necrosis factor receptor-associated periodic fever syndrome and Ehlers-Danlos syndrome.

    PubMed

    Yao, Qingping; Zhou, Lan; Tomecki, Kenneth J

    2012-07-01

    A 32-year-old Caucasian woman had periodic fevers, skin disease, polyarthralgia and hypermobile joints that were consistent with tumor necrosis factor receptor-associated periodic fever syndrome confirmed with a finding of R92Q missense mutation of the TNFRSFA1 gene with Ehlers-Danlos hypermobility type syndrome. They are both autosomal dominant disorders, and their coexistence suggests that they could share some phenotypic features that may require special consideration in management. Conceivably, they could share common gene mutations although no such data are available. PMID:21785959

  18. Aminoguanidine and curcumin attenuated tumor necrosis factor (TNF)-α-induced oxidative stress, colitis and hepatotoxicity in mice.

    PubMed

    Mouzaoui, Souad; Rahim, Ibtissem; Djerdjouri, Bahia

    2012-01-01

    The up regulation of gut mucosal cytokines such as tumor necrosis factor (TNF)-α and oxidative stress have been related to inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). This study investigated an immune-mediated model of colitis. TNF-α injected intraperitonally to mice induced a dose-dependent recruitment of neutrophils into abdominal mesentery. The leukocytes influx induced by TNF-α (10 μg kg(-1) body weight) increased by 3 fold liver and colon damage scores. TNF-α-colitis was characterized by hemorrhagic edemas and crypt abscesses massively infiltrated by inflammatory cells, namely neutrophils. Moreover, TNF-α-toxicity resulted in liver steatosis and foci of necrosis infiltrated by Kupffer cells and neutrophils in parenchyma and around the centrilobular veins. The involvement of oxidative stress was evaluated using aminoguanidine (AG) as selective inhibitor of inducible NO synthase (iNOS) and curcumin (Cur), the polyphenolic antioxidant of turmeric (Curcuma longa L.). TNF-α-toxicity led to significant increase in myeloperoxidase (MPO, an index of neutrophils infiltration), nitrites (stable nitric oxide metabolites) and malondialdehyde (MDA, a marker of lipid peroxides) levels and cell apoptosis in liver and colon. AG and Cur treatments significantly attenuated the hallmarks of oxidative stress, neutrophils influx and ROS-related cellular and histological damages, in TNF-α-treated mice. Taken together, our results provide insights into the role of phagocytes-derived oxidants in TNF-α-colitis in mice. Cur and AG, by inhibiting neutrophils priming and iNOsynthase could be effective against oxidative bowel damages induced in IBD by imbalanced gut immune response. PMID:22036766

  19. A novel mechanism for the inhibition of type 2 iodothyronine deiodinase by tumor necrosis factor α: involvement of proteasomal degradation.

    PubMed

    Ogiwara, Takayuki; Araki, Osamu; Morimura, Tadashi; Tsunekawa, Katsuhiko; Mori, Masatomo; Murakami, Masami

    2013-01-01

    Thyroxine (T₄) needs to be converted to 3,5,3'-triiodothyronine (T₃) by iodothyronine deiodinase to exert its biological activity. Recent studies revealed the presence of type 2 iodothyronine deiodinase (D2) in human thyroid tissue, human skeletal muscle and other tissues, suggesting that D2 is involved in maintaining plasma T₃ level in human. Tumor necrosis factor α (TNFα) is an inflammatory cytokine of which production is elevated in patients with nonthyroidal illness. Although several lines of evidence suggest the causal role of TNFα in nonthyroidal illness, detailed nature of the effect of TNFα on D2 remains unclear. In the present study, we identified D2 activity and D2 mRNA in TCO-1 cells, which were derived from human anaplastic thyroid carcinoma, and studied the mechanisms involved in the regulation of D2 expression by TNFα. The characteristics of the deiodinating activity in TCO-1 cells were compatible with those of D2 and Northern analysis demonstrated that D2 mRNA was expressed in TCO-1cells. D2 activity and D2 mRNA expression were rapidly increased by dibutyryl cAMP ((Bu)₂cAMP). TNFα showed an inhibitory effect on (Bu)₂cAMP-stimulated D2 activity in spite of little effect on (Bu)₂cAMP-stimulated D2 mRNA expression. MG132, a proteasome inhibitor abolished TNFα suppression of D2 activity whereas BAY11-7082 or 6-amino-4-(4-phenoxyphenylethylamino) quinazoline, inhibitors of nuclear factor-κB (NF-κB) failed to attenuate the effect of TNFα on D2 activity. These data suggest that a posttranslational mechanism through proteasomal degradation but not NF-κB activation is involved in the suppression of D2 by TNFα. PMID:23719846

  20. Transglutaminase 2 expression is enhanced synergistically by interferon-γ and tumour necrosis factor-α in human small intestine

    PubMed Central

    Bayardo, M; Punzi, F; Bondar, C; Chopita, N; Chirdo, F

    2012-01-01

    Transglutaminase 2 (TG2) is expressed ubiquitously, has multiple physiological functions and has also been associated with inflammatory diseases, neurodegenerative disorders, autoimmunity and cancer. In particular, TG2 is expressed in small intestine mucosa where it is up-regulated in active coeliac disease (CD). The aim of this work was to investigate the induction of TG2 expression by proinflammatory cytokines [interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ and IL-15] and the signalling pathways involved, in human epithelial and monocytic cells and in intestinal tissue from controls and untreated CD patients. Here we report that IFN-γ was the most potent inducer of TG2 expression in the small intestinal mucosa and in four [Caco-2, HT-29, Calu-6 and human acute monocytic leukaemia cell line (THP-1)] of five cell lines tested. The combination of TNF-α and IFN-γ produced a strong synergistic effect. The use of selective inhibitors of signalling pathways revealed that induction of TG2 by IFN-γ was mediated by phosphoinositide 3-kinase (PI3K), while c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) were required for TNF-α activation. Quantitative polymerase chain reaction (PCR), flow cytometry and Western blot analysis showed that TG2 expression was blocked completely when stimulation by either TNF-α or IFN-γ was performed in the presence of nuclear factor (NF)-κB inhibitors (sulphasalazine and BAY-117082). TG2 was up-regulated substantially by TNF-α and IFN-γ in intestinal mucosa in untreated CD compared with controls. This study shows that IFN-γ, a dominant cytokine in intestinal mucosa in active CD, is the most potent inducer of TG2, and synergism with TNF-α may contribute to exacerbate the pathogenic mechanism of CD. Selective inhibition of signalling pathways may be of therapeutic benefit. PMID:22385244

  1. Commercially Available Antibodies to Human Tumour Necrosis Factor-α Tested for Cross-Reactivity with Ovine and Bovine Tumour Necrosis Factor-α using Flow Cytometric Assays

    PubMed Central

    Dernfalk, J; Waller, K Persson; Johannisson, A

    2004-01-01

    A thorough understanding of the immune system, including the role of different cytokines, during inflammatory diseases in ruminants could lead to the development of new diagnostic methods and treatments. Tumour necrosis factor-α (TNF-α) is an important cytokine in the onset of the inflammatory responses. Unfortunately, the number of studies on cytokines, like TNF-α, in ruminants is limited due to a lack of species-specific reagents. As cytokines have remained rather conserved during evolution, cross-reactivity between animal species may occur. Therefore, the aim of the present study was to investigate 5 commercially available antibodies against human TNF-α for their ability to cross-react with ovine and/or bovine TNF-α, using a bead-based flow cytometric method. Two of the antibody clones (Mab 11 and 6401.1111) showed cross reactivity with ovine recombinant TNF-α in concentrations above 2.5 ng/ml. However, none of the antibodies detected TNF-α in bovine milk, or serum containing known concentrations of bovine TNF-α, as earlier determined with ELISA. The results could be due to inability of the antibodies to cross-react between species, but quenching of the signal by matrix proteins might also have lowered the response. PMID:15535090

  2. Risk of open angle glaucoma due to tumor necrosis factor alpha gene polymorphisms

    PubMed Central

    Hamid, Mona Abdel; Moemen, Leqaa; Labib, Hany; Helmy, Hazem; Elsergany, Tarek

    2016-01-01

    Introduction Axonal degeneration and retinal ganglion cell apoptosis in glaucoma is associated with tumor necrosis factor alpha (TNF-α), which is an important pro-inflammatory cytokine. The aim of this study was to determine the association between the risk of open angle glaucoma (OAG) in the Egyptian population and tumor necrosis factor alpha (TNF-α) gene polymorphisms. Methods Sixty OAG patients and 26 healthy unrelated controls were used to analyze TNF-α polymorphism G-308A using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Results the GG genotype was found at a higher frequency in the controls than in the patients, and the AA and GA genotypes were associated strongly with OAG. Conclusion In this study, we found that the TNF-α polymorphism G-308A was associated significantly with OAG in the Egyptian population. However, there is a need for population-based studies with large numbers of subjects. Also, long-term follow up is required to verify the association between TNF-α polymorphism G-308A and glaucoma susceptibility. PMID:27054008

  3. Interleukin 1 and Tumor Necrosis Factor Inhibit Cardiac Myocyte β -adrenergic Responsiveness

    NASA Astrophysics Data System (ADS)

    Gulick, Tod; Chung, Mina K.; Pieper, Stephen J.; Lange, Louis G.; Schreiner, George F.

    1989-09-01

    Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit β -adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in β -adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that β -receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.

  4. Interleukin-10 and tumour necrosis factor-alpha serum levels in chronic Chagas disease patients.

    PubMed

    Vasconcelos, R H T; Azevedo, E de A N; Diniz, G T N; Cavalcanti, M da G A de M; de Oliveira, W; de Morais, C N L; Gomes, Y de M

    2015-07-01

    In Chagas disease, chronically infected individuals may be asymptomatic or may present cardiac or digestive complications, and it is well known that the human immune response is related to different clinical manifestations. Different patterns of cytokine levels have been previously described in different clinical forms of this disease, but contradictory results are reported. Our aim was to evaluate the serum levels of interleukin-10 and tumour necrosis factor-alpha in patients with asymptomatic and cardiac Chagas disease. The serum interleukin-10 levels in patients with cardiomyopathy were higher than those in asymptomatic patients, mainly in those without heart enlargement. Although no significant difference was observed in serum tumour necrosis factor-alpha levels among the patients, we found that cardiac patients also present high levels of this cytokine, largely those with heart dilatation. Therefore, these cytokines play an important role in chronic Chagas disease cardiomyopathy. Follow-up investigations of these and other cytokines in patients with chronic Chagas disease need to be conducted to improve the understanding of the immunopathology of this disease. PMID:25728555

  5. Prognostic Factors in Cholinesterase Inhibitor Poisoning

    PubMed Central

    Sun, In O; Yoon, Hyun Ju; Lee, Kwang Young

    2015-01-01

    Background Organophosphates and carbamates are insecticides that are associated with high human mortality. The purpose of this study is to investigate the prognostic factors affecting survival in patients with cholinesterase inhibitor (CI) poisoning. Material/Methods This study included 92 patients with CI poisoning in the period from January 2005 to August 2013. We divided these patients into 2 groups (survivors vs. non-survivors), compared their clinical characteristics, and analyzed the predictors of survival. Results The mean age of the included patients was 56 years (range, 16–88). The patients included 57 (62%) men and 35 (38%) women. When we compared clinical characteristics between the survivor group (n=81, 88%) and non-survivor group (n=11, 12%), there were no differences in renal function, pancreatic enzymes, or serum cholinesterase level, except for serum bicarbonate level and APACHE II score. The serum bicarbonate level was lower in non-survivors than in survivors (12.45±2.84 vs. 18.36±4.73, P<0.01). The serum APACHE II score was higher in non-survivors than in survivors (24.36±5.22 vs. 12.07±6.67, P<0.01). The development of pneumonia during hospitalization was higher in non-survivors than in survivors (n=9, 82% vs. n=31, 38%, P<0.01). In multiple logistic regression analysis, serum bicarbonate concentration, APACHE II score, and pneumonia during hospitalization were the important prognostic factors in patients with CI poisoning. Conclusions Serum bicarbonate and APACHE II score are useful prognostic factors in patients with CI poisoning. Furthermore, pneumonia during hospitalization was also important in predicting prognosis in patients with CI poisoning. Therefore, prevention and active treatment of pneumonia is important in the management of patients with CI poisoning. PMID:26411989

  6. Predicting durable response or resistance to antitumor necrosis factor therapy in inflammatory bowel disease

    PubMed Central

    Kopylov, Uri; Seidman, Ernest

    2016-01-01

    Monoclonal antibodies to tumor necrosis factor (TNF) have become a mainstay of the therapeutic armamentarium in inflammatory bowel disease (IBD) over the last 15 years. Although highly effective, primary and secondary nonresponse are common and associated with poor clinical outcomes and significant costs. Multiple clinical, genetic and immunopharmacological factors may impact the response to anti-TNFs. Early stratification of IBD patients by the expected risk of therapeutic failure during the induction and maintenance phases of treatment may allow for treatment optimization and potentially optimal short- and long-term outcomes. The aim of this review is to summarize the current data concerning the potential predictors of therapeutic success and failure of anti-TNFs in IBD. PMID:27366220

  7. SLE - Complex cytokine effects in a complex autoimmune disease: tumor necrosis factor in systemic lupus erythematosus

    PubMed Central

    Aringer, Martin; Smolen, Josef S

    2003-01-01

    Tumor necrosis factor (TNF) is a proinflammatory cytokine and a B-cell growth factor. It has numerous possible effects on T lymphocytes and dendritic cells, and it influences apoptosis. These differential effects may in part explain why patients under TNF-blocker therapy can develop autoantibodies to nuclear antigens, and may shed some light on the finding that low TNF fosters autoimmune disease in some mouse strains. On the contrary, TNF is increased in the blood and in the inflamed kidneys of systemic lupus erythematosus patients. Several studies in lupus-prone mice other than the F1 generation of New Zealand Black mice crossed with New Zealand White mice suggest that TNF is highly proinflammatory in the efferent limb and is potentially detrimental in lupus organ disease. Therefore, TNF blockade probably constitutes an efficacious therapeutic option. PMID:12823847

  8. Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis.

    PubMed

    Matsumoto, Isao; Inoue, Asuka; Takai, Chinatsu; Umeda, Naoto; Tanaka, Yuki; Kurashima, Yuko; Sumida, Takayuki

    2014-07-01

    Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) have proved to be important in rheumatoid arthritis (RA) because the outcome of RA has greatly improved with the recent availability of biologics targeting them. It is well accepted that these cytokines are involved in the activation of the nuclear factor-κB (NF-κB) signaling pathway, but our understanding of the dependency of these pro-inflammatory cytokines and the link between them in RA is currently limited. Recently, we and others proved the importance of TNFα-induced protein (TNFAIP), due to the spontaneous development of arthritis in deficient animals that are dependent on IL-6. To date, nine TNFAIPs have been identified, and TNFAIP3 and TNFAIP9 were found to be clearly associated with mouse and human arthritis. In this review, we compare and discuss recent TNFAIP topics, especially focusing on TNFAIP3 and TNFAIP9 in autoimmune arthritis in mice and humans. PMID:24704577

  9. CD45 negatively regulates tumour necrosis factor and interleukin-6 production in dendritic cells.

    PubMed

    Piercy, Jenny; Petrova, Svetla; Tchilian, Elma Z; Beverley, Peter C L

    2006-06-01

    CD45 is known to regulate signalling through many different surface receptors in diverse haemopoietic cell types. Here we report for the first time that CD45-/- bone marrow dendritic cells (BMDC) are more activated than CD45+/+ cells and that tumour necrosis factor (TNF) and interleukin-6 (IL-6) production by BMDC and splenic dendritic cells (sDC), is increased following stimulation via Toll-like receptor (TLR)3 and TLR9. Nuclear factor-kappaB activation, an important downstream consequence of TLR3 and TLR9 signalling, is also increased in CD45-/- BMDC. BMDC of CD45-/- mice also produce more TNF and IL-6 following stimulation with the cytokines TNF and interferon-alpha. These results show that TLR signalling is increased in CD45-/- dendritic cells and imply that CD45 is a negative regulator of TLR and cytokine receptor signalling in dendritic cells. PMID:16771860

  10. ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5.

    PubMed

    Hsu, H; Solovyev, I; Colombero, A; Elliott, R; Kelley, M; Boyle, W J

    1997-05-23

    Members of tumor necrosis factor receptor (TNFR) family signal largely through interactions with death domain proteins and TRAF proteins. Here we report the identification of a novel TNFR family member ATAR. Human and mouse ATAR contain 283 and 276 amino acids, respectively, making them the shortest known members of the TNFR superfamily. The receptor is expressed mainly in spleen, thymus, bone marrow, lung, and small intestine. The intracellular domains of human and mouse ATAR share only 25% identity, yet both interact with TRAF5 and TRAF2. This TRAF interaction domain resides at the C-terminal 20 amino acids. Like most other TRAF-interacting receptors, overexpression of ATAR activates the transcription factor NF-kappaB. Co-expression of ATAR with TRAF5, but not TRAF2, results in synergistic activation of NF-kappaB, suggesting potentially different roles for TRAF2 and TRAF5 in post-receptor signaling. PMID:9153189

  11. Tumor necrosis factor-{alpha} enhances IL-15-induced natural killer cell differentiation

    SciTech Connect

    Lee, Jiwon; Lee, Suk Hyung; Shin, Nara; Jeong, Mira; Kim, Mi Sun; Kim, Mi Jeong; Yoon, Suk Ran; Chung, Jin Woong; Kim, Tae-Don; Choi, Inpyo

    2009-09-04

    The differentiation of natural killer (NK) cells is regulated by various factors including soluble growth factors and transcription factors. Here, we have demonstrated that tumor necrosis factor-{alpha} (TNF-{alpha}) is a positive regulator of NK cell differentiation. TNF-{alpha} augmented the IL-15-induced expression of NK1.1 and CD122 in mature NK cells, and TNF-{alpha} alone also induced NK cell maturation as well as IL-15. TNF-{alpha} also increased IFN-{gamma} production in NK cells in the presence of IL-15. Meanwhile, mRNA expression of several transcription factors, including T-bet and GATA-3, was increased by the addition of TNF-{alpha} and IL-15. In addition, TNF-{alpha} increased nuclear factor-kappa B (NF-{kappa}B) activity in NK cells and inhibition of NF-{kappa}B impeded TNF-{alpha}-enhanced NK cell maturation. Overall, these data suggest that TNF-{alpha} significantly increased IL-15-driven NK cell differentiation by increasing the expression of transcription factors that play crucial roles in NK cell maturation and inducing the NF-{kappa}B activity.

  12. Ferulic acid enhances the vasorelaxant effect of epigallocatechin gallate in tumor necrosis factor-alpha-induced inflammatory rat aorta.

    PubMed

    Zhao, Jian; Suyama, Aki; Tanaka, Mitsuru; Matsui, Toshiro

    2014-07-01

    Previously, we demonstrated synergistic enhancement of vasorelaxation by combination treatment with Trp-His and epigallocatechin gallate (EGCg) in intact rat aorta. The aim of the present study was to determine whether this vasorelaxant synergy could be recapitulated in tumor necrosis factor-alpha (TNF-α)-induced inflammatory rat aorta, and to determine the extent of its modulation by anti-inflammatory phenolic acids. Synergistic enhancement of vasorelaxation in rat aorta by Trp-His and EGCg was significantly attenuated in the presence of TNF-α, an effect that was reversed by the addition of ferulic acid (FA, 250 μM). Moreover, FA markedly enhanced EGCg-induced vasorelaxation, but not Trp-His-induced vasorelaxation, in TNF-α-treated aorta. Structure-activity analysis showed that the unsaturated 2-propenoic moiety and the methoxy group of FA were important for the enhancement of vasorelaxation by EGCg. The stimulation of EGCg-induced vasorelaxation by FA was antagonized by the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine acetate, while FA enhanced vasorelaxant properties of the endothelial nitric oxide (NO) synthase activator acetylcholine in TNF-α-treated inflammatory aorta. Moreover, the EGCg-stimulated NO production was also enhanced by FA in TNF-α-treated aorta. These data indicate that stimulation of NO production by FA enhances the vasorelaxant properties of EGCg in TNF-α-induced inflammatory aorta. PMID:24794014

  13. Canarypox Virus-Induced Maturation of Dendritic Cells Is Mediated by Apoptotic Cell Death and Tumor Necrosis Factor Alpha Secretion

    PubMed Central

    Ignatius, Ralf; Marovich, Mary; Mehlhop, Erin; Villamide, Loreley; Mahnke, Karsten; Cox, William I.; Isdell, Frank; Frankel, Sarah S.; Mascola, John R.; Steinman, Ralph M.; Pope, Melissa

    2000-01-01

    Recombinant avipox viruses are being widely evaluated as vaccines. To address how these viruses, which replicate poorly in mammalian cells, might be immunogenic, we studied how canarypox virus (ALVAC) interacts with primate antigen-presenting dendritic cells (DCs). When human and rhesus macaque monocyte-derived DCs were exposed to recombinant ALVAC, immature DCs were most susceptible to infection. However, many of the infected cells underwent apoptotic cell death, and dying infected cells were engulfed by uninfected DCs. Furthermore, a subset of DCs matured in the ALVAC-exposed DC cultures. DC maturation coincided with tumor necrosis factor alpha (TNF-α) secretion and was significantly blocked in the presence of anti-TNF-α antibodies. Interestingly, inhibition of apoptosis with a caspase 3 inhibitor also reduced some of the maturation induced by exposure to ALVAC. This indicates that both TNF-α and the presence of primarily apoptotic cells contributed to DC maturation. Therefore, infection of immature primate DCs with ALVAC results in apoptotic death of infected cells, which can be internalized by noninfected DCs driving DC maturation in the presence of the TNF-α secreted concomitantly by exposed cells. This suggests an important mechanism that may influence the immunogenicity of avipox virus vectors. PMID:11070033

  14. Tissue Destruction Induced by Porphyromonas gingivalis Infection in a Mouse Chamber Model Is Associated with Host Tumor Necrosis Factor Generation

    PubMed Central

    Lin, Yuh-Yih; Huang, Jan-Hung; Lai, Yo-Yin; Huang, Han-Ching; Hu, Suh-Woan

    2005-01-01

    Intrachamber challenge with Porphyromonas gingivalis strain 381 in a mouse subcutaneous chamber model results in a local infection that progresses to exfoliation of the chambers within 15 days. This study was designed to elucidate the contribution of host reactions to tissue destruction manifested by chamber exfoliation in animals infected with P. gingivalis. Chamber fluids showed increasing levels of prostaglandin E2 with infection, and the levels of tumor necrosis factor (TNF) in chamber fluids peaked just before chamber exfoliation. Intraperitoneal injection of a TNF inhibitor, thalidomide (TH), reduced the number of exfoliated chambers, while indomethacin had no effect. Exogenous TNF in chambers without bacterial infection did not cause chamber exfoliation but induced neutrophil infiltration. In a dual-chamber model, two chambers were implanted in the same mouse. One chamber was infected with P. gingivalis, and 9 days later exogenous TNF was added to the other chamber. Altogether, 66.67% of uninfected chambers were exfoliated between day 11 and day 16, although no bacteria were recovered from uninfected chambers. TH treatment alleviated both infected and uninfected chamber exfoliation. In this study, tissue destruction caused by P. gingivalis 381 infection was due to the elevation of the TNF levels and not due to local bacterial activities. Our results further indicate that local infection by P. gingivalis 381, a nondisseminating strain, actually has systemic effects on the host pathological outcome. PMID:16299286

  15. Ambient but not incremental oxidant generation effects intercellular adhesion molecule 1 induction by tumour necrosis factor alpha in endothelium.

    PubMed

    Arai, T; Kelly, S A; Brengman, M L; Takano, M; Smith, E H; Goldschmidt-Clermont, P J; Bulkley, G B

    1998-05-01

    Proinflammatory cytokines upregulate endothelial adhesion molecule expression, thereby initiating the microvascular inflammatory response. We re-evaluated the reported role of reactive oxygen metabolites (ROMs) in signalling upregulation of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells by tumour necrosis factor alpha (TNF-alpha) in vitro. TNF-alpha upregulation of endothelial-cell ICAM-1 expression was inhibited by the cell-permeable antioxidants, or by the adenovirus-mediated intracellular overexpression of Cu,Zn-superoxide dismutase, but not by the exogenous (extracellular) administration of the cell-impermeable antioxidants, superoxide dismutase and/or catalase. This ICAM-1 upregulation was also inhibited by inhibitors of NADH dehydrogenase, cytochrome bc1 complex and NADPH oxidase. However, a measurable increase in net cellular ROM generation in response to TNF-alpha was not seen using four disparate sensitive ROM assays. Moreover, the stimulation of exogenous or endogenous ROM generation did not upregulate ICAM-1, nor enhance ICAM-1 upregulation by TNF-alpha. These findings suggest that an ambient background flux of ROMs, generated intracellularly, but not their net incremental generation, is necessary for TNF-alpha to induce ICAM-1 expression in endothelium in vitro. PMID:9560314

  16. [Expression and analysis of the extracellular domain of human glucocorticoid-induced tumor necrosis factor receptor ligand in Escherichia coli].

    PubMed

    Jiao, Yanli; Zheng, Fang; Li, Xiaoxia; Wang, Baoli; Guo, Shanyi

    2009-05-01

    GITRL (Glucocorticoid-induced tumor necrosis factor receptor ligand) has been recently identified as a novel inhibitor of osteoclastogenesis and hence called Osteostat. In this study, we expressed recombinant extracellular domain of GITRL protein in Escherichia coli and analyzed its bioactivity. Using an Eco31I enzyme-based restriction and ligation method, we obtained an E. coli-preferred DNA sequence coding for the extracellular domain of human GITRL. The DNA was cloned into expression vector pQE-30Xa that encodes a fusion tag of 6xHis before the insert. The resultant recombinant expression vector pQE/GITRL was subsequently transformed into E. coli strain M15[pREP4]. After induction with Isopropyl beta-D-Thiogalactoside (IPTG), the cells produced the fusion protein mainly in the form of inclusion bodies as identified by SDS-PAGE. The recombinant protein was purified by affinity chromatography through Ni-NTA column and recognized by anti-His polyclonal antibody using Western blotting analysis. Moreover, we established a simple, efficient and sensitive reporter gene-based method to detect the activity of the recombinant protein. The results showed that the target protein was biologically active. PMID:19670639

  17. Glutathione and the rate of cellular proliferation determine tumour cell sensitivity to tumour necrosis factor in vivo.

    PubMed Central

    Obrador, E; Navarro, J; Mompo, J; Asensi, M; Pellicer, J A; Estrela, J M

    1997-01-01

    Low rates of cellular proliferation are associated with low GSH content and enhanced sensitivity of Ehrlich ascites-tumour (EAT) cells to the cytotoxic effects of recombinant human tumour necrosis factor (rhTNF-alpha). Buthionine sulphoximine, a selective inhibitor of GSH synthesis, inhibited tumour growth and increased rhTNF-alpha cytoxicity in vitro. Administration of sublethal doses (10(6)units/kg per day) of rhTNF-alpha to EAT-bearing mice promoted oxidative stress (as measured by increases in intracellular peroxide levels, O2(-); generation and mitochondrial GSSG) and resulted in a slight reduction (19%) in tumour cell number when controls showed the highest rate of cellular proliferation. ATP (1mmol/kg per day)-induced selective GSH depletion, when combined with rhTNF-alpha administration, afforded a 61% inhibition of tumour growth and resulted in a significant extension of host survival. Administration of N-acetylcysteine (1mmol/kg per day) or GSH ester (5mmol/kg per day) abolished the rhTNF-alpha- and ATP-induced effects on tumour growth by maintaining high GSH levels in the cancer cells. Our results demonstrate that the sensitivity of tumour cells to rhTNF-alpha in vivo depends on their GSH content and their rate of proliferation. PMID:9224645

  18. Transactivation of human immunodeficiency virus type 1 long terminal repeats by cell surface tumor necrosis factor alpha.

    PubMed Central

    Tadmori, W; Mondal, D; Tadmori, I; Prakash, O

    1991-01-01

    Tumor necrosis factor alpha (TNF-alpha) is expressed in secreted and cell surface (csTNF-alpha) forms by activated monocytic and T cells. In this report, we demonstrate that csTNF-alpha may predominantly regulate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) activation in the promonocytic cell line U937 and in the Epstein-Barr virus-transformed B-cell line BH1. Anti-TNF-alpha antibody suppressed both the constitutive expression of the HIV-1 LTR in BH1 cells and the expression induced by phorbol 12-myristate 13-acetate in U937 cells. This suppression was found to be mediated via csTNF-alpha. No correlation between the HIV-1 LTR activation and the secretion of TNF-alpha was evident in these cell lines. Suppression of TNF-alpha secretion by cyclosporin A or by a serine protease inhibitor did not suppress the HIV-1 LTR activation. These observations suggest a novel biological role for csTNF-alpha in the immunopathogenesis of AIDS. PMID:1942242

  19. Establishment and evaluation of a transgenic mouse model of arthritis induced by overexpressing human tumor necrosis factor alpha

    PubMed Central

    Li, Ge; Wu, Yu'e; Jia, Huanhuan; Tang, Lu; Huang, Ren; Peng, Yucai; Zhang, Yu

    2016-01-01

    ABSTRACT Tumor necrosis factor alpha (TNFα) plays a key role in the pathogenesis of rheumatoid arthritis (RA). Blockade of TNFα by monoclonal antibody has been widely used for the therapy of RA since the 1990s; however, its mechanism of efficacy, and potential safety concerns of the treatment are still not fully understood. This study sought to establish a transgenic arthritic mouse model by overexpressing human TNFα (hTNFα) and to apply this model as a means to evaluate therapeutic consequences of TNFα inhibitors. The transgenic mouse line (TgTC) with FVB background was generated by incorporating 3′-modified hTNFα gene sequences. A progressively erosive polyarthritis developed in the TgTC mice, with many characteristics observed in human rheumatoid arthritis, including polyarticular swelling, impairment of movement, synovial hyperplasia, and cartilage and bone erosion. Gene expression analysis demonstrated that hTNFα is not only expressed in hyperplastic synovial membrane, but also in tissues without lesions, including brain, lung and kidney. Treatment of the TgTC mice with anti-hTNFα monoclonal antibodies (mAb) significantly decreased the level of hTNFα in the diseased joint and effectively prevented development of arthritis in a dose-dependent response fashion. Our results indicated that the TgTC mice represent a genetic model which can be used to comprehensively investigate the pathogenesis and therapeutics of TNFα-related diseases. PMID:26977076

  20. Bioinformatic characterization and gene expression pattern of apoptosis inhibitor from Macrobrachium rosenbergii challenged with infectious hypodermal and hematopoietic necrosis virus.

    PubMed

    Arockiaraj, Jesu; Vanaraja, Puganeshwaran; Easwvaran, Sarasvathi; Singh, Arun; Othman, Rofina Yasmin; Bhassu, Subha

    2011-12-01

    Apoptosis is genetically programmed cellular killing processes that execute unnecessary or infected cells. It plays an important role in embryogenesis, homeostasis, insect metamorphosis and immunity. Apoptosis inhibitor (MrIAP) was sequenced from the freshwater giant prawn Macrobrachium rosenbergii using Illumina Solexa Genome Analyzer Technique. MrIAP consisted of 1753 base pair nucleotides encoded 535 polypeptide with an estimated molecular mass of 60 kDa. MrIAP amino acid sequence contains IAP superfamily domain between 5 and 490. The deduced amino acid sequences of the MrIAP were aligned with the other IAP family members. The highest sequence similarity was observed in IAP-5 from ant Camponotus floridanus (67%) followed by IAP from body louse Pediculus humanus corporis (66%) and the lowest (62%) in IAP-5 isoform-5 from common chimpanzee Pan troglodytes and IAP-5 from Aedes aegypti. The IAP phylogenetic tree showed that MrIAP closely related to other arthropod blacklegged tick Ixodes scapularis, formed a sister group with IAP from a hemichordate acorn worm Saccoglossus kowalevskii and finally clustered together with IAPs from fish groups. The quantitative real time PCR analysis revealed that significantly (P < 0.05) highest expression was noticed in hepatopancreas and significantly (P < 0.05) lowest expression in pleopods. Based on the results of gene expression analysis, MrIAP mRNA transcription in M. rosenbergii challenged to infectious hypodermal and hematopoietic necrosis virus (IHHNV) was highly induced in hepatopancreas. The collective results of this study indicate that the MrIAP is an essential immune gene and influences the immune response against IHHNV infection in M. rosenbergii. PMID:21945707

  1. The increased gastroprotective effect of pioglitazone in cholestatic rats: role of nitric oxide and tumour necrosis factor alpha.

    PubMed

    Moezi, Leila; Janahmadi, Zeinab; Amirghofran, Zahra; Nekooeian, Ali Akbar; Dehpour, Ahmad R

    2014-02-01

    The prevalence of gastric ulcers is high in cholestatic patients, but the exact mechanism of this increased frequency remains uncertain. It has been shown that pioglitazone accelerates the healing of pre-existing gastric ulcers. The present study was designed to investigate the effect of pioglitazone, on the gastric mucosal lesions in cholestatic rats. Cholestasis was induced by surgical ligation of common bile duct and sham-operated rats served as control. Different groups of sham and cholestatic animals received solvent or pioglitazone (5, 15, 30 mg/kg) for 7 days. On the day eight rats were killed after oral ethanol administration and the area of gastric lesions was measured. The serums of rats were also collected to determine serum levels of tumour necrosis factor alpha (TNF-α), IL-1β and bilirubin. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than sham-operated ones. Pretreatment with pioglitazone dose-dependently attenuated gastric lesions induced by ethanol in both sham and cholestatic rats, but this effect was more prominent in cholestatic ones. The effect of pioglitazone was associated with a significant fall in serum levels of TNF-α in cholestatic rats. L-NAME, a non-selective nitric oxide synthase (NOS) inhibitor, and decreased pioglitazone-induced gastroprotective effect in cholestatic rats, while aminoguanidine, a selective inducible NOS inhibitor, potentiated pioglitazone-induced gastroprotective effect in the cholestatic rats. Chronic treatment with pioglitazone exerts an enhanced gastroprotective effect on the stomach ulcers of cholestatic rats compared to sham rats probably due to constitutive NOS induction and/or inducible NOS inhibition and attenuating release of TNF-α. PMID:24456333

  2. Paradoxical effects of tumour necrosis factor-α in adjuvant-induced arthritis

    PubMed Central

    Williams, Richard O

    2008-01-01

    Anti-tumour necrosis factor (TNF)α therapy is highly effective in rheumatoid arthritis and it is surprising, therefore, that a recent study showed that intraperitoneal administration of recombinant TNFα reduced the severity of adjuvant-induced arthritis and decreased IFNγ expression in cultured draining lymph node cells. Furthermore, in untreated arthritic rats, maximal TNFα expression in draining lymph node cells coincided with spontaneous disease remission, suggesting a role for endogenous TNFα in recovery from arthritis. If confirmed in further studies, these findings suggest that, in addition to its well-established pro-inflammatory properties, TNFα may also play a disease-limiting role in this model of rheumatoid arthritis by suppressing effector T cell responses. PMID:18564403

  3. Treatment of ulcerative colitis in the cottontop tamarin using antibody to tumour necrosis factor alpha.

    PubMed Central

    Watkins, P E; Warren, B F; Stephens, S; Ward, P; Foulkes, R

    1997-01-01

    BACKGROUND: The aetiology and pathophysiology of ulcerative colitis remains unclear; however, there is increasing recognition of the critical role of inflammatory cytokines in the pathogenesis of this disease. Among these, tumour necrosis factor alpha (TNF alpha) seems to play an important role. AIM: To study the effects of an engineered human monoclonal antibody to TNF alpha (CDP571) in the treatment of idiopathic ulcerative colitis in the cottontop tamarin. METHODS: Six cottontop tamarins with confirmed ulcerative colitis received repeated doses of CDP571. Progression of disease was assessed by measuring both body weight and rectal biopsy pathology. RESULTS: All animals showed a rapid improvement in clinical condition and rectal biopsy pathology that was maintained following completion of the therapy. CONCLUSION: These studies indicate the efficacy of selective antibody therapy to TNF alpha for the treatment of ulcerative colitis in a primate and suggest that similar therapy in human could be of value. Images PMID:9203942

  4. Tumor necrosis factor receptor-associated periodic syndrome managed with the couple canakinumab-alendronate.

    PubMed

    Lopalco, Giuseppe; Rigante, Donato; Vitale, Antonio; Frediani, Bruno; Iannone, Florenzo; Cantarini, Luca

    2015-04-01

    Management of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is puzzling, and therapeutic choices can be complicated, due to both wide genetic heterogeneity and protean clinical phenotype. We report on a 35-year-old female who was diagnosed with TRAPS, after finding the V95M mutation on the TNFRSF1A gene; who was treated in order with etanercept, anakinra, and canakinumab (150 mg/every 8 weeks by subcutaneous injection, then increased to 150 mg every 4 weeks); and who started therapy with oral alendronate (70 mg/weekly) to control her osteoporosis. Alendronate combined with canakinumab led to the optimal clinical control of all TRAPS manifestations and normalization of inflammatory markers. Further studies should be performed to clarify bisphosphonates' role in the scenery of autoinflammatory disorders. PMID:24609716

  5. [Viral transfer of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in gene therapy].

    PubMed

    Wędrowska, Ewelina; Wandtke, Tomasz; Dyczek, Andrzej; Woźniak, Joanna

    2015-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces carcinoma cell death through the extrinsic pathway of apoptosis. Preclinical trials of gene therapy have been conducted using viral transfer of the TRAIL transgene into prostate, bladder, breast, kidney, liver, non-small cell lung cancer and also glioblastoma cells. Experiments in vitro demonstrated the extensive apoptosis of target cells as well as frequent disease regression or remission. TRAIL transfer did not show any side effects, opposite to chemotherapy. Encouraging results of TRAIL-related gene therapy were observed in rheumatoid arthritis and type 1 diabetes. Adenoviral vectors (AdV) encoding TRAIL are the most promising tool in anti-tumor therapy. They have undergone numerous modifications by increasing transfection efficiency and transgene expression in target cells. However, only one clinical phase I trial has been performed. AdV encoding the TRAIL transgene caused local inflammation and apoptosis in patients with prostate cancer. PMID:27259213

  6. Tumor necrosis factor antagonists in the treatment of multicentric reticulohistiocytosis: Current clinical evidence.

    PubMed

    Zhao, Hongjun; Wu, Chunmei; Wu, Mengyun; Zhou, Yaou; Zhu, Honglin; Li, Yisha; You, Yunhui; Luo, Hui; Wang, Lijing; Zuo, Xiaoxia

    2016-07-01

    Multicentric reticulohistiocytosis (MRH) is a rare and debilitating systemic disorder characterized by cutaneous nodules and destructive polyarthritis. Due to its unknown etiology, the treatment of MRH varies with different rates of success, which causes treatment options to be rather independent and empirical. In the present study, a case of a 48‑year‑old woman with a 12‑month history of polyarthralgia and skin nodules was reported. Biopsy samples, which were obtained from her skin eruption exhibited dermal infiltration with histiocytes and multinucleated giant cells. Immunohistochemical staining indicated positivity for CD68. The patient was diagnosed with MRH and treated with a combination therapy of infliximab, prednisolone and methotrexate. Her symptoms improved markedly within 2 weeks. Following the results of this case study, a systematic review of 17 cases of MRH treated with tumor necrosis factor (TNF) antagonists was performed, and the efficacy of anti‑TNF treatment in MRH was analyzed. PMID:27175854

  7. Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease.

    PubMed

    Fernandes, Carlos; Allocca, Mariangela; Danese, Silvio; Fiorino, Gionata

    2015-01-01

    Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient's disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn's disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn's disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease. PMID:25713992

  8. Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

    PubMed Central

    Bonora, M; De Marchi, E; Patergnani, S; Suski, J M; Celsi, F; Bononi, A; Giorgi, C; Marchi, S; Rimessi, A; Duszyński, J; Pozzan, T; Wieckowski, M R; Pinton, P

    2014-01-01

    Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-α) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-α exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-α induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation. PMID:24658399

  9. Tumor necrosis factor antagonists in the treatment of multicentric reticulohistiocytosis: Current clinical evidence

    PubMed Central

    ZHAO, HONGJUN; WU, CHUNMEI; WU, MENGYUN; ZHOU, YAOU; ZHU, HONGLIN; LI, YISHA; YOU, YUNHUI; LUO, HUI; WANG, LIJING; ZUO, XIAOXIA

    2016-01-01

    Multicentric reticulohistiocytosis (MRH) is a rare and debilitating systemic disorder characterized by cutaneous nodules and destructive polyarthritis. Due to its unknown etiology, the treatment of MRH varies with different rates of success, which causes treatment options to be rather independent and empirical. In the present study, a case of a 48-year-old woman with a 12-month history of polyarthralgia and skin nodules was reported. Biopsy samples, which were obtained from her skin eruption exhibited dermal infiltration with histiocytes and multinucleated giant cells. Immunohistochemical staining indicated positivity for CD68. The patient was diagnosed with MRH and treated with a combination therapy of infliximab, prednisolone and methotrexate. Her symptoms improved markedly within 2 weeks. Following the results of this case study, a systematic review of 17 cases of MRH treated with tumor necrosis factor (TNF) antagonists was performed, and the efficacy of anti-TNF treatment in MRH was analyzed. PMID:27175854

  10. Tumour necrosis factor production in Falciparum malaria and its association with schizont rupture.

    PubMed Central

    Kwiatkowski, D; Cannon, J G; Manogue, K R; Cerami, A; Dinarello, C A; Greenwood, B M

    1989-01-01

    To investigate the involvement of tumour necrosis factor (TNF) in human malaria, we studied TNF production in patients infected with Plasmodium falciparum, and in co-cultures of human mononuclear cells and malaria parasites in vitro. In the examined sample, plasma TNF levels of over 39 pg/ml were detected in the plasma of 59% of Gambian children with acute malaria, 17% of convalescents, 9% of children with mild infections other than malaria, and 7% of healthy Gambian adults. Mononuclear cells of acute malaria patients, when stimulated with endotoxin in vitro, secreted twice as much TNF as did those of convalescent individuals, and three times that of healthy adult controls. Erythrocytic cultures of P. falciparum stimulated increased TNF secretion by mononuclear cells from uninfected individuals, and a sharp rise in the rate of secretion occurred shortly after schizont rupture. We suggest that malaria fever is mediated, at least in part, through paroxysmal TNF release associated with schizont rupture. PMID:2680183

  11. Alopecia secondary to anti-tumor necrosis factor-alpha therapy.

    PubMed

    Ribeiro, Lara Beatriz Prata; Rego, Juliana Carlos Gonçalves; Estrada, Bruna Duque; Bastos, Paula Raso; Piñeiro Maceira, Juan Manuel; Sodré, Celso Tavares

    2015-01-01

    Biologic drugs represent a substantial progress in the treatment of chronic inflammatory immunologic diseases. However, its crescent use has revealed seldom reported or unknown adverse reactions, mainly associated with anti-tumor necrosis factor (anti-TNF). Psoriasiform cutaneous reactions and few cases of alopecia can occur in some patients while taking these drugs. Two cases of alopecia were reported after anti-TNF therapy. Both also developed psoriasiform lesions on the body. This is the second report about a new entity described as 'anti-TNF therapy-related alopecia', which combines clinical and histopathological features of both alopecia areata and psoriatic alopecia. The recognition of these effects by specialists is essential for the proper management and guidance of these patients. PMID:25830994

  12. Fatigue mechanisms in patients with cancer: effects of tumor necrosis factor and exercise on skeletal muscle

    NASA Technical Reports Server (NTRS)

    St Pierre, B. A.; Kasper, C. E.; Lindsey, A. M.

    1992-01-01

    Fatigue is a common adverse effect of cancer and its therapy. However, the specific mechanisms underlying cancer fatigue are unclear. One physiologic mechanism may involve changes in skeletal muscle protein stores or metabolite concentration. A reduction in skeletal muscle protein stores may result from endogenous tumor necrosis factor (TNF) or from TNF administered as antineoplastic therapy. This muscle wasting would require patients to exert an unusually high amount of effort to generate adequate contractile force during exercise performance or during extended periods of sitting or standing. This additional effort could result in the onset of fatigue. Additionally, cancer fatigue may develop or become exacerbated during exercise as a consequence of changes in the concentration of skeletal muscle metabolites. These biochemical alterations may interfere with force that is produced by the muscle contractile proteins. These physiologic changes may play a role in the decision to include exercise in the rehabilitation plans of patients with cancer. They also may affect ideas about fatigue.

  13. Tumor necrosis factor and stroke: role of the blood-brain barrier

    PubMed Central

    Pan, Weihong; Kastin, Abba J.

    2008-01-01

    The progression and outcome of stroke is affected by the intricate relationship between the blood-brain barrier (BBB) and tumor necrosis factor α (TNFα). TNFα crosses the intact BBB by a receptor-mediated transport system that is upregulated by CNS trauma and inflammation. In this review, we discuss intracellular trafficking and transcytosis of TNFα, regulation of TNFα transport after stroke, and the effects of TNFα on stroke preconditioning. TNFα can activate cytoprotective pathways by pretreatment or persistent exposure to low doses. This explains the paradoxical observation that transport of this proinflammatory cytokine improves the survival and function of hypoxic cells and of mice with stroke. The dual effects of TNFα may be related to differential regulation of TNFα trafficking downstream to TNFR1 and TNFR2 receptors. As we better understand how peripheral TNFα affects its own transport and modulates neuroregeneration, we may be in a better position to pharmacologically manipulate its regulatory transport system to treat stroke. PMID:17913328

  14. The effect of Escherichia coli lipopolysaccharide and Tumor Necrosis Factor alpha on ovarian function

    PubMed Central

    Williams, Erin J.; Sibley, Kelly; Miller, Aleisha N.; Lane, Elizabeth A.; Fishwick, John; Nash, Deborah M.; Herath, Shan; England, Gary CW; Dobson, Hilary; Sheldon, I. Martin

    2009-01-01

    Problem Pelvic inflammatory disease and metritis are important causes of infertility in humans and domestic animals. Uterine infection with Escherichia coli in cattle is associated with reduced ovarian follicle growth and decreased estradiol secretion. We hypothesized that this effect could be mediated by the bacterial lipopolysaccharide (LPS) or cytokines such as tumor necrosis factor alpha (TNFα). Method of study In vitro, bovine ovarian theca and granulosa cells were treated with LPS or TNFα and steroid secretion measured. In vivo, the effect of LPS or TNFα intrauterine infusion was determined by ovarian ultrasonography and measurement of hormones in cattle. Results LPS reduced granulosa cell estradiol secretion, whilst TNFα decreased theca and granulosa cell androstenedione and estradiol production, respectively. In vivo, fewer animals ovulated following intrauterine infusion with LPS or TNFα. Conclusion LPS and TNFα suppress ovarian cell function, supporting the concept that pelvic inflammatory disease and metritis are detrimental for bovine ovarian health. PMID:19238751

  15. Extensive genetic polymorphism in the human tumor necrosis factor region and relation to extended HLA haplotypes.

    PubMed Central

    Jongeneel, C V; Briant, L; Udalova, I A; Sevin, A; Nedospasov, S A; Cambon-Thomsen, A

    1991-01-01

    We have identified three polymorphic microsatellites (which we call TNFa, TNFb, and TNFc) within a 12-kilobase region of the human major histocompatibility complex (MHC) that includes the tumor necrosis factor (TNF) locus. TNFc is located within the first intron of the TNF-beta gene and has only 2 alleles. TNFa and TNFb are 3.5 kilobases upstream (telomeric) of the TNF-beta gene and have at least 13 and 7 alleles, respectively. TNFa, -b, and -c alleles are in linkage disequilibrium with alleles at other loci within the MHC, including class I, class II, and class III. TNFa, -b, and -c alleles are also associated with extended HLA haplotypes. These TNF polymorphisms will allow a thorough genetic analysis of the involvement of TNF in MHC-linked pathologies. Images PMID:1946393

  16. Tumour necrosis factor-α and adenosine in endotoxin shockleading related cardiovascular symptoms

    PubMed Central

    Seres, T.; Dinya, Z.; Szekanecz, Z.; Szentmiklósi, J.; Bodolay, E.; Szegedi, G.

    1995-01-01

    We have observed uncontrollable cardiogenic shock as a cardiovascular manifestation of systemic inflammatory response syndrome (SIRS) leading to death in a 62-year-old woman. The diagnosis of SIRS was based on the demonstration of endotoxinaemia, and highly elevated plasma levels of tumour necrosis factor (TNF)-α, and interleukin (IL)-10. We suggest that these cytokines may contribute to the terminal SIRS-related arrythmias, impaired myocardial contractility, as well as increased vascular permeability. In addition, the increased production of adenosine, a counter-regulatory mediator of inflammation, may also play a role in cardiodepression. We suggest a relationship between the action of TNF-α , IL-10 and adenosine in the pathogenesis of circulatory symptoms described above. PMID:18475680

  17. Trapped without a diagnosis: Tumour necrosis factor receptor-associated periodic syndrome (TRAPS).

    PubMed

    Kirresh, Ali; Everitt, Alex; Kon, Onn Min; DasGupta, Ranan; Pickering, Matthew C; Lachmann, Helen J

    2016-08-01

    Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant condition caused by mutations in the TNFRSF1A gene. It is characterised by recurrent episodes of myalgia, followed by prolonged fever, migratory rashes, headache, serositis, arthralgia, abdominal pain and periorbital oedema. We describe a 49-year-old man with a self-limiting episode of paraparesis who reported recurrent bouts of abdominal symptoms and headaches since childhood. He had a persistent inflammatory response with night sweats and weight loss. We diagnosed TRAPS 2 years after having identified a TNFRSF1A gene mutation. His symptoms and inflammatory response resolved dramatically with the interleukin-1 receptor antagonist anakinra. PMID:26965498

  18. Phase I study of recombinant human tumor necrosis factor-alpha in patients with advanced malignancies.

    PubMed

    Bartsch, H H; Nagel, G A; Mull, R; Flener, R; Pfizenmaier, K

    1988-01-01

    A clinical phase I trial with recombinant human tumor necrosis factor-alpha (rTNF-alpha) was performed in 30 patients with advanced malignancies. The maximal tolerated dose (MTD) by 3 times weekly intramuscular (i.m.) application was 150 micrograms m-2. Main subjective toxicities including chills, fever, hypotension, fatigue, and anorexia were dose-related. In addition, transient changes in hematologic parameters and lipid metabolism were noted. Two out of 25 evaluated patients showed a minor tumor response after eight weeks of therapy. There was evidence for an improvement of in vivo immuneresponsiveness as revealed from positive delayed type hypersensitivity (DTH) skin tests of 3 out of 6 pretherapeutically anergic patients. We conclude from this phase I trial that rTNF-alpha can be safely administered at doses up to 150 micrograms m-2 i.m., 3 times weekly, without evidence of cumulative toxicity in long-term treatment. PMID:3267369

  19. Modulation of Endogenous Hormone Action by Recombinant Human Tumor Necrosis Factor

    NASA Astrophysics Data System (ADS)

    Warren, Robert S.; Donner, David B.; Fletcher Starnes, H.; Brennan, Murray F.

    1987-12-01

    Tumor necrosis factor (TNF) has been implicated in the toxic manifestations of overwhelming bacterial infection and in the tissue wasting that often accompanies prolonged infections and malignancy. We have examined a possible role of TNF in the early metabolic alterations following acute tissue injury or sepsis. Recombinant human TNF stimulated rat liver amino acid uptake up to 5-fold in vivo and there was a concomitant increase in plasma glucagon. In vitro TNF had no direct effect on hepatocyte amino acid uptake, but it markedly enhanced the stimulation of amino acid transport by glucagon, without an alteration in binding of glucagon to hepatocytes. This permissive effect of TNF on glucagon action represents an interrelationship between the immune and endocrine systems, and it may help to explain the mechanism of hormonal regulation of both the anabolic and catabolic responses to acute injury.

  20. Targeting of the Tumor Necrosis Factor Receptor Superfamily for Cancer Immunotherapy

    PubMed Central

    2013-01-01

    The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective induction of cell death in potentially dangerous and superfluous cells to providing costimulatory signals that help mount an effective immune response. This diverse and important regulatory role in immunity has sparked great interest in the development of TNFL/TNFR-targeted cancer immunotherapeutics. In this review, I will discuss the biology of the most prominent proapoptotic and co-stimulatory TNF ligands and review their current status in cancer immunotherapy. PMID:23840967

  1. Phospholipase C-{delta}{sub 1} regulates interleukin-1{beta} and tumor necrosis factor-{alpha} mRNA expression

    SciTech Connect

    Chung, Eric; Jakinovich, Paul; Bae, Aekyung; Rebecchi, Mario

    2012-10-01

    Phospholipase C-{delta}{sub 1} (PLC{delta}{sub 1}) is a widely expressed highly active PLC isoform, modulated by Ca{sup 2+} that appears to operate downstream from receptor signaling and has been linked to regulation of cytokine production. Here we investigated whether PLC{delta}{sub 1} modulated expression of the pro-inflammatory cytokines interleukin-1{beta} (IL-1{beta}), tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6 (IL-6) in rat C6 glioma cells. Expression of PLC{delta}{sub 1} was specifically suppressed by small interfering RNA (siRNA) and the effects on cytokine mRNA expression, stimulated by the Toll-like receptor (TLR) agonist, lipopolysaccharide (LPS), were examined. Real-time polymerase chain reaction (RT-PCR) results showed that PLC{delta}{sub 1} knockdown enhanced expression IL-1{beta} and tumor necrosis factor-{alpha} (TNF-{alpha}) mRNA by at least 100 fold after 4 h of LPS stimulation compared to control siRNA treatment. PLC{delta}{sub 1} knock down caused persistently high Nf{kappa}b levels at 4 h of LPS stimulation compared to control siRNA-treated cells. PLC{delta}{sub 1} knockdown was also associated with elevated nuclear levels of c-Jun after 30 min of LPS stimulation, but did not affect LPS-stimulated p38 or p42/44 MAPK phosphorylation, normally associated with TLR activation of cytokine gene expression; rather, enhanced protein kinase C (PKC) phosphorylation of cellular proteins was observed in the absence of LPS stimulation. An inhibitor of PKC, bisindolylmaleimide II (BIM), reversed phosphorylation, prevented elevation of nuclear c-Jun levels, and inhibited LPS-induced increases of IL-1{beta} and TNF-{alpha} mRNA's induced by PLC{delta}{sub 1} knockdown. Our results show that loss of PLC{delta}{sub 1} enhances PKC/c-Jun signaling and up-modulates pro-inflammatory cytokine gene transcription in concert with the TLR-stimulated p38MAPK/Nf{kappa}b pathway. Our findings are consistent with the idea that PLC{delta}{sub 1} is a

  2. Use of the tumor necrosis factor-blockers for Crohn's disease

    PubMed Central

    Thomson, Alan BR; Gupta, Milli; Freeman, Hugh J

    2012-01-01

    The use of anti-tumor necrosis factor-α therapy for inflammatory bowel disease represents the most important advance in the care of these patients since the publication of the National Co-operative Crohn’s disease study thirty years ago. The recommendations of numerous consensus groups worldwide are now supported by a wealth of clinical trials and several meta-analyses. In general, it is suggested that tumor necrosis factor-α blockers (TNFBs) are indicated (1) for persons with moderately-severe Crohn’s disease or ulcerative colitis (UC) who have failed two or more causes of glucocorticosteroids and an acceptably long cause (8 wk to 12 wk) of an immune modulator such as azathioprine or methotrexate; (2) non-responsive perianal disease; and (3) severe UC not responding to a 3-d to 5-d course of steroids. Once TNFBs have been introduced and the patient is responsive, therapy given by the IV and SC rate must be continued. It remains open to definitive evidence if concomitant immune modulators are required with TNFB maintenance therapy, and when or if TNFB may be weaned and discontinued. The supportive evidence from a single study on the role of early versus later introduction of TNFB in the course of a patient’s illness needs to be confirmed. The risk/benefit profile of TNFB appears to be acceptable as long as the patient is immunized and tested for tuberculosis and viral hepatitis before the initiation of TNFB, and as long as the long-term adverse effects on the development of lymphoma and other tumors do not prone to be problematic. Because the rates of benefits to TNFB are modest from a population perspective and the cost of therapy is very high, the ultimate application of use of TNFBs will likely be established by cost/benefit studies. PMID:23002356

  3. Tumor necrosis factor alpha negatively regulates hepatitis B virus gene expression in transgenic mice.

    PubMed Central

    Gilles, P N; Fey, G; Chisari, F V

    1992-01-01

    It is well known that several inflammatory cytokines can modulate hepatocellular gene expression in a complex physiological process known as the hepatic acute-phase response. Since hepatitis B virus (HBV) characteristically induces a vigorous lymphomononuclear inflammatory response in the liver during acute and chronic hepatitis, it is possible that hepatocellular HBV gene expression may also be modulated by one or more of the cytokines produced by these cells. Using bacterial lipopolysaccharide (LPS) as a surrogate inducer of inflammatory cytokines in vivo, we have tested this hypothesis in a transgenic mouse model system. In experiments with two independent transgenic mouse lineages that express the HBV envelope region under the control of either HBV or cellular promoters, we observed a 50 to 80% reduction in the hepatic steady-state content of a 2.1-kb HBV mRNA following administration of a single intraperitoneal dose of LPS. The regulatory influence of several inflammatory cytokines known to be induced by LPS was also examined in this system. The negative regulatory effect of LPS was consistently reproduced by the administration of a single nontoxic dose of tumor necrosis factor alpha, and it was occasionally observed following the administration of high doses of alpha interferon and interleukin-6, while no effect was detectable in response to high-dose interleukin-1 alpha or to gamma interferon. These observations suggest that tumor necrosis factor alpha and perhaps other cytokines may activate a heretofore unsuspected intracellular pathway that negatively regulates HBV gene expression. The intracellular mechanism(s) responsible for this effect and its pathophysiologic relevance remain to be elucidated. Images PMID:1583737

  4. Tumor necrosis factor primes hepatocytes for DNA replication in the rat.

    PubMed

    Webber, E M; Bruix, J; Pierce, R H; Fausto, N

    1998-11-01

    Signaling through tumor necrosis factor receptor type 1 (TNFR-1) using a pathway that involves nuclear factor kappaB (NF-kappaB), interleukin-6 (IL-6), and STAT3 is required for the initiation of liver regeneration. We have proposed that TNF primes hepatocytes to respond to the mitogenic effect of growth factors, but so far, there has been no experimental demonstration that TNF enhances growth factor responses of hepatocytes. To test this hypothesis, we infused hepatocyte growth factor (HGF) and transforming growth factor (TGF-) (40 microgram/24 h) directly into the portal vein of rats for 24 hours using osmotic pumps and determined whether TNF injection (5 microgram per rat) would significantly increase hepatocyte DNA labeling in these animals. All rats received 5-bromo-2'-deoxyuridine (BrdU) by intraperitoneal delivery during a 48-hour period (i.e., BrdU infusion continued for 24 hours after the end of growth factor administration). BrdU labeling in the liver was measured by both immunohistochemistry and flow cytometry, and the results obtained by these methods showed excellent concordance. The results demonstrate that TNF transiently activates NF-kappaB and STAT3 and increases the proliferative response of hepatocytes to HGF or TGF- by fourfold. Priming effects on hepatocyte DNA replication were also obtained with injection of lipopolysaccharide (LPS) and gadolinium chloride (GdCl3), agents that release TNF in the liver. Similarly to TNF, GdCl3 injection caused the activation of NF-kappaB and STAT3, reaching a maximum 8 to 12 hours after the injection. The results show that TNF acts as a primer to sensitize hepatocytes to the proliferative effects of growth factors and offers a mechanism to explain the initiation and progression phases of liver regeneration after partial hepatectomy (PH). PMID:9794905

  5. Tumour necrosis factor (TNF) as a mediator of macrophage helminthotoxic activity.

    PubMed

    James, S L; Glaven, J; Goldenberg, S; Meltzer, M S; Pearce, E

    1990-01-01

    Lymphokine-activated macrophages are cytotoxic for larvae of the helminth parasite Schistosoma mansoni. That soluble secreted factors may mediate this cytotoxicity was suggested by the observation that culture supernatant fluids from stimulated macrophages also exhibited larvacidal activity. These fluids contain the monokine tumour necrosis factor (TNF). Several observations indicated that TNF is directly toxic to schistosome larvae. Cytotoxic sera taken from BCG- or S. mansoni-immunized mice after endotoxin challenge killed schistosomula in vitro, and upon gel filtration the larvacidal factor(s) in the sera co-eluted with the tumoricidal activity defined as TNF. Recombinant-derived TNF exhibited direct toxicity to schistosomula at high concentrations, or at lower concentrations in the presence of IFN gamma. The larvacidal activity of macrophage supernatant fluids was abrogated by addition of either anti-TNF antisera or Zn+2, which has been shown to inhibit TNF-induced damage of tumour cells. Anti-TNF and Zn+2 likewise suppressed schistosomulum killing by lymphokine-activated peritoneal macrophages or the IC-21 macrophage line, indicating that TNF also plays a role in the effector mechanism of larval killing by whole cells. PMID:2314921

  6. Multiorgan chronic inflammatory hepatobiliary pancreatic murine model deficient in tumor necrosis factor receptors 1 and 2

    PubMed Central

    Oz, Helieh S

    2016-01-01

    AIM: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues. METHODS: Tumor necrosis factor receptors 1 and 2 (TNFR1/R2) deficient mice reared in-house were given dibutyltin dichloride (DBTC) twice within 10 d by oral gavage delivery. Sham control animals received vehicle treatment and naïve animals remained untreated throughout the study. Animals were monitored daily for symptoms of pain and discomfort. The abdominal and hindpaw hypersensitivity were assessed with von Frey microfilaments. Exploratory behaviors were recorded at the baseline, after initiation of treatment, and before study termination. Histopathological changes were examined postmortem in tissues. Collagen accumulation and fibrosis were confirmed with Sirius Red staining. RESULTS: Animals lost weight after oral administration of DBTC and developed persistent inflammatory abdominal and hindpaw hypersensitivity compared to sham-treated controls (P < 0.0001). These pain related secondary mechanical hypersensitivity responses increased more than 2-fold in DBTC-treated animals. The drastically diminished rearing and grooming rates persisted after DBTC administration throughout the study. Gross as well as micropathology at one month confirmed that animals treated with DBTC developed chronic hepatobiliary injuries evidenced with activation of stellate cells, multifocal necrosis, fatty degeneration of hepatocytes, periportal infiltration of inflammatory cells, and prominent biliary ductal dilation. The severity of hepatitis was scored 3.7 ± 0.2 (severe) in DBTC-treated animals vs score 0 (normal) in sham-treated animals. Fibrotic thickening was extensive around portal ducts, in hepatic parenchyma as well as in lobular pancreatic structures and confirmed with Sirius Red histopathology. In addition, pancreatic microarchitecture was presented with distortion of islets, and parenchyma, infiltration of

  7. Tumor necrosis factor-alpha and interleukin-1 antagonists alleviate inflammatory skin changes associated with epidermal growth factor receptor antibody therapy in mice.

    PubMed

    Surguladze, David; Deevi, Dhanvanthri; Claros, Nidia; Corcoran, Erik; Wang, Su; Plym, Mary Jane; Wu, Yan; Doody, Jacqueline; Mauro, David J; Witte, Larry; Busam, Klaus J; Pytowski, Bronek; Rodeck, Ulrich; Tonra, James R

    2009-07-15

    Cancer patients receiving epidermal growth factor receptor (EGFR) antibody therapy often experience an acneiform rash of uncertain etiology in skin regions rich in pilosebaceous units. Currently, this condition is treated symptomatically with very limited, often anecdotal success. Here, we show that a monoclonal antibody targeting murine EGFR, ME1, caused a neutrophil-rich hair follicle inflammation in mice, similar to that reported in patients. This effect was preceded by the appearance of lipid-filled hair follicle distensions adjacent to enlarged sebaceous glands. The cytokine tumor necrosis factor-alpha (TNFalpha), localized immunohistochemically to this affected region of the pilosebaceous unit, was specifically up-regulated by ME1 in skin but not in other tissues examined. Moreover, skin inflammation was reduced by cotreatment with the TNFalpha signaling inhibitor, etanercept, indicating the involvement of TNFalpha in this inflammatory process. Interleukin-1, a cytokine that frequently acts in concert with TNFalpha, is also involved in this process given the efficacy of the interleukin-1 antagonist Kineret. Our results provide a mechanistic framework to develop evidence-based trials for EGFR antibody-induced skin rash in patients with cancer. PMID:19584274

  8. Local delivery of antitumor necrosis factor-α through conjugation to hyaluronic acid: dosing strategies and early healing effects in a rat burn model.

    PubMed

    Friedrich, Emily E; Azofiefa, Andrea; Fisch, Evan; Washburn, Newell R

    2015-01-01

    The objective of this study was to measure dose-response effects of topical delivery of inhibitors of tumor necrosis factor-α (TNF-α) through conjugation to hyaluronic acid in a rat burn model to determine effects on inflammatory responses, burn progression, and early stages of healing. Monoclonal antibodies against TNF-α were conjugated to hyaluronic acid and applied topically in a rat partial-thickness burn model. Metrics of inflammatory responses and tissue necrosis were measured as well as the quantitative analysis of collagen composition and organization. The minimum effective conjugated antibody dose was found to be 100 μg with three applications 48 hours apart. Nonviable tissue thicknesses decreased with increasing dose and dose frequency. Free antibody retarded macrophage infiltration in the periphery but not at the surface, while the conjugated antibody was able to hinder macrophage infiltration at both the periphery and the surface. Quantification of collagen I and III staining ratios at days 4, 7, and 14 and quantitative image analysis of collagen organization at day 14 demonstrated differences between saline and conjugate treatment. This correlated with increases in re-epithelialization observed in conjugate-treated sites. Reductions in inflammatory markers and secondary tissue necrosis under treatment with the conjugates were understood in terms of differences in antibody transport compared to nonconjugated antibody. Differences in collagen composition and organization at Day 14 suggested that the reductions in inflammatory responses altered early healing responses. These results indicate anti-TNF-α conjugated to hyaluronic acid can be an effective treatment for reducing secondary necrosis and improving healing outcomes in burns. PMID:25526179

  9. Lithium chloride potentiates tumor necrosis factor-mediated cytotoxicity in vitro and in vivo.

    PubMed Central

    Beyaert, R; Vanhaesebroeck, B; Suffys, P; Van Roy, F; Fiers, W

    1989-01-01

    Tumor necrosis factor (TNF) is cytotoxic for several transformed cell lines in vitro. In the presence of LiCl, the murine fibrosarcoma cell lines L929 and WEHI 164 clone 13 became greater than 10 times more sensitive to TNF-mediated cytotoxicity. The human tumor cell lines BT20 and HeLa D98/AH2 were also responsive to the cytotoxicity-enhancing effect of LiCl. Other monovalent or divalent cations did not affect TNF-mediated cytotoxicity. The potentiating effect of LiCl on TNF cytotoxicity was largely independent of transcription, and LiCl could be added to the cells as early as 2 hr before or as late as 4 hr after TNF without loss of effectiveness. The mechanism by which LiCl increases the cytotoxic response seems to differ from the sensitizing effect of actinomycin D or interferon gamma, since the latter treatments overcame TNF resistance of several cell lines, whereas LiCl did not. Evidence is presented that LiCl acts, either directly or indirectly, via the TNF-activated phospholipase A2 pathway. In nude mice, a combination of TNF and LiCl led to hemorrhagic necrosis and growth inhibition of L929 tumors, whereas little effect was observed when TNF was administered alone. HeLa D98/AH2 tumors also were sensitive to the potentiating effect of LiCl in vivo. We conclude that LiCl enhances the effectiveness of TNF in vitro and in vivo, results that may have therapeutic implications. PMID:2556714

  10. Activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB in tumour necrosis factor-induced eotaxin release of human eosinophils

    PubMed Central

    WONG, C K; ZHANG, J P; IP, W K; LAM, C W K

    2002-01-01

    The CC chemokine eotaxin is a potent eosinophil-specific chemoattractant that is crucial for allergic inflammation. Allergen-induced tumour necrosis factor (TNF) has been shown to induce eotaxin synthesis in eosinophils. Nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPK) have been found to play an essential role for the eotaxin-mediated eosinophilia. We investigated the modulation of NF-κB and MAPK activation in TNF-induced eotaxin release of human eosinophils. Human blood eosinophils were purified from fresh buffy coat using magnetic cell sorting. NF-κB pathway-related genes were evaluated by cDNA expression array system. Degradation of IκBα and phosphorylation of MAPK were detected by Western blot. Activation of NF-κB was determined by electrophoretic mobility shift assay. Eotaxin released into the eosinophil culture medium was measured by ELISA. TNF was found to up-regulate the gene expression of NF-κB and IκBα in eosinophils. TNF-induced IκBα degradation was inhibited by the proteasome inhibitor N-cbz-Leu-Leu-leucinal (MG-132) and a non-steroidal anti-inflammatory drug sodium salicylate (NaSal). Using EMSA, both MG-132 and NaSal were found to suppress the TNF-induced NF-κB activation in eosinophils. Furthermore, TNF was shown to induce phosphorylation of p38 MAPK time-dependently but not extracellular signal-regulated kinases (ERK). Inhibition of NF-κB activation and p38 MAPK activity decreased the TNF-induced release of eotaxin from eosinophils. These results indicate that NF-κB and p38 MAPK play an important role in TNF-activated signalling pathway regulating eotaxin release by eosinophils. They have also provided a biochemical basis for the potential of using specific inhibitors of NF-κB and p38 MAPK for treating allergic inflammation. PMID:12067303

  11. Tumor necrosis factor-α modifies the effects of Shiga toxin on glial cells.

    PubMed

    Leu, Hue; Sugimoto, Naotoshi; Shimizu, Masaki; Toma, Tomoko; Wada, Taizo; Ohta, Kunio; Yachie, Akihiro

    2016-09-01

    Shiga toxin (STX) is one of the main factors inducing hemorrhagic colitis and hemolytic-uremic syndrome (HUS) in infections with STX-producing Escherichia coli (STEC). Approximately 62% of patients with HUS showed symptoms of encephalopathy in the 2011 Japanese outbreak of STEC infections. At that time, we reported elevated serum concentrations of tumor necrosis factor (TNF)-α in patients with acute encephalopathy during the HUS phase. In the current study, we investigated whether TNF-α augments the effects of STX in glial cell lines and primary glial cells. We found that TNF-α alone or STX in combination with TNF-α activates nuclear factor-κB (NF-κB) signaling and inhibits growth of glial cells. The magnitude of the NF-κB activation and the inhibition of cell growth by the STX and TNF-α combination was greater than that obtained with TNF-α alone or STX alone. Thus, this in vitro study reveals the role of TNF-α in glial cells during STEC infections. PMID:27268285

  12. Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols.

    PubMed

    Gupta, Subash C; Tyagi, Amit K; Deshmukh-Taskar, Priya; Hinojosa, Myriam; Prasad, Sahdeo; Aggarwal, Bharat B

    2014-10-01

    Human tumor necrosis factor (TNF), first isolated by our group as an anticancer agent, has been now shown to be a primary mediator of inflammation. Till today 19 different members of the TNF superfamily which interact with 29 different receptors, have been identified. Most members of this family exhibit pro-inflammatory activities, in part through the activation of the transcription factor, nuclear factor-kappaB (NF-κB). Thus TNF and the related pro-inflammatory cytokines have been shown to play a key role in most chronic diseases such as cancer, rheumatoid arthritis, cardiovascular diseases, psoriasis, neurologic diseases, Crohn's disease, and metabolic diseases. Therefore, agents that can modulate the TNF-mediated inflammatory pathways may have potential against these pro-inflammatory diseases. Although blockers of TNF-α, such as infliximab (antibody against TNF-α), adalimumab (humanized antibody against TNF-α), and etanercept (soluble form of TNFR2) have been approved for human use, these blockers exhibit numerous side effects. In this review, we describe various plant-derived polyphenols that can suppress TNF-α activated inflammatory pathways both in vitro and in vivo. These polyphenols include curcumin, resveratrol, genistein, epigallocatechin gallate, flavopiridol, silymarin, emodin, morin isoliquiritigenin, naringenin, ellagic acid, apigenin, kaempferol, catechins, myricetin, xanthohumol, fisetin, vitexin, escin, mangostin and others. Thus these polyphenols are likely to have potential against various pro-inflammatory diseases. PMID:24946050

  13. Environmental and Pathogenic Factors Inducing Brown Apical Necrosis on Fruit of English (Persian) Walnut.

    PubMed

    Scotton, Michele; Bortolin, Enrico; Fiorin, Antonio; Belisario, Alessandra

    2015-11-01

    Brown apical necrosis (BAN) is a most recently described disease affecting English (Persian) walnut fruit. BAN was only recorded in intensively managed walnut orchards and was found to be a disease complex mainly caused by Fusarium species. All fungi associated with this disease are polyphagous and ubiquitous, not specific to walnut. Consequently, BAN occurrence is more strictly dependent, than generally, on the interaction between pathological features and environmental conditions. Environmental variables identified with regression analysis showed that maximum temperature, angle of main wind direction versus tree row orientation, and orchard distance to the closest river/canal, all representative of climatic conditions occurring in the orchard, were related to fruit drop. The factor displaying the highest influence on severity of BAN fruit drop was maximum temperature and only subordinately factors are associated with relative humidity. BAN symptoms were reproduced with in planta artificial inoculation, and fruit drop of symptomatic fruit was significantly higher than that of the noninoculated trees for each type of inoculum (Fusarium semitectum, F. graminearum, and Alternaria spp.). F. semitectum and F. graminearum were more aggressive than Alternaria species, and the earliest artificial inoculations in mid-May resulted in the highest fruit drop. The extension of walnut fruit susceptibility and the conducive environmental factors to BAN are discussed. PMID:26214123

  14. Role of Reactive Oxygen Species in Tumor Necrosis Factor-alpha Induced Endothelial Dysfunction

    PubMed Central

    Chen, Xiuping; Andresen1, Bradley T.; Hill, Michael; Zhang, Jing; Booth, Frank; Zhang, Cuihua

    2010-01-01

    Endothelial cell injury and dysfunction are the major triggers of pathophysiological processes leading to cardiovascular disease. Endothelial dysfunction (ED) has been implicated in atherosclerosis, hypertension, coronary artery disease, vascular complications of diabetes, chronic renal failure, insulin resistance and hypercholesterolemia. Although now recognized as a class of physiological second messengers, reactive oxygen species (ROS) are important mediators in cellular injury, specifically, as a factor in endothelial cell damage. Uncontrolled ROS production and/or decreased antioxidant activity results in a deleterious state referred to as ‘oxidative stress’. A candidate factor in causing ROS production in endothelial cells is tumor necrosis factor alpha (TNF-α), a pleiotropic inflammatory cytokine. TNF-α has been shown to both be secreted by endothelial cells and to induce intracellular ROS formation. These observations provide a potential mechanism by which TNF-α may activate and injure endothelial cells resulting in ED. In this review, we focus on the relationship between intracellular ROS formation and ED in endothelial cells or blood vessels exposed to TNF-α to provide insight into the role of this important cytokine in cardiovascular disease. PMID:20559453

  15. Small Molecule Inhibitors of Anthrax Lethal Factor Toxin

    PubMed Central

    Williams, John D.; Khan, Atiyya R.; Cardinale, Steven C.; Butler, Michelle M.; Bowlin, Terry L.; Peet, Norton P.

    2014-01-01

    This manuscript describes the preparation of new small molecule inhibitors of Bacillus anthracis lethal factor. Our starting point was the symmetrical, bis-quinolinyl compound 1 (NSC 12155). Optimization of one half of this molecule led to new LF inhibitors that were desymmetrized to afford more drug-like compounds. PMID:24290062

  16. Rheumatoid arthritis, anti-tumour necrosis factor treatment, and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden

    PubMed Central

    Simard, Julia F; Asker Hagelberg, Charlotte; Askling, Johan

    2016-01-01

    Objective To investigate the risk of squamous cell and basal cell skin cancer in patients with rheumatoid arthritis naive to biologic drugs, in patients starting tumour necrosis factor (TNF) inhibitor treatment, and in the general population. Design Population based cohort study. Setting Nationwide data from Sweden. Participants Cohort of patients with rheumatoid arthritis naive to biologics (n=46 409), cohort of patients with rheumatoid arthritis starting TNF inhibitor treatment as first biologic in 1998-2012 (n=12 558), and matched general population comparator cohort, identified through national quality of care and health registers. Main outcome measure Hazard ratio of first in situ or invasive squamous cell skin cancer (1998-2012) and first basal cell cancer (2004-12). Results For basal cell cancer, the hazard ratio was 1.22 (95% confidence interval 1.07 to 1.41) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.14 (0.98 to 1.33; 236 v 1587 events) comparing TNF inhibitor treated patients with biologics-naive patients. For squamous cell cancer, the hazard ratio was 1.88 (1.74 to 2.03) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.30 (1.10 to 1.55; 191 v 847 events) comparing TNF inhibitors with biologics-naive patients; the latter translated to an annual number needed to harm in the order of 1600. Among people with a history of squamous cell or basal cell cancer, TNF inhibitors did not further increase risks. Conclusion A small to moderately increased risk of basal cell cancer was seen in biologics-naive rheumatoid arthritis patients, with no further effect of TNF inhibitors. For squamous cell cancer, the risk was nearly doubled in biologics-naive patients, with a further 30% increase in risk among patients treated with TNF inhibitors; this translates to one additional case for every 1600 years of treatment experience, assuming that this association reflected causality

  17. Tumor necrosis factor alpha transcription in macrophages is attenuated by an autocrine factor that preferentially induces NF-kappaB p50.

    PubMed

    Baer, M; Dillner, A; Schwartz, R C; Sedon, C; Nedospasov, S; Johnson, P F

    1998-10-01

    Macrophages are a major source of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), which are expressed during conditions of inflammation, infection, or injury. We identified an activity secreted by a macrophage tumor cell line that negatively regulates bacterial lipopolysaccharide (LPS)-induced expression of TNF-alpha. This activity, termed TNF-alpha-inhibiting factor (TIF), suppressed the induction of TNF-alpha expression in macrophages, whereas induction of three other proinflammatory cytokines (interleukin-1beta [IL-1beta], IL-6, and monocyte chemoattractant protein 1) was accelerated or enhanced. A similar or identical inhibitory activity was secreted by IC-21 macrophages following LPS stimulation. Inhibition of TNF-alpha expression by macrophage conditioned medium was associated with selective induction of the NF-kappaB p50 subunit. Hyperinduction of p50 occurred with delayed kinetics in LPS-stimulated macrophages but not in fibroblasts. Overexpression of p50 blocked LPS-induced transcription from a TNF-alpha promoter reporter construct, showing that this transcription factor is an inhibitor of the TNF-alpha gene. Repression of the TNF-alpha promoter by TIF required a distal region that includes three NF-kappaB binding sites with preferential affinity for p50 homodimers. Thus, the selective repression of the TNF-alpha promoter by TIF may be explained by the specific binding of inhibitory p50 homodimers. We propose that TIF serves as a negative autocrine signal to attenuate TNF-alpha expression in activated macrophages. TIF is distinct from the known TNF-alpha-inhibiting factors IL-4, IL-10, and transforming growth factor beta and may represent a novel cytokine. PMID:9742085

  18. Tumor Necrosis Factor Alpha Transcription in Macrophages Is Attenuated by an Autocrine Factor That Preferentially Induces NF-κB p50

    PubMed Central

    Baer, Mark; Dillner, Allan; Schwartz, Richard C.; Sedon, Constance; Nedospasov, Sergei; Johnson, Peter F.

    1998-01-01

    Macrophages are a major source of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), which are expressed during conditions of inflammation, infection, or injury. We identified an activity secreted by a macrophage tumor cell line that negatively regulates bacterial lipopolysaccharide (LPS)-induced expression of TNF-α. This activity, termed TNF-α-inhibiting factor (TIF), suppressed the induction of TNF-α expression in macrophages, whereas induction of three other proinflammatory cytokines (interleukin-1β [IL-1β], IL-6, and monocyte chemoattractant protein 1) was accelerated or enhanced. A similar or identical inhibitory activity was secreted by IC-21 macrophages following LPS stimulation. Inhibition of TNF-α expression by macrophage conditioned medium was associated with selective induction of the NF-κB p50 subunit. Hyperinduction of p50 occurred with delayed kinetics in LPS-stimulated macrophages but not in fibroblasts. Overexpression of p50 blocked LPS-induced transcription from a TNF-α promoter reporter construct, showing that this transcription factor is an inhibitor of the TNF-α gene. Repression of the TNF-α promoter by TIF required a distal region that includes three NF-κB binding sites with preferential affinity for p50 homodimers. Thus, the selective repression of the TNF-α promoter by TIF may be explained by the specific binding of inhibitory p50 homodimers. We propose that TIF serves as a negative autocrine signal to attenuate TNF-α expression in activated macrophages. TIF is distinct from the known TNF-α-inhibiting factors IL-4, IL-10, and transforming growth factor β and may represent a novel cytokine. PMID:9742085

  19. Tumor necrosis factor-alpha-induced apoptosis in hepatocytes in long-term culture.

    PubMed Central

    Bour, E. S.; Ward, L. K.; Cornman, G. A.; Isom, H. C.

    1996-01-01

    Apoptosis occurs naturally in the liver and increases in specific pathogenic processes. We previously described the use of a chemically defined medium supplemented with epidermal growth factor and dimethylsulfoxide to maintain rat hepatocytes in a highly differentiated state for more than 30 days (long-term culture). In this study, we showed that hepatocytes in long-term dimethylsulfoxide culture have definite advantages over using cells in short-term culture (cells in culture for 2 to 4 days) to study apoptosis. We demonstrated that treatment with tumor necrosis factor (TNF)-alpha induced apoptosis (detected morphologically and by formation of an oligonucleosomal DNA ladder) only in hepatocytes that had been subjected to dimethylsulfoxide removal. Neither treatment with TNF-alpha alone or dimethylsulfoxide removal alone induced apoptosis. Apoptosis could be induced by concentrations as low as 500 U of TNF-alpha/ml. Although a DNA ladder was not detected by 12 hours after TNF-alpha treatment, it was easily identified by 24 hours. We conclude that this system can be used 1) to examine the underlying mechanism by which TNF-alpha causes apoptosis in hepatocytes and 2) to study induction of apoptosis in hepatocytes by other agents. Images Figure 1 Figure 2 Figure 3 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:8579111

  20. Matrix metalloproteinase-mediation of tumor targeting human recombinant tumor necrosis factor-α fusion protein.

    PubMed

    Ren, Hui; Shao, Xin; Zeng, Liang; Wang, Fa; Huang, Di-Nan; Hou, Gan

    2015-08-01

    The aim of the present study was to use genetic engineering in order to establish an efficient tumor necrosis factor (TNF)-α fusion protein with low toxicity, which may be used to target tumors. Four types of matrix metalloproteinase (MMP)-mediated tumor targeting human recombinant TNF-α (rhTNF-α) fusion protein vectors were constructed. These were subsequently introduced into Escherichia coli. rhTNF-α fusion protein with a glutathione S-transferase (GST)-tag was purified using GST resin affinity chromatography, and GST-tags were digested using factor Xa. The cytotoxic effects of the fusion protein on L929 cells were determined using MTT assays. At a concentration of 1 pM, the GST-tagged fusion protein exerted no cytotoxic effects on the cells, compared with the negative control cells (P=0.975>0.05). However, at a concentration of 1000 pM, the deblocking fusion protein exerted greater cytotoxic effects on L929 cells, compared with positive control cells (P<0.05). Treatment with the fusion protein also induced cell apoptosis in the nasopharyngeal cancer cell line, CNE-2Z, which secretes high levels of MMP-1. In conclusion, the results of the present study suggested that MMP-mediated rhTNF-α fusion protein induces CNE-2Z cells apoptosis. rhTNF-α exhibits high efficacy and tumor cell targeting capability, with low toxicity effects on healthy cells. PMID:25891416

  1. Safety of anti-tumor necrosis factor therapy during pregnancy in patients with inflammatory bowel disease.

    PubMed

    Androulakis, Ioannis; Zavos, Christos; Christopoulos, Panagiotis; Mastorakos, George; Gazouli, Maria

    2015-12-21

    Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has classified these factors in category B, which means that they do not demonstrate a fetal risk. However, during pregnancy fetuses are exposed to high anti-tumor necrosis factor (TNF) levels that are measurable in their plasma after birth. Since antibodies can transfer through the placenta at the end of the second and during the third trimesters, it is important to know the safety profile of these drugs, particularly for the fetus, and whether maintaining relapse of the disease compensates for the potential risks of fetal exposure. The limited data available for the anti-TNF drugs to date have not demonstrated any significant adverse outcomes in the pregnant women who continued their therapy from conception to the first trimester of gestation. However, data suggest that anti-TNFs should be discontinued during the third trimester, as they may affect the immunological system of the newborn baby. Each decision should be individualized, based on the distinct characteristics of the patient and her disease. Considering all the above, there is a need for more clinical studies regarding the effect of anti-TNF therapeutic agents on pregnancy outcomes. PMID:26715803

  2. Molecular Basis for Defining the Pineal Gland and Pinealocytes as Targets for Tumor Necrosis Factor

    PubMed Central

    Carvalho-Sousa, Claudia Emanuele; da Silveira Cruz-Machado, Sanseray; Tamura, Eduardo Koji; Fernandes, Pedro A. C. M.; Pinato, Luciana; Muxel, Sandra M.; Cecon, Erika; Markus, Regina P.

    2011-01-01

    The pineal gland, the gland that translates darkness into an endocrine signal by releasing melatonin at night, is now considered a key player in the mounting of an innate immune response. Tumor necrosis factor (TNF), the first pro-inflammatory cytokine to be released by an inflammatory response, suppresses the translation of the key enzyme of melatonin synthesis (arylalkylamine-N-acetyltransferase, Aanat). Here, we show that TNF receptors of the subtype 1 (TNF-R1) are expressed by astrocytes, microglia, and pinealocytes. We also show that the TNF signaling reduces the level of inhibitory nuclear factor kappa B protein subtype A (NFKBIA), leading to the nuclear translocation of two NFKB dimers, p50/p50, and p50/RelA. The lack of a transactivating domain in the p50/p50 dimer suggests that this dimer is responsible for the repression of Aanat transcription. Meanwhile, p50/RelA promotes the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide, which inhibits adrenergically induced melatonin production. Together, these data provide a mechanistic basis for considering pinealocytes a target of TNF and reinforce the idea that the suppression of pineal melatonin is one of the mechanisms involved in mounting an innate immune response. PMID:22654792

  3. The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand

    PubMed Central

    Richter, Christine; Messerschmidt, Sylvia; Holeiter, Gerlinde; Tepperink, Jessica; Osswald, Sylvia; Zappe, Andrea; Branschädel, Marcus; Boschert, Verena; Mann, Derek A.; Scheurich, Peter

    2012-01-01

    The family of tumor necrosis factor receptors (TNFRs) and their ligands form a regulatory signaling network that controls immune responses. Various members of this receptor family respond differently to the soluble and membrane-bound forms of their respective ligands. However, the determining factors and underlying molecular mechanisms of this diversity are not yet understood. Using an established system of chimeric TNFRs and novel ligand variants mimicking the bioactivity of membrane-bound TNF (mTNF), we demonstrate that the membrane-proximal extracellular stalk regions of TNFR1 and TNFR2 are crucial in controlling responsiveness to soluble TNF (sTNF). We show that the stalk region of TNFR2, in contrast to the corresponding part of TNFR1, efficiently inhibits both the receptor's enrichment/clustering in particular cell membrane regions and ligand-independent homotypic receptor preassembly, thereby preventing sTNF-induced, but not mTNF-induced, signaling. Thus, the stalk regions of the two TNFRs not only have implications for additional TNFR family members, but also provide potential targets for therapeutic intervention. PMID:22547679

  4. Tumor Necrosis Factor-alpha Stimulates the Overproduction of Intestinal Apolipoprotein B48-containing Very Low Density Lipoproproteins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tumor necrosis factor-alpha(a)(TNFa), a proinflammatory cytokine, is involved in obesity-associated pathologies including type 2 diabetes and atherosclerosis. TNFa enhanced postprandial apoB48-VLDL1 overproduction by about 89% compared with the control after 90 min olive oil loading; TNFa did not si...

  5. The role of nitric oxide in cardiac depression induced by interleukin-1 beta and tumour necrosis factor-alpha.

    PubMed Central

    Schulz, R; Panas, D L; Catena, R; Moncada, S; Olley, P M; Lopaschuk, G D

    1995-01-01

    1. Myocardial dysfunction during septic shock is associated with enhanced production of cytokines such as interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha). These cytokines depress cardiac mechanical function by a mechanism which is not well defined. 2. Bacterial endotoxin or cytokines cause the expression of Ca(2+)-independent nitric oxide (NO) synthase in cardiac myocytes, vascular endothelial cells and endocardial endothelial cells, causing enhanced production of NO. As NO has negative inotropic actions on cardiac muscle, we tested the sum effects of IL-1 beta plus TNF-alpha in the intact heart to determine whether enhanced expression of NO synthase activity in the cells that comprise the heart is involved in cardiac depression associated with cytokine stimulation. 3. Rat isolated working hearts perfused with IL-1 beta plus TNF-alpha showed a markedly greater depression in contractile function, measured as cardiac work, after 2 h of perfusion compared with time-matched control hearts. The depressant action of IL-1 beta plus TNF-alpha was first apparent after 1 h of perfusion; no early (15 min) cardiac depressant actions were seen. 4. The competitive inhibitor of Ca(2+)-dependent and Ca(2+)-independent NO synthases, NG-nitro-L-arginine methyl ester (L-NAME, 3 microM) when given concurrently with IL-1 beta plus TNF-alpha prevented the loss in contractile function such that these hearts after 2 h of perfusion had similar function to time-matched controls. L-NAME did not acutely reverse the loss of contractile function in hearts exposed for 2 h to IL-1 beta plus TNF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7536096

  6. Tumour Necrosis Factor Alpha, Interferon Gamma and Substance P Are Novel Modulators of Extrapituitary Prolactin Expression in Human Skin

    PubMed Central

    Langan, Ewan A.; Vidali, Silvia; Pigat, Natascha; Funk, Wolfgang; Lisztes, Erika; Bíró, Tamás; Goffin, Vincent; Griffiths, Christopher E. M.; Paus, Ralf

    2013-01-01

    Human scalp skin and hair follicles (HFs) are extra-pituitary sources of prolactin (PRL). However, the intracutaneous regulation of PRL remains poorly understood. Therefore we investigated whether well-recognized regulators of pituitary PRL expression, which also impact on human skin physiology and pathology, regulate expression of PRL and its receptor (PRLR) in situ. This was studied in serum-free organ cultures of microdissected human scalp HFs and skin, i.e. excluding pituitary, neural and vascular inputs. Prolactin expression was confirmed at the gene and protein level in human truncal skin, where its expression significantly increased (p = 0.049) during organ culture. There was, however, no evidence of PRL secretion into the culture medium as measured by ELISA. PRL immunoreactivity (IR) in female human epidermis was decreased by substance P (p = 0.009), while neither the classical pituitary PRL inhibitor, dopamine, nor corticotropin-releasing hormone significantly modulated PRL IR in HFs or skin respectively. Interferon (IFN) γ increased PRL IR in the epithelium of human HFs (p = 0.044) while tumour necrosis factor (TNF) α decreased both PRL and PRLR IR. This study identifies substance P, TNFα and IFNγ as novel modulators of PRL and PRLR expression in human skin, and suggests that intracutaneous PRL expression is not under dopaminergic control. Given the importance of PRL in human hair growth regulation and its possible role in the pathogenesis of several common skin diseases, targeting intracutaneous PRL production via these newly identified regulatory pathways may point towards novel therapeutic options for inflammatory dermatoses. PMID:23626671

  7. Relative expression and correlation of tumor necrosis factor-α, interferon-γ, and interleukin-17 in the rheumatoid synovium.

    PubMed

    Nakajima, Arata; Aoki, Yasuchika; Sonobe, Masato; Watanabe, Fusako; Takahashi, Hiroshi; Saito, Masahiko; Nakagawa, Koichi

    2016-07-01

    Although tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-17 (IL-17) play important roles in RA, their relative expression and possible correlation in synovial tissues are not well understood. In this study, mRNA expression levels of IFN-γ, IL-17, and TNF-α were investigated in individual patients with RA and the correlations between pairs of these three pro-inflammatory cytokines were analyzed. Synovial tissues were obtained during arthroplasties from 24 joints of 24 RA patients. After harvesting synovial tissues, total RNA was isolated then quantitative real-time polymerase chain reaction (qRT-PCR) for IFN-γ, IL-17, and TNF-α was performed. Correlation of expression levels between them was also analyzed. Expression levels of TNF-α, IFN-γ, and IL-17 in patients receiving TNF inhibitors (TNFi) and those treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) alone were also compared between groups. Based on relative expression levels of the three pro-inflammatory cytokines, patients were classified into three major types; an IFN-γ plus TNF-α-dominant type, an IL-17-dominant type, and the other type. TNF-α expression levels were correlated with IFN-γ. In addition, there was a negative correlation between TNF-α and IL-17, and IFN-γ and IL-17. Median relative expression levels of TNF-α have no significant difference between the TNFi and the csDMARDs groups. In the rheumatoid synovial tissues, expression levels of TNF-α were modulated in parallel with IFN-γ, and TNF-α and IL-17, or IFN-γ and IL-17 did not co-express at high levels. This characteristic expression pattern of the three pro-inflammatory cytokines may be clinically useful information in the current cytokine-targeted treatment with biological DMARDs for RA. PMID:27038187

  8. Tumor necrosis factor-α inhibition attenuates middle cerebral artery remodeling but increases cerebral ischemic damage in hypertensive rats

    PubMed Central

    Girgla, Saavia S.; Moreno, Guillermo; McClain, Jonathon L.; Dorrance, Anne M.

    2014-01-01

    Hypertension causes vascular inflammation evidenced by an increase in perivascular macrophages and proinflammatory cytokines in the arterial wall. Perivascular macrophage depletion reduced tumor necrosis factor (TNF)-α expression in cerebral arteries of hypertensive rats and attenuated inward remodeling, suggesting that TNF-α might play a role in the remodeling process. We hypothesized that TNF-α inhibition would improve middle cerebral artery (MCA) structure and reduce damage after cerebral ischemia in hypertensive rats. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with the TNF-α inhibitor etanercept (ETN; 1.25 mg·kg−1·day−1 ip daily) or PBS (equivolume) for 6 wk. The myogenic tone generation, postischemic dilation, and passive structure of MCAs were assessed by pressure myography. Cerebral ischemia was induced by MCA occlusion (MCAO). Myogenic tone was unchanged, but MCAs from SHRSP + ETN had larger passive lumen diameter and reduced wall thickness and wall-to-lumen ratio. Cerebral infarct size was increased in SHRSP + ETN after transient MCAO, despite an improvement in dilation of nonischemic MCA. The increase in infarct size was linked to a reduction in the number of microglia in the infarct core and upregulation of markers of classical macrophage/microglia polarization. There was no difference in infarct size after permanent MCAO or when untreated SHRSP subjected to transient MCAO were given ETN at reperfusion. Our data suggests that TNF-α inhibition attenuates hypertensive MCA remodeling but exacerbates cerebral damage following ischemia/reperfusion injury likely due to inhibition of the innate immune response of the brain. PMID:25015967

  9. Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis

    SciTech Connect

    Chen, Pei-Lin; Easton, Alexander S.

    2010-01-01

    Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24 h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10{sup -5} mol/l) and TRAIL increased caspase-3 activity 1 h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

  10. Tumour necrosis factor alpha-induced oxidative burst in neutrophils adherent to fibronectin: effects of cyclic AMP-elevating agents.

    PubMed

    Ottonello, L; Morone, M P; Dapino, P; Dallegri, F

    1995-11-01

    Human neutrophils, plated on fibronectin-coated polystyrene wells, were found to exhibit a prolonged production of superoxide anion (O2-) in response to tumour necrosis factor-alpha (TNF). The TNF-triggered O2- production was significantly reduced by 10 microM prostaglandin E2 (PGE2), which was ineffective at lower doses. Moreover, the O2- production was slightly reduced by the phosphodiesterase type IV (PDE IV) inhibitor RO 20-1724. When PGE2 and RO 20-1724 were added together to TNF-triggered neutrophils they caused a marked synergistic inhibition of O2- production. The action of PGE2 could be mimicked by forskolin (FK), a well-known direct activator of adenylate cyclase. These results suggest that cyclic AMP (cAMP)-elevating agents (PGE2, FK, RO 20-1724) down-regulate the capacity of adherent neutrophils to mount the respiratory burst in response to TNF. Consistent with this interpretation, PGE2 and RO 20-1724 increased the intracellular levels of cAMP displaying synergistic activity. Moreover, the membrane-permeable analogue of cAMP, dibutyryl cAMP, was found to inhibit the TNF-induced O2- production in a dose-dependent manner. As all the aforementioned cAMP-elevating agents did not affect the O2- production in response to phorbol myristate acetate, they appear to act by interfering with the assembly of the O2(-)-generating NADPH oxidase complex rather than by directly inhibiting the activity of already working oxidase complex. In conclusion, taking into account the TNF capacity to promote PGE2 formation at sites of inflammation, our observations suggest the existence of a negative PGE2-dependent feed-back, potentially capable of controlling the neutrophil response to TNF and susceptible to amplification by PDE IV-inhibiting compounds. PMID:8555055

  11. Tumour necrosis factor alpha, interferon gamma and substance P are novel modulators of extrapituitary prolactin expression in human skin.

    PubMed

    Langan, Ewan A; Vidali, Silvia; Pigat, Natascha; Funk, Wolfgang; Lisztes, Erika; Bíró, Tamás; Goffin, Vincent; Griffiths, Christopher E M; Paus, Ralf

    2013-01-01

    Human scalp skin and hair follicles (HFs) are extra-pituitary sources of prolactin (PRL). However, the intracutaneous regulation of PRL remains poorly understood. Therefore we investigated whether well-recognized regulators of pituitary PRL expression, which also impact on human skin physiology and pathology, regulate expression of PRL and its receptor (PRLR) in situ. This was studied in serum-free organ cultures of microdissected human scalp HFs and skin, i.e. excluding pituitary, neural and vascular inputs. Prolactin expression was confirmed at the gene and protein level in human truncal skin, where its expression significantly increased (p = 0.049) during organ culture. There was, however, no evidence of PRL secretion into the culture medium as measured by ELISA. PRL immunoreactivity (IR) in female human epidermis was decreased by substance P (p = 0.009), while neither the classical pituitary PRL inhibitor, dopamine, nor corticotropin-releasing hormone significantly modulated PRL IR in HFs or skin respectively. Interferon (IFN) γ increased PRL IR in the epithelium of human HFs (p = 0.044) while tumour necrosis factor (TNF) α decreased both PRL and PRLR IR. This study identifies substance P, TNFα and IFNγ as novel modulators of PRL and PRLR expression in human skin, and suggests that intracutaneous PRL expression is not under dopaminergic control. Given the importance of PRL in human hair growth regulation and its possible role in the pathogenesis of several common skin diseases, targeting intracutaneous PRL production via these newly identified regulatory pathways may point towards novel therapeutic options for inflammatory dermatoses. PMID:23626671

  12. Effect of Mycobacterium tuberculosis-Specific 10-Kilodalton Antigen on Macrophage Release of Tumor Necrosis Factor Alpha and Nitric Oxide

    PubMed Central

    Trajkovic, Vladimir; Singh, Gyanesh; Singh, Balwan; Singh, Sarman; Sharma, Pawan

    2002-01-01

    Secreted proteins of Mycobacterium tuberculosis are major targets of the specific immunity in tuberculosis and constitute promising candidates for the development of more efficient vaccines and diagnostic tests. We show here that M. tuberculosis-specific antigen 10 (MTSA-10, originally designated CFP-10) can bind to the surface of mouse J774 macrophage-like cells and stimulate the secretion of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). MTSA-10 also synergized with gamma interferon (IFN-γ) for the induction of the microbicidal free radical nitric oxide (NO) in J774 cells, as well as in bone marrow-derived and peritoneal macrophages. On the other hand, pretreatment of J774 cells with MTSA-10 markedly reduced NO but not TNF-α or interleukin 10 (IL-10) release upon subsequent stimulation with lipopolysaccharide or the cell lysate of M. tuberculosis. The presence of IFN-γ during stimulation with M. tuberculosis lysate antagonized the desensitizing effect of MTSA-10 pretreatment on macrophage NO production. The activation of protein tyrosine kinases (PTK) and the serine/threonine kinases p38 MAPK and ERK was apparently required for MTSA-10 induction of TNF-α and NO release, as revealed by specific kinase inhibitors. However, only p38 MAPK activity, not PTK or ERK activity, was partly responsible for MTSA-10-mediated macrophage desensitization. The modulation of macrophage function by MTSA-10 suggests a novel mechanism for its involvement in immunopathogenesis of tuberculosis and might have implications for the prevention, diagnosis, and therapy of this disease. PMID:12438325

  13. Regulation of Adipose Tissue Stem Cells Angiogenic Potential by Tumor Necrosis Factor-Alpha.

    PubMed

    Zubkova, Ekaterina S; Beloglazova, Irina B; Makarevich, Pavel I; Boldyreva, Maria A; Sukhareva, Olga Yu; Shestakova, Marina V; Dergilev, Konstantin V; Parfyonova, Yelena V; Menshikov, Mikhail Yu

    2016-01-01

    Tissue regeneration requires coordinated "teamwork" of growth factors, proteases, progenitor and immune cells producing inflammatory cytokines. Mesenchymal stem cells (MSC) might play a pivotal role by substituting cells or by secretion of growth factors or cytokines, and attraction of progenitor and inflammatory cells, which participate in initial stages of tissue repair. Due to obvious impact of inflammation on regeneration it seems promising to explore whether inflammatory factors could influence proangiogenic abilities of MSC. In this study we investigated effects of TNF-α on activity of adipose-derived stem cells (ADSC). We found that treatment with TNF-α enhances ADSC proliferation, F-actin microfilament assembly, increases cell motility and migration through extracellular matrix. Exposure of ADSC to TNF-α led to increased mRNA expression of proangiogenic factors (FGF-2, VEGF, IL-8, and MCP-1), inflammatory cytokines (IL-1β, IL-6), proteases (MMPs, uPA) and adhesion molecule ICAM-1. At the protein level, VEGF, IL-8, MCP-1, and ICAM-1 production was also up-regulated. Pre-incubation of ADSC with TNF-α-enhanced adhesion of monocytes to ADSC but suppressed adherence of ADSC to endothelial cells (HUVEC). Stimulation with TNF-α triggers ROS generation and activates a number of key intracellular signaling mediators known to positively regulate angiogenesis (Akt, small GTPase Rac1, ERK1/2, and p38 MAP-kinases). Pre-treatment with TNF-α-enhanced ADSC ability to promote growth of microvessels in a fibrin gel assay and accelerate blood flow recovery, which was accompanied by increased arteriole density and reduction of necrosis in mouse hind limb ischemia model. These findings indicate that TNF-α plays a role in activation of ADSC angiogenic and regenerative potential. PMID:26096299

  14. Andrographolide Inhibits Nuclear Factor-κB Activation through JNK-Akt-p65 Signaling Cascade in Tumor Necrosis Factor-α-Stimulated Vascular Smooth Muscle Cells

    PubMed Central

    Chen, Yu-Ying; Hsieh, Cheng-Ying; Lee, Lin-Wen; Sheu, Joen-Rong

    2014-01-01

    Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs) exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α). Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK), Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism. PMID:25114952

  15. Molecular mechanism of ER stress-induced gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in macrophages.

    PubMed

    Huang, Yan; Wang, Yarui; Li, Xiaofeng; Chen, Zhaolin; Li, Xiaohui; Wang, Huan; Ni, Mingming; Li, Jun

    2015-06-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, whose members are capable of inducing apoptosis and inflammation. Endoplasmic reticulum stress (ERS) plays a key role in immune surveillance in macrophages. TRAIL mRNA and protein expression have previously been detected in macrophages; however, whether ERS has any effects on TRAIL expression in macrophages has not yet been determined. Here, we demonstrate that thapsigargin (TG) and tunicamycin (TM), two ERS inducers activated macrophages were able to increase TRAIL mRNA and protein expression in RAW264.7 macrophages, the culture supernatant of THP-1 cells, and mouse peritoneal macrophages, indicating that ERS as a potent inducer of TRAIL transcription and expression in macrophages. This effect was blocked by the specific JNK inhibitor SP600125 and transcription factor AP-1 inhibitor SR 1130. Interestingly, at the molecular level, regulation of TRAIL expression by ERS was accompanied by a significant decrease in cytokine signaling suppressor 3 (SOCS3). SOCS3 siRNA clearly increased the expression of TRAIL mRNA and protein under ERS by activating the AP-1 components phosphorylated c-Jun and phosphorylated c-Fos in RAW264.7 cells. In contrast, over-expression of SOCS3 reversed ERS-induced TRAIL expression. These findings provide in vitro evidence that SOCS3 plays a critical negative role in the regulation of ERS-induced TRAIL expression via the Jun N-terminal kinase/AP-1 signaling pathway in macrophages. PMID:25827060

  16. Effect of Melilotus extract on lung injury via the upregulation of tumor necrosis factor-α-induced protein-8-like 2 in septic mice

    PubMed Central

    LIU, MING-WEI; SU, MEI-XIAN; WANG, YUN-HUI; QIAN, CHUAN-YUN

    2015-01-01

    As a Traditional Chinese Medicine, Melilotus extracts have been reported to function as an anti-inflammatory agent, antioxidant and inhibitor of capillary permeability. The present study aimed to identify the mechanisms by which Melilotus interferes with inflammation-associated and oxidative stress pathways during sepsis. An animal model of cecal ligation-perforation (CLP)-induced sepsis was established. Two hours prior to surgery, animals in the treatment group were administered 25 mg/kg Melilotus extract tablets and subsequently every 8 h. At 24 h post-administration, pathological modifications in lung tissue and expression levels of tumor necrosis factor-α-induced protein-8-like 2 (TIPE2) expression, nuclear factor (NF)-κB, toll-like receptor 4 (TLR4), heme oxygenase-1 (HO-1), inhibitor of κB kinase (IκB), pro-inflammatory mediators (interleukin-6 and tumor necrosis factor-α), myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD), were examined. The results showed that Melilotus extract had a marked effect on the pathological manifestation of lung tissue and lung inflammatory response, the upregulation of TIPE2, HO-1 and IκB expression, and the inhibition of TLR4 and NF-κB activities. In addition, following treatment with Melilotus extract, the model animals demonstrated decreased levels of MPO and MDA as well as increased levels of SOD. In conclusion, these results indicated that Melilotus extract may be a potential therapeutic agent for the treatment of CLP-induced lung injury, the mechanism of which proceeded via inflammation- and oxidation-associated pathways by increasing TIPE2 expression. PMID:25405912

  17. Tumor necrosis factor receptor associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system

    PubMed Central

    Walsh, Matthew C.; Lee, JangEun; Choi, Yongwon

    2016-01-01

    Summary Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adaptor protein that mediates a wide array of protein-protein interactions via its TRAF domain and a RING finger domain that possesses non-conventional E3 ubiquitin ligase activity. First identified nearly two decades ago as a mediator of IL-1 receptor (IL-1R)-mediated activation of NFκB, TRAF6 has since been identified as an actor downstream of multiple receptor families with immunoregulatory functions, including members of the TNFR superfamily, the toll-like receptor (TLR) family, tumor growth factor-β receptors (TGFβR), and T cell receptor (TCR). In addition to NFκB, TRAF6 may also direct activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor (IRF) pathways. In the context of the immune system, TRAF6-mediated signals have proven critical for the development, homeostasis, and/or activation of B cells, T cells, and myeloid cells, including macrophages, dendritic cells, and osteoclasts, as well as for organogenesis of thymic and secondary lymphoid tissues. In multiple cellular contexts, TRAF6 function is essential not only for proper activation of the immune system, but also for maintaining immune tolerance, and more recent works have begun to identify mechanisms of contextual specificity for TRAF6, involving both regulatory protein interactions, and messenger RNA regulation by microRNAs. PMID:26085208

  18. The effect of the pro-inflammatory cytokine tumor necrosis factor-alpha on human joint capsule myofibroblasts

    PubMed Central

    2010-01-01

    Introduction Previous studies have shown that the number of myoblastically differentiated fibroblasts known as myofibroblasts (MFs) is significantly increased in stiff joint capsules, indicating their crucial role in the pathogenesis of post-traumatic joint stiffness. Although the mode of MFs' function has been well defined for different diseases associated with tissue fibrosis, the underlying mechanisms of their regulation in the pathogenesis of post-traumatic joint capsule contracture are largely unknown. Methods In this study, we examined the impact of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) on cellular functions of human joint capsule MFs. MFs were challenged with different concentrations of TNF-α with or without both its specifically inactivating antibody infliximab (IFX) and cyclooxygenase-2 (COX2) inhibitor diclofenac. Cell proliferation, gene expression of both alpha-smooth muscle actin (α-SMA) and collagen type I, the synthesis of prostaglandin derivates E2, F1A, and F2A, as well as the ability to contract the extracellular matrix were assayed in monolayers and in a three-dimensional collagen gel contraction model. The α-SMA and COX2 protein expressions were evaluated by immunofluorescence staining and Western blot analysis. Results The results indicate that TNF-α promotes cell viability and proliferation of MFs, but significantly inhibits the contraction of the extracellular matrix in a dose-dependent manner. This effect was associated with downregulation of α-SMA and collagen type I by TNF-α application. Furthermore, we found a significant time-dependent upregulation of prostaglandin E2 synthesis upon TNF-α treatment. The effect of TNF-α on COX2-positive MFs could be specifically prevented by IFX and partially reduced by the COX2 inhibitor diclofenac. Conclusions Our results provide evidence that TNF-α specifically modulates the function of MFs through regulation of prostaglandin E2 synthesis and therefore may play a

  19. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey

    PubMed Central

    Gupta, Subash C.; Kim, Ji Hye

    2012-01-01

    Although activity that induced tumor regression was observed and termed tumor necrosis factor (TNF) as early as the 1960s, the true identity of TNF was not clear until 1984, when Aggarwal and coworkers reported, for the first time, the isolation of 2 cytotoxic factors: one, derived from macrophages (molecular mass 17 kDa), was named TNF, and the second, derived from lymphocytes (20 kDa), was named lymphotoxin. Because the 2 cytotoxic factors exhibited 50% amino acid sequence homology and bound to the same receptor, they came to be called TNF-α and TNF-β. Identification of the protein sequences led to cloning of their cDNA. Based on sequence homology to TNF-α, now a total of 19 members of the TNF superfamily have been identified, along with 29 interacting receptors, and several molecules that interact with the cytoplasmic domain of these receptors. The roles of the TNF superfamily in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, and morphogenesis have been documented. Their roles in immunologic, cardiovascular, neurologic, pulmonary, and metabolic diseases are becoming apparent. TNF superfamily members are active targets for drug development, as indicated by the recent approval and expanding market of TNF blockers used to treat rheumatoid arthritis, psoriasis, Crohns disease, and osteoporosis, with a total market of more than US $20 billion. As we learn more about this family, more therapeutics will probably emerge. In this review, we summarize the initial discovery of TNF-α, and the insights gained regarding the roles of this molecule and its related family members in normal physiology and disease. PMID:22053109

  20. Tumor necrosis factor beta and ultraviolet radiation are potent regulators of human keratinocyte ICAM-1 expression

    SciTech Connect

    Krutmann, J.; Koeck, A.S.; Schauer, E.; Parlow, F.; Moeller, A.K.; Kapp, A.; Foerster, E.S.; Schoepf, E.L.; Luger, T.A. )

    1990-08-01

    Intercellular adhesion molecule-1 (ICAM-1) functions as a ligand of leukocyte function-associated antigen-1 (LFA-1), as well as a receptor for human picorna virus, and its regulation thus affects various immunologic and inflammatory reactions. The weak, constitutive ICAM-1 expression on human keratinocytes (KC) can be up-regulated by cytokines such as interferon-gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha). In order to further examine the regulation of KC ICAM-1 expression, normal human KC or epidermoid carcinoma cells (KB) were incubated with different cytokines and/or exposed to ultraviolet (UV) radiation. Subsequently, ICAM-1 expression was monitored cytofluorometrically using a monoclonal anti-ICAM-1 antibody. Stimulation of cells with recombinant human (rh) interleukin (IL) 1 alpha, rhIL-4, rhIL-5, rhIL-6, rh granulocyte/macrophage colony-stimulating factor (GM-CSF), rh interferon alpha (rhIFN alpha), and rh transforming growth factor beta (TGF beta) did not increase ICAM-1 surface expression. In contrast, rhTNF beta significantly up-regulated ICAM-1 expression in a time- and dose-dependent manner. Moreover, the combination of rhTNF beta with rhIFN gamma increased the percentage of ICAM-1-positive KC synergistically. This stimulatory effect of rhTNF beta was further confirmed by the demonstration that rhTNF beta was capable of markedly enhancing ICAM-1 mRNA expression in KC. Finally, exposure of KC in vitro to sublethal doses of UV radiation (0-100 J/m2) prior to cytokine (rhIFN tau, rhTNF alpha, rhTNF beta) stimulation inhibited ICAM-1 up-regulation in a dose-dependent fashion. These studies identify TNF beta and UV light as potent regulators of KC ICAM-1 expression, which may influence both attachment and detachment of leukocytes and possibly viruses to KC.

  1. Calcium-dependent regulation of tumour necrosis factor-alpha receptor signalling by copine.

    PubMed Central

    Tomsig, Jose Luis; Sohma, Hitoshi; Creutz, Carl E

    2004-01-01

    The role of copines in regulating signalling from the TNF-alpha (tumour necrosis factor-alpha) receptor was probed by the expression of a copine dominant-negative construct in HEK293 (human embryonic kidney 293) cells. The construct was found to reduce activation of the transcription factor NF-kappaB (nuclear factor-kappaB) by TNF-alpha. The introduction of calcium into HEK293 cells either through the activation of muscarinic cholinergic receptors or through the application of the ionophore A23187 was found to enhance TNF-alpha-dependent activation of NF-kappaB. This effect of calcium was completely blocked by the copine dominant-negative construct. TNF-alpha was found to greatly enhance the expression of endogenous copine I, and the responsiveness of the TNF-alpha signalling pathway to muscarinic stimulation increased in parallel with the increased copine I expression. The copine dominant-negative construct also inhibited the TNF-alpha-dependent degradation of IkappaB, a regulator of NF-kappaB. All of the effects of the dominant-negative construct could be reversed by overexpression of full-length copine I, suggesting that the construct acts specifically through competitive inhibition of copine. One of the identified targets of copine I is the NEDD8-conjugating enzyme UBC12 (ubiquitin C12), that promotes the degradation of IkappaB through the ubiquitin ligase enzyme complex SCF(betaTrCP). Therefore the copine dominant-negative construct might inhibit TNF-alpha signalling by dysregulation or mislocalization of UBC12. Based on these results, a hypothesis is presented for possible roles of copines in regulating other signalling pathways in animals, plants and protozoa. PMID:14674885

  2. Tumor necrosis factor-alpha inhibits albumin gene expression in a murine model of cachexia.

    PubMed Central

    Brenner, D A; Buck, M; Feitelberg, S P; Chojkier, M

    1990-01-01

    The mechanisms responsible for decreased serum albumin levels in patients with cachexia-associated infection, inflammation, and cancer are unknown. Since tumor necrosis factor-alpha (TNF alpha) is elevated in cachexia-associated diseases, and chronic administration of TNF alpha induces cachexia in animal models, we assessed the regulation of albumin gene expression by TNF alpha in vivo. In this animal model of cachexia, Chinese hamster ovary cells transfected with the functional gene for human TNF alpha were inoculated into nude mice (TNF alpha mice). TNF alpha mice became cachectic and manifested decreased serum albumin levels, albumin synthesis, and albumin mRNA levels. However, even before the TNF alpha mice lost weight, their albumin mRNA steady-state levels were decreased approximately 90%, and in situ hybridization revealed a low level of albumin gene expression throughout the hepatic lobule. The mRNA levels of several other genes were unchanged. Hepatic nuclei from TNF alpha mice before the onset of weight loss were markedly less active in transcribing the albumin gene than hepatic nuclei from control mice. Therefore, TNF alpha selectively inhibits the genetic expression of albumin in this model before weight loss. Images PMID:2295699

  3. Interleukin-6 and tumor necrosis factor-alpha values in elk neonates

    USGS Publications Warehouse

    Barber-Meyer, S. M.; Johnson, C.R.; Murtaugh, M.P.; Mech, L.D.; White, P.J.

    2007-01-01

    Serological indicators of general condition would be helpful for monitoring or assessing ungulate wildlife. Toward that end, we report the 1st reference values for 2 cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-??), in neonatal elk (Cervus elaphus). We obtained blood samples from 140 calves ??? 6 days old in Yellowstone National Park during summer 2003-2005. TL-6 values ranged from 0 to 1.21 pg/ml with a median of 0.03 pg/ml. TNF-?? values ranged from 0 to 225.43 pg/ml with a median of 1.85 pg/ml. IL-6 and TNF-?? concentrations were not significant predictors of elk calf survival through 21 days. Development of ungulate-based IL-6 and TNF-?? assays that provide greater sensitivity than cross-reacting human-based assays could be helpful in monitoring ungulate condition and health status comparisons among herds. Such information could provide indirect assessments of range quality or environmental influences among herds. ?? 2007 American Society of Mammalogists.

  4. Induction of release of tumor necrosis factor from human monocytes by staphylococci and staphylococcal peptidoglycans.

    PubMed Central

    Timmerman, C P; Mattsson, E; Martinez-Martinez, L; De Graaf, L; Van Strijp, J A; Verbrugh, H A; Verhoef, J; Fleer, A

    1993-01-01

    The role of cytokines in gram-positive infections is still relatively poorly defined. The purpose of this study was to establish whether or not intact staphylococci and purified peptidoglycans and peptidoglycan components derived from staphylococci are capable of stimulating the release of tumor necrosis factor (TNF) by human monocytes. We show here that intact staphylococci and purified peptidoglycans, isolated from three Staphylococcus epidermidis and three S. aureus strains, were indeed able to induce secretion of TNF by human monocytes in a concentration-dependent fashion. TNF release was detected by both enzyme immunoassay and the L929 fibroblast bioassay. In the enzyme immunoassay, a minimal concentration of peptidoglycan of 1 micrograms/ml was required to detect TNF release by monocytes, whereas in the bioassay a peptidoglycan concentration of 10 micrograms/ml was needed to detect a similar amount of TNF release. Peptidoglycan components such as the stem peptide, tetra- and pentaglycine, and muramyl dipeptide were unable to induce TNF release from human monocytes. PMID:8406805

  5. Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis.

    PubMed Central

    Mulcahy, B.; Waldron-Lynch, F.; McDermott, M. F.; Adams, C.; Amos, C. I.; Zhu, D. K.; Ward, R. H.; Clegg, D. O.; Shanahan, F.; Molloy, M. G.; O'Gara, F.

    1996-01-01

    The major histocompatibility complex class III tumor necrosis factor-lymphotoxin (TNF-LT) region (6p21.3) was investigated as a possible susceptibility locus for rheumatoid arthritis (RA). Inheritance of five TNF microsatellite markers was determined in 50 multiplex families. Overall, 47 different haplotypes were observed. One of these, the TNF a6, b5, c1, d3, e3 (H1) haplotype, was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P < .005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3% not transmitted to affected offspring (P = .0003). The TNF a6 and TNF c1 alleles were individually associated with RA (P = .0005 and .0008, respectively), as were the HLA-DRB1 "shared epitope" (SE) (P = .0001) and HLA-DRB1*0401 (P = .0018). Both univariate and bivariate conditional logistic regression analysis showed significant effects of TNF c1 and SE in increasing risk to RA (P < .001). Stratification by the presence of SE indicated an independent effect of the TNFc1 allele (P = .0003) and the HLA A1, B8, DR3 extended haplotype (always TNFa2, b3, c1, d1, e3) (P = .0027) in SE heterozygotes, while the H1 haplotype was associated with RA in SE homozygotes (P = .0018). The TNF-LT region appears to influence susceptibility to RA, distinct from HLA-DR. PMID:8751869

  6. Tumor Necrosis Factor-Alpha in Peripical Tissue Exudates of Teeth with Apical Periodontitis

    PubMed Central

    Pezelj-Ribarić, Sonja; Magašić, Karolina; Prpić, Jelena; Miletić, Ivana; Karlović, Zoran

    2007-01-01

    Aim. The aim of this study was to determine tumor necrosis factor-alpha (TNF-α) levels in periapical exudates and to evaluate their relationship with radiological findings. Methodology. Periapical exudates were collected from root canals of 60 single-rooted teeth using absorbent paper points. TNF-α levels were determined by enzyme-linked immunosorbent assays. The samples were divided into three groups according to the periapical radiolucent area. Results. Nonparametric Kruskal-Wallis test revealed significant differences between TNF-α concentrations in control group (40, 57±28, 15 pg/mL) and group with larger radiolucent areas (2365, 79±582, 95 pg/mL), as well as between control and canals with small radiolucent areas (507, 66±278, 97) (P<.05). Conclusions. The levels of TNF-α increase significantly in teeth with periapical pathosis, from smaller to bigger lesions. This research and its results have shown that objective analysis of the TNF-α levels enables establishment of a relationship between different concentrations of TNF-α and different radiological changes. PMID:18320014

  7. Association between serum soluble tumor necrosis factor-α receptors and early childhood obesity.

    PubMed

    Ouyang, Shengrong; Li, Wei; Liu, Zhuo; Li, Yuanyuan; Li, Sen; Wu, Jianxin

    2016-06-30

    This study aimed to characterize the inflammatory cytokine profiles and further validate the significantly different cytokines in the serum obtained from obese children aged 36-48 months. Four obese children and four lean controls were randomly selected for inflammatory cytokine array assay, in which two cytokines [soluble tumor necrosis factor-α receptors (sTNFRs) 1 and 2] were found to be significantly different. Both cytokines (sTNFR1 and sTNFR2) were then further validated through enzyme-linked immunosorbent assay (ELISA) in 61 obese children and 52 lean children. ELISA results revealed that serum sTNFR1 level in obese children significantly increased (p = 0.003), whereas sTNFR2 did not change significantly (p = 0.069). Stratified analysis by gender showed that only obese girls presented increased sTNFR1 (p = 0.005) and sTNFR2 (p = 0.049) levels. We conclude that serum sTNFR1 is elevated in early childhood obesity. Moreover, serum sTNFR1 and sTNFR2 are associated with obese girls but not obese boys, thereby suggesting that serum sTNFRs in early childhood obesity may be sex related. PMID:27040725

  8. Imbalance of tumor necrosis factor receptors during progression in bovine leukemia virus infection

    SciTech Connect

    Konnai, Satoru . E-mail: konnai@vetmed.hokudai.ac.jp; Usui, Tatsufumi; Ikeda, Manabu; Kohara, Junko; Hirata, Toh-ichi; Okada, Kosuke; Ohashi, Kazuhiko; Onuma, Misao

    2005-09-01

    Previously, we found an up-regulation of tumor necrosis factor alpha (TNF)-{alpha} and an imbalance of TNF receptors in sheep experimentally infected with bovine leukemia virus (BLV). In order to investigate the different TNF-{alpha}-induced responses, in this study we examined the TNF-{alpha}-induced proliferative response and the expression levels of two distinct TNF receptors on peripheral blood mononuclear cells (PBMC) derived from BLV-uninfected cattle and BLV-infected cattle that were aleukemic (AL) or had persistent lymphocytosis (PL). The proliferative response of PBMC isolated from those cattle with PL in the presence of recombinant bovine TNF-{alpha} (rTNF-{alpha}) was significantly higher than those from AL cattle and uninfected cattle and the cells from PL cattle expressed significantly higher mRNA levels of TNF receptor type II (TNF-RII) than those from AL and BLV-uninfected cattle. No difference was found in TNF-RI mRNA levels. Most cells expressing TNF-RII in PL cattle were CD5{sup +} or sIgM{sup +} cells and these cells showed resistance to TNF-{alpha}-induced apoptosis. Additionally, there were significant positive correlations between the changes in provirus load and TNF-RII mRNA levels, and TNF-{alpha}-induced proliferation and TNF-RII mRNA levels. These data suggest that imbalance in the expression of TNF receptors could at least in part contribute to the progression of lymphocytosis in BLV infection.

  9. Growth promoting effect of recombinant interleukin I and tumor necrosis factor for human astrocytoma cells

    SciTech Connect

    Giulian, D.; Dinarello, C.A.; Brown, D.C.; Lachman, L.B.

    1986-03-01

    Human IL I has been demonstrated to stimulate the growth of rat astrocytes in vitro. To determine if IL I has a similar growth promoting effect upon human brain cells, two astrocytoma cell lines were tested for their ability to incorporate /sup 3/H-thymidine in response to various types of IL I and tumor necrosis factor (TNF). The U373 astrocytoma was found to respond mitogenically to human native IL I, human recombinant IL I, rat IL I and murine recombinant IL I. The cell line failed to respond to recombinant IL 2 and recombinant ..cap alpha.. and ..gamma.. interferon. The sensitivity of the U373 cells paralleled the murine thymocyte assay for IL I. Interestingly, the U373 responded mitogenically to recombinant TNF prepared by two different companies, thus indicating that TNF stimulates proliferation of this cell line and does not lead to cell death. In the murine thymocyte assay for IL I, TNF was not active. The results indicate that 1) both IL I and TNF are mitogenic for a human astrocytoma cell line and 2) the U373 cells may be used to assay both IL I and TNF in a highly sensitive mitogenic assay.

  10. Production of tumor necrosis factor and interleukin-1 by macrophages from human atheromatous plaques.

    PubMed Central

    Tipping, P. G.; Hancock, W. W.

    1993-01-01

    The production of cytokines by atheromatous plaque macrophages from human endarterectomy tissue was assessed in vitro by short-term cell culture and in situ by immunohistology. Macrophages were isolated from plaques of 14 patients undergoing carotid endarterectomy and 7 patients undergoing reconstructive procedures on atheromatous distal aortic and femoral arteries. Tumor necrosis factor (TNF) and interleukin 1 (IL-1) production by plaque macrophages and blood monocytes isolated concurrently from these patients was assessed. TNF release by macrophages from carotid plaques (0.39 +/- 0.12 ng/10(6) cells/24 hours) was significantly augmented compared to the release by corresponding blood monocytes (0.014 +/- 0.011 ng/10(6) cells/24 hours, P = 0.03), and by macrophages from noncarotid lesions (0.038 +/- 0.036 ng/10(6) cells/24 hours, P < 0.04). Cellular TNF expression by macrophages within carotid plaques was also more prominent than in noncarotid lesions. By contrast, IL-1 production by plaque macrophages from both carotid and noncarotid plaques was not augmented compared to blood monocytes, and only infrequent and low-intensity labeling for IL-1 was present on macrophages within plaques from either group. These results provide functional and immunohistological evidence for increased production of TNF but not IL-1 by activated macrophages, indicating local and selective augmentation of cytokine production within carotid plaques. This suggests that macrophages play an active role in the inflammatory response within atheromatous carotid plaques. Images Figure 3 PMID:8506944

  11. Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension.

    PubMed

    Hameed, Abdul G; Arnold, Nadine D; Chamberlain, Janet; Pickworth, Josephine A; Paiva, Claudia; Dawson, Sarah; Cross, Simon; Long, Lu; Zhao, Lan; Morrell, Nicholas W; Crossman, David C; Newman, Christopher M H; Kiely, David G; Francis, Sheila E; Lawrie, Allan

    2012-10-22

    Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies. PMID:23071256

  12. Critical role of tumor necrosis factor receptor 1 in the pathogenesis of pulmonary emphysema in mice

    PubMed Central

    Fujita, Masaki; Ouchi, Hiroshi; Ikegame, Satoshi; Harada, Eiji; Matsumoto, Takemasa; Uchino, Junji; Nakanishi, Yoichi; Watanabe, Kentaro

    2016-01-01

    COPD is a major cause of chronic morbidity and mortality throughout the world. Although tumor necrosis factor-α (TNF-α) has a critical role in the development of COPD, the role of different TNF receptors (TNFRs) in pulmonary emphysema has not been resolved. We aimed to clarify the role of TNFRs in the development of pulmonary emphysema. TNF-α transgenic mice, a murine model of COPD in which the mice spontaneously develop emphysema with a large increase in lung volume and pulmonary hypertension, were crossed with either TNFR1-deficient mice or TNFR2-deficient mice. After 6 months, the gross appearance of the lung, lung histology, and pulmonary and cardiac physiology were determined. In addition, the relationship between apoptosis and emphysema was investigated. Pulmonary emphysema-like changes disappeared with deletion of TNFR1. However, slight improvements were attained with deletion of TNFR2. Apoptotic cells in the interstitium of the lung were observed in TNF-α transgenic mice. The apoptotic signals through TNFR1 appear critical for the pathogenesis of pulmonary emphysema. In contrast, the inflammatory process has a less important role for the development of emphysema. PMID:27555760

  13. Genetically engineered bacteriophage delivers a tumor necrosis factor alpha antagonist coating on neural electrodes.

    PubMed

    Kim, Young Jun; Jin, Young-Hyun; Salieb-Beugelaar, Georgette B; Nam, Chang-Hoon; Stieglitz, Thomas

    2014-02-01

    This paper reports a novel approach for the formation of anti-inflammatory surface coating on a neural electrode. The surface coating is realized using a recombinant f88 filamentous bacteriophage, which displays a short platinum binding motif and a tumor necrosis factor alpha antagonist (TNF-α antagonist) on p3 and p8 proteins, respectively. The recombinant bacteriophages are immobilized on the platinum surface by a simple dip coating process. The selective and stable immobilization of bacteriophages on a platinum electrode is confirmed by quartz crystal microbalance with dissipation monitoring, atomic force microscope and fluorescence microscope. From the in vitro cell viability test, the inflammatory cytokine (TNF-α) induced cell death was prevented by presenting recombinant bacteriophage coating, albeit with no significant cytotoxic effect. It is also observed that the bacteriophage coating does not have critical effects on the electrochemical properties such as impedance and charge storage capacities. Thus, this approach demonstrates a promising anti-apoptotic as well as anti-inflammatory surface coating for neural implant applications. PMID:24448635

  14. Cytokine expression in mice exposed to diesel exhaust particles by inhalation. Role of tumor necrosis factor

    PubMed Central

    Saber, Anne T; Jacobsen, Nicklas R; Bornholdt, Jette; Kjær, Sanna L; Dybdahl, Marianne; Risom, Lotte; Loft, Steffen; Vogel, Ulla; Wallin, Håkan

    2006-01-01

    Background Particulate air pollution has been associated with lung and cardiovascular disease, for which lung inflammation may be a driving mechanism. The pro-inflammatory cytokine, tumor necrosis factor (TNF) has been suggested to have a key-role in particle-induced inflammation. We studied the time course of gene expression of inflammatory markers in the lungs of wild type mice and Tnf-/- mice after exposure to diesel exhaust particles (DEPs). Mice were exposed to either a single or multiple doses of DEP by inhalation. We measured the mRNA level of the cytokines Tnf and interleukin-6 (Il-6) and the chemokines, monocyte chemoattractant protein (Mcp-1), macrophage inflammatory protein-2 (Mip-2) and keratinocyte derived chemokine (Kc) in the lung tissue at different time points after exposure. Results Tnf mRNA expression levels increased late after DEP-inhalation, whereas the expression levels of Il-6, Mcp-1 and Kc increased early. The expression of Mip-2 was independent of TNF if the dose was above a certain level. The expression levels of the cytokines Kc, Mcp-1 and Il-6, were increased in the absence of TNF. Conclusion Our data demonstrate that Tnf is not important in early DEP induced inflammation and rather exerts negative influence on Mcp-1 and Kc mRNA levels. This suggests that other signalling pathways are important, a candidate being one involving Mcp-1. PMID:16504008

  15. Tumor necrosis factor-alpha deficiency impairs host defense against Streptococcus pneumoniae

    PubMed Central

    Jeong, Dong-Gu; Seo, Jin-Hee; Heo, Seung-Ho; Choi, Yang-Kyu

    2015-01-01

    Streptococcus pneumoniae is a major human pathogen that is involved in community-acquired pneumonia. Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine that activates immune responses against infection, invasion, injury, or inflammation. To study the role of TNF-α during S. pneumoniae infection, a murine pneumococcal pneumonia model was used. We intranasally infected C57BL/6J wild-type (WT) and TNF-α knockout (KO) mice with S. pneumoniae D39 serotype 2. In TNF-α KO mice, continuous and distinct loss of body weight, and low survival rates were observed. Bacterial counts in the lungs and blood of TNF-α KO mice were significantly higher than those in WT mice. Histopathological lesions in the spleen of TNF-α KO mice were more severe than those in WT mice. In TNF-α KO mice, severe depletion of white pulp was observed and the number of apoptotic cells was significantly increased. Interferon-gamma (IFN-γ), IL-12p70 and IL-10 levels in serum were significantly increased in TNF-α KO mice. TNF-α is clearly involved in the regulation of S. pneumoniae infections. Early death and low survival rates of TNF-α KO mice were likely caused by a combination of impaired bacterial clearance and damage to the spleen. Our findings suggest that TNF-α plays a critical role in protecting the host from systemic S. pneumoniae infection. PMID:26155202

  16. Retrospective cohort study of anti-tumor necrosis factor agent use in a veteran population

    PubMed Central

    Madkour, Nermeen; Kazerooni, Rashid

    2014-01-01

    Introduction. Anti-tumor necrosis factor (TNF) agents are effective for several immunologic conditions (rheumatoid arthritis (RA), Crohn’s disease (CD), and psoriasis). The purpose of this study was to evaluate the efficacy and safety of anti-TNF agents via chart review. Methods. Single-site, retrospective cohort study that evaluated the efficacy and safety of anti-TNF agents in veterans initiated between 2010 and 2011. Primary aim evaluated response at 12 months post-index date. Secondary aims evaluated initial response prior to 12 months post-index date and infection events. Results. A majority of patients were prescribed anti-TNF agents for CD (27%) and RA (24%). Patients were initiated on etanercept (41%), adalimumab (40%), and infliximab (18%) between 2010 and 2011. No differences in patient demographics were reported. Response rates were high overall. Sixty-five percent of etanercept patients, 82% of adalimumab patients, and 59% of infliximab patients were either partial or full responders, respectively. Approximately 16%, 11%, and 12% of etanercept, adalimumab, and infliximab were non-responders, respectively. Infections between the groups were non-significant. Etanercept and adalimumab patients had higher but non-significant odds of being a responder relative to infliximab. Conclusions. Most patients initiated with anti-TNF agent were responders at 12 months follow-up for all indications in a veteran population. PMID:24883246

  17. Orthodontic forces increase tumor necrosis factor alpha in the human gingival sulcus.

    PubMed

    Lowney, J J; Norton, L A; Shafer, D M; Rossomando, E F

    1995-11-01

    The production of cytokines has been associated with the biology of tooth movement in animal populations. The purpose of this study was to measure tumor necrosis factor-alpha (TNF) directly in the human gingival sulcus before and after the application of an orthodontic force. To recover TNF from the sulcus, paramagnetic beads, coated with monoclonal antibodies for TNF, were introduced into the gingival sulcus of 50 teeth undergoing orthodontic tooth movement (by two force systems) in 20 patients. Retrieval was performed by a permanent magnetic device designed to fit the periodontal sulcus. The samples were taken before force application (controls), and at a fixed time after force application. The amount of immunoabsorbed TNF was quantified with an immunochemical assay. There was a greater than twofold increase in TNF recoverable from the gingival sulcus after application of orthodontic forces (mean of 12.9 ng vs 30.5 ng). A Student's t test for paired samples demonstrated statistical significance at p < 0.01. We conclude that the quantity of paradental TNF, found in human gingival sulcus, is elevated during tooth movement. The source may be from the adjacent gingiva, but more likely the compressed periodontal ligament and the resorbing bone adjacent to the root surface. PMID:7484971

  18. Glucocorticoids Regulate Tristetraprolin Synthesis and Posttranscriptionally Regulate Tumor Necrosis Factor Alpha Inflammatory Signaling▿

    PubMed Central

    Smoak, Kathleen; Cidlowski, John A.

    2006-01-01

    Glucocorticoids are used to treat various inflammatory disorders, but the mechanisms underlying these actions are incompletely understood. The zinc finger protein tristetraprolin (TTP) destabilizes several proinflammatory cytokine mRNAs by binding to AU-rich elements within their 3′ untranslated regions, targeting them for degradation. Here we report that glucocorticoids induce the synthesis of TTP mRNA and protein in A549 lung epithelial cells and in rat tissues. Dexamethasone treatment leads to a sustained induction of TTP mRNA expression that is abrogated by RU486. Glucocorticoid induction of TTP mRNA is also blocked by actinomycin D but not by cycloheximide, suggesting a transcriptional mechanism which has been confirmed by transcription run-on experiments. The most widely characterized TTP-regulated gene is the AU-rich tumor necrosis factor alpha (TNF-α) gene. Dexamethasone represses TNF-α mRNA in A549 cells and decreases luciferase expression of a TNF-α 3′ untranslated region reporter plasmid in an orientation-dependent manner. Small interfering RNAs to TTP significantly prevent this effect, and a cell line stably expressing a short-hairpin RNA to TTP conclusively establishes that TTP is critical for dexamethasone inhibition of TNF-α mRNA expression. These studies provide the molecular evidence for glucocorticoid regulation of human TTP and reflect a novel inductive anti-inflammatory signaling pathway for glucocorticoids that acts via posttranscriptional mechanisms. PMID:16982682

  19. Perirenal fat promotes renal arterial endothelial dysfunction in obese swine through tumor necrosis factor

    PubMed Central

    Ma, Shuangtao; Zhu, Xiang-Yang; Eirin, Alfonso; Woollard, John R.; Jordan, Kyra L.; Tang, Hui; Lerman, Amir; Lerman, Lilach O.

    2015-01-01

    Purpose Perirenal fat is associated with poor blood pressure control and chronic kidney disease, but the underlying mechanisms remain elusive. We tested the hypothesis that perirenal fat impairs renal arterial endothelial function in pigs with obesity-metabolic derangements (ObM). Material and Methods Fourteen domestic pigs were studied after 16 weeks of a high-fat/high-fructose diet (ObM) or standard chow (Lean). Renal blood flow (RBF), glomerular filtration rate (GFR), and visceral fat volumes were studied in-vivo with CT. Renal arterial endothelial function was also studied ex-vivo in the organ bath. Results ObM pigs demonstrated increased body weight, blood pressure, cholesterol, and intra-abdominal fat compared to lean pigs, and perirenal fat volume was significantly larger. RBF and GFR were markedly elevated, while urinary protein level was preserved. Ex-vivo acetylcholine-induced endothelium-dependent vasodilation of renal artery rings was substantially impaired in ObM compared to Lean. Endothelial function was further blunted in both ObM and Lean arterial rings by incubation with perirenal fat harvested from ObM, but not from Lean pigs, and was restored by inhibition of tumor necrosis factor (TNF)-α. ObM perirenal fat also showed increased pro-inflammatory macrophage infiltration and TNF-α expression. Conclusions ObM perirenal fat directly causes renal artery endothelial dysfunction, partly mediated by TNF-α. PMID:26417644

  20. Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma

    PubMed Central

    Howarth, P; Babu, K; Arshad, H; Lau, L; Buckley, M; McConnell, W; Beckett, P; Al, A; Chauhan, A; Wilson, S; Reynolds, A; Davies, D; Holgate, S

    2005-01-01

    Background: Tumour necrosis factor α (TNFα) is a major therapeutic target in a range of chronic inflammatory disorders characterised by a Th1 type immune response in which TNFα is generated in excess. By contrast, asthma is regarded as a Th2 type disorder, especially when associated with atopy. However, as asthma becomes more severe and chronic, it adopts additional characteristics including corticosteroid refractoriness and involvement of neutrophils suggestive of an altered inflammatory profile towards a Th1 type response, incriminating cytokines such as TNFα. Methods: TNFα levels in bronchoalveolar lavage (BAL) fluid of 26 healthy controls, 42 subjects with mild asthma and 20 with severe asthma were measured by immunoassay, and TNFα gene expression was determined in endobronchial biopsy specimens from 14 patients with mild asthma and 14 with severe asthma. The cellular localisation of TNFα was assessed by immunohistochemistry. An open label uncontrolled clinical study was then undertaken in 17 subjects with severe asthma to evaluate the effect of 12 weeks of treatment with the soluble TNFα receptor-IgG1Fc fusion protein, etanercept. Results: TNFα levels in BAL fluid, TNFα gene expression and TNFα immunoreative cells were increased in subjects with severe corticosteroid dependent asthma. Etanercept treatment was associated with improvement in asthma symptoms, lung function, and bronchial hyperresponsiveness. Conclusions: These findings may be of clinical significance in identifying TNFα as a new therapeutic target in subjects with severe asthma. The effects of anti-TNF treatment now require confirmation in placebo controlled studies. PMID:16166100

  1. Curcumin half analog modulates interleukin-6 and tumor necrosis factor-alpha in inflammatory bowel disease

    PubMed Central

    Kondamudi, Phani Krishna; Kovelamudi, Hemalatha; Nayak, Pawan G.; Rao, Mallikarjuna Chamallamudi; Shenoy, Rekha Raghuveer

    2015-01-01

    Background: The present study was aimed at examining the effect of dehydrozingerone (DHZ), half analogue of curcumin which is the active constituent of turmeric (Curcuma longa) in the di-nitrochlorobenzene (DNCB) induced model for inflammatory bowel disease (IBD). Materials and Methods: Male Wistar rats (200–220 g) were divided into four groups (n = 6). Chemical induction of IBD was done by sensitizing with 300 µL of 20 g/L of DNCB (in acetone) onto the nape of rats for 14 days followed by intra-colonic instillation of 250 µL of DNCB (0.1% DNCB in 50% alcohol) solution on day 15. Rats in Group 1 (normal control) and Group 2 (DNCB control) were treated with vehicle. Rats in Group 3 were treated with DHZ (100 mg/kg, p.o.; 8 days) and Group 4 animals were treated with sulfasalazine (SS) (100 mg/kg, p.o.; 8 days). On 24th day, the rats were killed, colon removed and the macroscopic, biochemical, and histopathological evaluations were performed. Results: The levels of myeloperoxidase, thiobarbituric acid reactive substrate, and nitrite increased significantly (P < 0.05) in the DNCB group whereas reduced significantly in the DHZ and SS treated groups. Serum nitrite levels were found to be insignificant between the different groups. Interleukin-6, tumor necrosis factor-alpha level was significantly high in the DNCB group. Conclusion: These findings show that DHZ can be a promising molecule for the treatment of IBD. PMID:26664018

  2. Tumor Necrosis Factor-α-Induced Ototoxicity in Mouse Cochlear Organotypic Culture

    PubMed Central

    Wu, Qian; Wang, Guo-Peng; Xie, Jing; Guo, Jing-Ying; Gong, Shu-Sheng

    2015-01-01

    Tumor necrosis factor (TNF)-α is a cytokine involved in acute inflammatory phase reactions, and is the primary upstream mediator in the cochlear inflammatory response. Treatment of the organ of Corti with TNF-α can induce hair cell damage. However, the resulting morphological changes have not been systematically examined. In the present study, cochlear organotypic cultures from neonatal mice were treated with various concentrations and durations of TNF-α to induce inflammatory responses. Confocal microscopy was used to evaluate the condition of hair cells and supporting cells following immunohistochemical staining. In addition, the ultrastructure of the stereocilia bundle, hair cells, and supporting cells were examined by scanning and transmission electron microscopy. TNF-α treatment resulted in a fusion and loss of stereocilia bundles in hair cells, swelling of mitochondria, and vacuolation and degranulation of the endoplasmic reticulum. Disruption of tight junctions between hair cells and supporting cells was also observed at high concentrations. Hair cell loss was preceded by apoptosis of Deiters’ and pillar cells. Taken together, these findings detail the morphological changes in the organ of Corti after TNF-α treatment, and provide an in vitro model of inflammatory-induced ototoxicity. PMID:26000970

  3. Production of tumor necrosis factor alpha in human leukocytes stimulated by Cryptococcus neoformans.

    PubMed Central

    Levitz, S M; Tabuni, A; Kornfeld, H; Reardon, C C; Golenbock, D T

    1994-01-01

    Tumor necrosis factor alpha (TNF-alpha) is a key mediator of inflammation and may promote human immunodeficiency virus replication in latently infected cells. Since cryptococcosis often is associated with aberrations in the host inflammatory response and occurs preferentially in persons with AIDS, we defined the conditions under which human leukocytes produce TNF-alpha when stimulated by Cryptococcus neoformans. Peripheral blood mononuclear cells (PBMC) produced comparable amounts of TNF-alpha following stimulation with C. neoformans and lipopolysaccharide. Detectable TNF-alpha release in response to C. neoformans occurred only when fungi with small-sized capsules were used and complement-sufficient serum was added. Fractionation of PBMC established that monocytes were the predominant source of TNF-alpha. TNF-alpha gene expression and release occurred significantly later in PBMC stimulated with C. neoformans than in PBMC stimulated with LPS. C. neoformans was also a potent inducer of TNF-alpha from freshly isolated bronchoalveolar macrophages (BAM). Upon in vitro culture, BAM and monocytes bound greater numbers of fungal cells, yet their capacity to produce TNF-alpha following cryptococcal stimulation declined by 74 to 100%. However, this decline was reversed if the BAM and monocytes were cultured with gamma interferon. These data establish that C. neoformans can potently stimulate TNF-alpha release from human leukocytes. However, several variables profoundly affected the amount of TNF-alpha released, including the type of leukocyte and its state of activation, the size of the cryptococcal capsule, and the availability of opsonins. PMID:8168965

  4. Tumour-infiltrating lymphocytes bear the 75 kDa tumour necrosis factor receptor.

    PubMed Central

    Trentin, L.; Zambello, R.; Bulian, P.; Cerutti, A.; Enthammer, C.; Cassatella, M.; Nitti, D.; Lise, M.; Agostini, C.; Semenzato, G.

    1995-01-01

    Tumour necrosis factor alpha (TNF-alpha) is a cytokine with a variety of immunological properties. The identification of two receptors for this molecule, i.e. the 75 kDa and the 55 kDa TNF receptors (TNF-R), recently clarified the mechanisms through which this cytokine provides its wide range of immunomodulatory activities. In this study we have investigated the expression and the functional properties of these receptors on tumour-infiltrating lymphocytes (TILs) recovered from 17 patients with solid cancers (melanoma, colorectal carcinoma and lung cancer). To this end, TIL lines and freshly isolated TILs were evaluated for (a) the expression and the functional role of TNF receptors following culture in the presence of interleukin 2 (IL-2) and (b) the production of TNF-alpha following culture with IL-2 and the role of this cytokine in IL-2-driven TIL proliferation. Flow cytometry analysis demonstrated that TILs bear the 75 kDa TNF-R. Moreover, TIL lines express detectable messages for TNF-alpha and release this cytokine. Functional in vitro studies have shown that anti-TNF-alpha, as well as anti-75 kDa TNF-R antibodies, are able to inhibit the IL-2-induced TIL proliferation. These data demonstrate that TILs are equipped with a fully functional TNF-R system and suggest a putative role for this receptor and its ligand in the activation and expression of TILs following immunotherapy with IL-2. Images Figure 2 PMID:7841036

  5. Varicella zoster meningitis complicating combined anti-tumor necrosis factor and corticosteroid therapy in Crohn's disease.

    PubMed

    Ma, Christopher; Walters, Brennan; Fedorak, Richard N

    2013-06-01

    Opportunistic viral infections are a well-recognized complication of anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD). Cases of severe or atypical varicella zoster virus infection, both primary and latent reactivation, have been described in association with immunosuppression of Crohn's disease (CD) patients. However, central nervous system varicella zoster virus infections have been rarely described, and there are no previous reports of varicella zoster virus meningitis associated with anti-TNF therapy among the CD population. Here, we present the case of a 40-year-old male with severe ileocecal-CD who developed a reactivation of dermatomal herpes zoster after treatment with prednisone and adalimumab. The reactivation presented as debilitating varicella zoster virus meningitis, which was not completely resolved despite aggressive antiviral therapy with prolonged intravenous acyclovir and subsequent oral valacyclovir. This is the first reported case of opportunistic central nervous system varicella zoster infection complicating anti-TNF therapy in the CD population. This paper also reviews the literature on varicella zoster virus infections of immunosuppressed IBD patients and the importance of vaccination prior to initiation of anti-TNF therapy. PMID:23745038

  6. Demyelinizing Neurological Disease after Treatment with Tumor Necrosis Factor-α Antagonists

    PubMed Central

    Bruè, Claudia; Mariotti, Cesare; Rossiello, Ilaria; Saitta, Andrea; Giovannini, Alfonso

    2016-01-01

    Purpose Demyelinizing neurological disease is a rare complication after treatment with tumor necrosis factor (TNF)α antagonists. We report on a case of multiple sclerosis after TNFα antagonist treatment and discuss its differential diagnosis. Methods This is an observational case study. Results A 48-year-old male was referred to Ophthalmology in January 2015 for an absolute scotoma in the superior quadrant of the visual field in his right eye. Visual acuity was 20/50 in the right eye and 20/20 in the left. Fundus examination was unremarkable bilaterally. Spectral domain optical coherence tomography revealed a normal macular retina structure. Visual field examination revealed a superior hemianopsia in the right eye. Head magnetic resonance imaging showed findings compatible with optic neuritis. The visual evoked potentials confirmed the presence of optic neuritis. The patient had been under therapy with adalimumab since January 2014, for Crohn's disease. Suspension of adalimumab was recommended, and it was substituted with tapered deltacortene, from 1 mg/kg/day. After 1 month, the scotoma was resolved completely. Conclusions TNFα antagonists can provide benefit to patients with inflammatory autoimmune diseases. However, they can also be associated with severe adverse effects. Therefore, adequate attention should be paid to neurological abnormalities in patients treated with TNFα antagonists. PMID:27504093

  7. Are circulating cytokines interleukin-6 and tumor necrosis factor alpha involved in chlorpyrifos-induced fever?

    PubMed

    Gordon, C J; Rowsey, P J

    1999-05-01

    Oral exposure to chlorpyrifos (CHP) in the rat results in an initial hypothermic response followed by a delayed fever. Fever from infection is mediated by the release of cytokines, including interleukin-6 (IL-6) and tumor necrosis factor (TNF alpha). This study determined if the CHP-induced fever involves cytokine-mediated mechanisms similar to that of infectious fevers. Long-Evans rats were gavaged with the corn oil vehicle or CHP (10-50 mg/kg). The rats were euthanized and blood collected at various times that corresponded with the hypothermic and febrile effects of CHP. Plasma IL-6, TNF alpha, cholinesterase activity (ChE), total iron, unsaturated iron binding capacity (UIBC), and zinc were measured. ChE activity was reduced by approximately 50% 4 h after CHP. There was no effect of CHP on IL-6 when measured during the period of CHP-induced hypothermia or fever. TNF alpha levels nearly doubled in female rats 48 h after 25 mg/kg CHP. The changes in plasma cytokine levels following CHP were relatively small when compared to > 1000-fold increase in IL-6 and > 10-fold rise in TNF alpha following lipopolysaccharide (E. coli; 50 microg/kg; i.p.)-induced fever. This does not preclude a role of cytokines in CHP-induced fever. Nonetheless, the data suggest that the delayed fever from CHP is unique, involving mechanisms other than TNF alpha and IL-6 release into the circulation characteristic of infectious fevers. PMID:10413184

  8. Hepatic expression of tumour necrosis factor-alpha in chronic hepatitis B virus infection.

    PubMed Central

    Hussain, M J; Lau, J Y; Williams, R; Vergani, D

    1994-01-01

    AIM--To determine the hepatic expression of tumour necrosis factor-alpha (TNF alpha) in patients with chronic hepatitis B virus (HBV) infection. METHODS--Frozen liver biopsy sections from 19 patients with chronic HBV infection were studied, 12 of whom were HBeAg positive and 10 serum HBV DNA positive. Hepatic expression of TNF alpha was determined using immunohistochemistry. RESULTS--Only infiltrating mononuclear cells showed immunoreactive staining for TNF alpha (median 2, range 0-3; n = 19) which appeared as diffuse positive staining material in the cytoplasm. Patients with active liver disease, assessed histologically and biochemically, had a higher level of expression, both in the number of TNF alpha positive cells and the proportion of TNF alpha positive infiltrating mononuclear cells. There was no correlation between the expression of TNF alpha and serological parameters of viral infection (HBeAg and HBV DNA status and HBV DNA concentrations). CONCLUSION--Hepatic expression of TNF alpha is increased in chronic HBV infection and is related to the activity of liver disease and not to the level of HBV replication. Images PMID:7876386

  9. Endothelial cells undergo morphological, biomechanical, and dynamic changes in response to tumor necrosis factor-α.

    PubMed

    Stroka, Kimberly M; Vaitkus, Janina A; Aranda-Espinoza, Helim

    2012-11-01

    The immune response triggers a complicated sequence of events, one of which is release of the cytokine tumor necrosis factor-α (TNF-α) from stromal cells, for example monocytes and macrophages. In this work we investigated the biophysical effects of TNF-α on endothelial cells (ECs), including changes in cell morphology, biomechanics, migration, and cytoskeletal dynamics. We found that TNF-α induces a wide distribution of cell area and aspect ratio, with these properties increasing on average during treatment. Interestingly, aspect ratio peaks after approximately 10 h of exposure to TNF-α, corresponding also to a peak in exerted traction forces. Meanwhile, ECs treated with TNF-α soften, and we associate this with significant increases in estimated cellular volume. In addition, our evaluation of migratory dynamics revealed an inverse correlation between cell aspect ratio and migration speed after TNF-α treatment, suggesting that cell shape may be an important functional regulator of EC migration during an inflammatory response. Finally, we addressed the basic mechanics of how the reorganization of F-actin filaments occurs during TNF-α treatment, and observed a dynamic shift of existing actin filaments. Together, our results suggest a functional link between EC morphology, biomechanics, migration, and cytoskeletal dynamics during an inflammatory response. PMID:22940754

  10. Endothelial cells undergo morphological, biomechanical, and dynamic changes in response to tumor necrosis factor

    PubMed Central

    Stroka, Kimberly M.; Vaitkus, Janina A.; Aranda-Espinoza, Helim

    2012-01-01

    The immune response triggers a complicated sequence of events, one of which is release of the cytokine tumor necrosis factor-α (TNF-α) from stromal cells such as monocytes and macrophages. In this work we explored the biophysical effects of TNF-α on endothelial cells (ECs), including changes in cell morphology, biomechanics, migration, and cytoskeletal dynamics. We found that TNF-α induces a wide distribution of cell area and aspect ratio, with these properties increasing on average during treatment. Interestingly, aspect ratio peaks around 10 hours of exposure to TNF-α, corresponding also to a peak in exerted traction forces. Meanwhile, ECs treated with TNF-α soften, and we associate this with significant increases in estimated cellular volume. In addition, our evaluation of migratory dynamics demonstrates an inverse correlation between cell aspect ratio and migration speed after TNF-α treatment, suggesting that cell shape may be an important functional regulator of EC migration during an inflammatory response. Finally, we address the basic mechanics of how the reorganization of F-actin filaments occurs during TNF-α treatment, and we demonstrate a dynamic shift of existing actin filaments. Together, our results suggest a functional link between EC morphology, biomechanics, migration, and cytoskeletal dynamics during an inflammatory response. PMID:22940754

  11. [Mechanism of production and release of tumor necrosis factor implicated in inflammatory diseases].

    PubMed

    Hide, Izumi

    2003-03-01

    Tumor necrosis factor (TNF) is a potent inflammatory cytokine involved in many pathophysiological conditions including rheumatoid arthritis and Crohn's disease. Despite recent evidence regarding signal transduction via TNF receptor and its biological actions, the mechanism of TNF release remains poorly understood. To clarify how production and release of TNF are regulated, we focused on mast cells and microglia which are involved in allergic inflammation and brain damage or recovery, respectively. In RBL-2H3 mast cells, anti-allergic drugs including azelastine inhibited the release of TNF more potently than degranulation in response to antigen or ionomycin. It was also demonstrated that TNF releasing steps are regulated via the PKC alpha-dependent pathway. Furthermore, Rho GTPases, possibly Rac, were shown to be involved in antigen-induced TNF transcription through activating PKC beta I. In cultured rat brain microglia, we found that extracellular ATP triggers the release of TNF via the P2X7 receptor. ERK and JNK are also involved in ATP-induced TNF transcription, while p38 regulates the transport of TNF mRNA from the nucleus to the cytosol. Additionally, JNK and p38, but not ERK, are activated via the P2X7 receptor. A better understanding of the specific pathways that regulate TNF release for each effector cell may offer further possible therapeutic targets for inflammatory diseases. PMID:12673950

  12. African Swine Fever Virus Infection Induces Tumor Necrosis Factor Alpha Production: Implications in Pathogenesis

    PubMed Central

    Gómez del Moral, M.; Ortuño, E.; Fernández-Zapatero, P.; Alonso, F.; Alonso, C.; Ezquerra, A.; Domínguez, J.

    1999-01-01

    We have analyzed the production of tumor necrosis factor alpha (TNF-α) induced by in vitro infection with African swine fever (ASF) virus (ASFV) and the systemic and local release of this inflammatory cytokine upon in vivo infection. An early increase in TNF-α mRNA expression was detected in ASFV-infected alveolar macrophages, and high levels of TNF-α protein were detected by ELISA in culture supernatants from these cells. When animals were experimentally infected with a virulent isolate (E-75), enhanced TNF-α expression in mainly affected organs correlated with viral protein expression. Finally, elevated levels of TNF-α were detected in serum, corresponding to the onset of clinical signs. TNF-α has been reported to be critically involved in the pathogenesis of major clinical events in ASF, such as intravascular coagulation, tissue injury, apoptosis, and shock. In the present study, TNF-α containing supernatants from ASFV-infected cultures induced apoptosis in uninfected lymphocytes; this effect was partially abrogated by preincubation with an anti-TNF-α specific antibody. These results suggest a relevant role for TNF-α in the pathogenesis of ASF. PMID:9971800

  13. Tumor necrosis factor-alpha is expressed by glomerular visceral epithelial cells in human membranous nephropathy.

    PubMed Central

    Neale, T. J.; Rüger, B. M.; Macaulay, H.; Dunbar, P. R.; Hasan, Q.; Bourke, A.; Murray-McIntosh, R. P.; Kitching, A. R.

    1995-01-01

    The role of tumor necrosis factor alpha (TNF-alpha) was examined in biopsy-proven glomerulonephritis by immunohistochemistry, in situ hybridization, immunogold electron microscopy, immunoassay in serum and urine, and urinary immunoblot. Striking glomerular capillary wall and visceral glomerular epithelial cell TNF-alpha protein staining was observed in all cases of membranous nephropathy and membranous lupus nephropathy. Staining was less frequently observed in crescentic glomerulonephritis and in isolated cases of other histological subtypes of glomerulonephritis, usually in association with glomerular macrophages. By immunogold electron microscopy TNF-alpha was localized in membranous nephropathy within the visceral glomerular epithelial cells, and also in the glomerular basement membrane, especially in relation to immune deposits. In situ hybridization localized TNF-alpha mRNA exclusively to glomerular epithelial cells in all biopsies with membranous morphology but not in other histological subtypes. Concentrations of TNF-alpha were significantly increased compared with normal controls in the urine of patients with membranous nephropathy and with crescentic glomerulonephritis. The expression of TNF-alpha by glomerular epithelial cells exclusively and universally in biopsies showing a membranous morphology strongly suggests this cytokine has a role in the pathogenesis of membranous nephropathy. Images Figure 1 Figure 2 Figure 3 Figure 5 PMID:7778683

  14. Efficacy of monoclonal antibody against human recombinant tumor necrosis factor in E. coli-challenged swine.

    PubMed Central

    Jesmok, G.; Lindsey, C.; Duerr, M.; Fournel, M.; Emerson, T.

    1992-01-01

    Monoclonal antibody against human tumor necrosis factor alpha (TNF MAb) prevents death induced by intravenous gram-negative bacteria or lipopolysaccharide (LPS) in primates. Although these studies have demonstrated that TNF plays a prominent role in the development of lethal septic shock, exploration of dose-response relationships and possible mechanisms of protection have been limited. We addressed these questions in a series of experiments conducted in E. coli-challenged pigs. First, we determined that TNF MAb neutralized the cytotoxic activity found in septic pig plasma and in culture media from pig monocytes incubated with LPS. Second, we demonstrated that pretreatment with TNF MAb promotes survival, in a dose-dependent fashion, in an otherwise lethal E. coli bacteremic pig model. The results of the survival study highly correlate (r = 0.96, P < 0.01) the presence of TNF in the circulation with mortality. In an additional series of physiologic monitoring experiments designed to delineate possible mechanisms of protection, the authors demonstrate that TNF MAb pretreatment abrogates the prolonged leukopenia, thrombocytopenia, and microvascular leakiness resulting from intravenous bacterial challenge and maintains arterial blood pressure while diminishing pulmonary edema. These findings may provide a mechanism whereby neutralization of TNF systemically affords protection against the lethal sequelae of bacteremia. PMID:1443053

  15. LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner

    PubMed Central

    Mattijssen, Sandy

    2015-01-01

    LARP4 is a protein with unknown function that independently binds to poly(A) RNA, RACK1, and the poly(A)-binding protein (PABPC1). Here, we report on its regulation. We found a conserved AU-rich element (ARE) in the human LARP4 mRNA 3′ untranslated region (UTR). This ARE, but not its antisense version or a point-mutated version, significantly decreased the stability of β-globin reporter mRNA. We found that overexpression of tristetraprolin (TTP), but not its RNA binding mutant or the other ARE-binding proteins tested, decreased cellular LARP4 levels. RNA coimmunoprecipitation showed that TTP specifically associated with LARP4 mRNA in vivo. Consistent with this, mouse LARP4 accumulated to higher levels in TTP gene knockout (KO) cells than in control cells. Stimulation of WT cells with tumor necrosis factor alpha (TNF-α), which rapidly induces TTP, robustly decreased LARP4 with a coincident time course but had no such effect on LARP4B or La protein or on LARP4 in the TTP KO cells. The TNF-α-induced TTP pulse was followed by a transient decrease in LARP4 mRNA that was quickly followed by a subsequent transient decrease in LARP4 protein. Involvement of LARP4 as a target of TNF-α–TTP regulation provides a clue as to how its functional activity may be used in a physiologic pathway. PMID:26644407

  16. Protective effects of tanshinone IIA on endothelial progenitor cells injured by tumor necrosis factor

    PubMed Central

    WANG, XING-XIANG; YANG, JIN-XIU; PAN, YAN-YUN; ZHANG, YE-FEI

    2015-01-01

    Tanshinone IIA (Tan IIA) is a Traditional Chinese Medicine commonly used in Asian and Western countries for the prevention and treatment of cardiovascular disorders, such as atherosclerosis. Endothelial dysfunction and associated inflammatory processes have a critical role in the development of atherosclerosis. Endothelial progenitor cells (EPCs) have been demonstrated to be involved in certain aspects of the endothelial repair process. The present study aimed to investigate the putative protective effects of Tan IIA on EPCs injured by tumor necrosis factor-α (TNF-α). The potential effects of Tan IIA on TNF-α-stimulated EPC proliferation, migration, adhesion, in vitro tube formation ability and paracrine activity were investigated in the current study. The results indicated that TNF-α impaired EPC proliferation, migration, adhesion capacity and vasculogenesis ability in vitro as well as promoted EPC secretion of inflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and soluble CD40 ligand (sCD40L). However, Tan IIA was able to reverse these effects. In conclusion, these findings demonstrated that Tan IIA may have the potential to protect EPCs against damage induced by TNF-α. Therefore, these results may provide evidence for the pharmacological basis of Tan IIA and its potential use in the prevention and treatment of early atherosclerosis associated with EPC and endothelial damage. PMID:26095681

  17. Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease.

    PubMed Central

    Murch, S H; Braegger, C P; Walker-Smith, J A; MacDonald, T T

    1993-01-01

    This study determined the location and tissue density of cells immunoreactive for tumour necrosis factor alpha (TNF alpha) in intestinal specimens from 24 patients with chronic inflammatory bowel disease (15 with Crohn's disease, nine with ulcerative colitis) and 11 controls. There was significantly increased density of TNF alpha immunoreactive cells in the lamina propria of both ulcerative colitis and Crohn's disease specimens, although the distribution of these cells differed in the two conditions. In ulcerative colitis most of the TNF alpha immunoreactivity was seen in the subepithelial macrophages, with comparatively less in the deep lamina propria, while in Crohn's disease immunoreactive cells were distributed evenly throughout the lamina propria. Increased submucosal immunoreactivity was found only in Crohn's disease, in which TNF alpha positive macrophages tended to cluster around arterioles and venules, often infiltrating and disrupting vascular endothelium. It is suggested that this degree of TNF alpha production probably contributes significantly to the pathogenesis of both Crohn's disease and ulcerative colitis, by impairing the integrity of epithelial and endothelial membranes, increasing inflammatory cell recruitment, and by prothrombotic effects on the vascular endothelium. Images Figure 2 PMID:8031350

  18. Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes.

    PubMed

    Sauvé, Meghan; Hui, Sonya K; Dinh, Danny D; Foltz, Warren D; Momen, Abdul; Nedospasov, Sergei A; Offermanns, Stefan; Husain, Mansoor; Kroetsch, Jeffrey T; Lidington, Darcy; Bolz, Steffen-Sebastian

    2016-07-01

    Diabetes strongly associates with microvascular complications that ultimately promote multiorgan failure. Altered myogenic responsiveness compromises tissue perfusion, aggravates hypertension, and sets the stage for later permanent structural changes to the microcirculation. We demonstrate that skeletal muscle resistance arteries isolated from patients with diabetes have augmented myogenic tone, despite reasonable blood glucose control. To understand the mechanisms, we titrated a standard diabetes mouse model (high-fat diet plus streptozotocin [HFD/STZ]) to induce a mild increase in blood glucose levels. HFD/STZ treatment induced a progressive myogenic tone augmentation in mesenteric and olfactory cerebral arteries; neither HFD nor STZ alone had an effect on blood glucose or resistance artery myogenic tone. Using gene deletion models that eliminate tumor necrosis factor (TNF) or sphingosine kinase 1, we demonstrate that vascular smooth muscle cell TNF drives the elevation of myogenic tone via enhanced sphingosine-1-phosphate (S1P) signaling. Therapeutically antagonizing TNF (etanercept) or S1P (JTE013) signaling corrects this defect. Our investigation concludes that vascular smooth muscle cell TNF augments resistance artery myogenic vasoconstriction in a diabetes model that induces a small elevation of blood glucose. Our data demonstrate that microvascular reactivity is an early disease marker and advocate establishing therapies that strategically target the microcirculation. PMID:27207546

  19. Inositol lipid metabolism in vasopressin stimulated hepatocytes from rats infused with tumor necrosis factor

    SciTech Connect

    Spitzer, J.A.; Rodriguez de Turco, E.B. )

    1989-05-30

    We studied the effect of i.v. infusion of human recombinant tumor necrosis factor alpha (rHuTNF alpha, Cetus, 15 micrograms/100 g bw over 3 h) on vasopressin (VP)-stimulated {sup 32}P-inositol lipid turnover and the release of {sup 3}H-inositol phosphates in isolated rat hepatocytes. The early VP-induced decrease (within 30 s) in {sup 32}P-phosphatidylinositol 4-phosphate and {sup 32}P-phosphatidylinositol 4,5-bisphosphate labeling was significantly reduced (-40%) and at the same time the uptake of {sup 32}P into phosphatidic acid was 50% lower than in saline-infused (matched control) rats. Within 5 min of VP-stimulation, lower {sup 32}P phosphatidylinositol (-40%) and higher {sup 32}P-phosphatidic acid (+30%) labeling were observed in rHuTNF alpha-infused rats. Infusion of rHuTNF alpha also affected the VP-induced release of {sup 3}H-inositol phosphates. The accumulation of {sup 3}H-inositol-labeled water soluble products was decreased by 25% and 17% at 30 s and 10 min, respectively. These data show that rHuTNF alpha mimics early perturbations induced by Escherichia coli endotoxin infusion in VP-stimulated inositol lipid metabolism in rat hepatocytes.

  20. Tuberculosis infection versus anti-tumor necrosis factor therapy: screening challenges in psoriatic patients

    PubMed Central

    Solovan, Caius; Chiticariu, Elena; Timofte, Adelina; Stoia-Djeska, Irina

    2012-01-01

    Objectives The aim of this study was to analyze the performance of the tuberculin skin test (TST) for screening and monitoring patients treated with anti-tumor necrosis factor agents, in a high-incidence area. Methods A 3-year retrospective study was carried out on 268 subjects. The study included 68 patients with moderate-to-severe psoriasis, screened for latent tuberculosis infection (LTBI) and subjects without psoriasis (100 adults and 100 children) with close contact with infected individuals. Results Positive tuberculin skin test (TST) results (induration >5 mm) were observed in 70.5% (48/68) of patients with psoriasis, higher than those observed in subjects with suspicion of tuberculosis or with close contact with infected individuals: 51% (51/100) in the adult group and 30% (30/100) in the children group. Conclusions These results show that the prevalence of LTBI evaluated with the TST in the psoriatic group is higher than in subjects without psoriasis. Limitation The positive reactions were not confirmed by other verification methods.

  1. Protective effects of Tougu Xiaotong capsule on tumor necrosis factor-α-injured UMR-106 cells

    PubMed Central

    LIAO, NAISHUN; HUANG, YUNMEI; YE, JINXIA; CHEN, WENLIE; LI, ZUAN FANG; LIN, RUHUI; LI, XIHAI; ZHENG, LIANGPU; LIU, XIANXIANG

    2015-01-01

    Tumor necrosis factor-α (TNF-α) plays an important role in the abnormal metabolism of osteoblasts (OBs), which leads to subchondral bone (SB) alterations in osteoarthritis. In the present study, Tougu Xiaotong capsule (TXC), a traditional Chinese medicine, was used to treat TNF-α-injured OB-like cells. The cellular viability, mortality and ultramicroscopic morphology were evaluated. Thereafter, the activity of alkaline phosphatase (ALP), secretion of osteocalcin (OCN) and mineralization of nodules were analyzed. The results showed that TXC treatment significantly promoted cell proliferation, reduced cellular mortality and improved cellular ultrastructure, particularly that of the endoplasmic reticulum and nucleus. These data indicate that TXC is able to promote cell growth, as well as prevent inflammation in OB-like cells. Furthermore, the activity of ALP, secretion of OCN and mineralization of nodules were accelerated, and the calcium content of the TNF-α-injured OB-like cells was promoted by TXC treatment. These results indicate that TXC protected the OB-like cells from TNF-α-induced injuries. This may be a potential mechanism through which TXC regulates SB remodeling in the clinical treatment of osteoarthritis. PMID:26640571

  2. Human tumor necrosis factor alpha gene regulation by virus and lipopolysaccharide.

    PubMed Central

    Goldfeld, A E; Doyle, C; Maniatis, T

    1990-01-01

    We have identified a region of the human tumor necrosis factor alpha (TNF-alpha) gene promoter that is necessary for maximal constitutive, virus-induced, and lipopolysaccharide (LPS)-induced transcription. This region contains three sites that match an NF-kappa B binding-site consensus sequence. We show that these three sites specifically bind NF-kappa B in vitro, yet each of these sites can be deleted from the TNF-alpha promoter with little effect on the induction of the gene by virus or LPS. Moreover, when multimers of these three sites are placed upstream from a truncated TNF-alpha promoter, or a heterologous promoter, an increase in the basal level of transcription is observed that is influenced by sequence context and cell type. However, these multimers are not sufficient for virus or LPS induction of either promoter. Thus, unlike other virus- and LPS-inducible promoters that contain NF-kappa B binding sites, these sites from the TNF-alpha promoter are neither required nor sufficient for virus or LPS induction. Comparison of the sequence requirements of virus induction of the human TNF-alpha gene in mouse L929 and P388D1 cells reveals significant differences, indicating that the sequence requirements for virus induction of the gene are cell type-specific. However, the sequences required for virus and LPS induction of the gene in a single cell type, P388D1, overlap. Images PMID:2263628

  3. Phase I trial of intramuscularly administered tumor necrosis factor in patients with advanced cancer.

    PubMed

    Jakubowski, A A; Casper, E S; Gabrilove, J L; Templeton, M A; Sherwin, S A; Oettgen, H F

    1989-03-01

    A phase I trial of intramuscularly administered recombinant human tumor necrosis factor (rTNF) was conducted in 19 adult patients with advanced solid tumors. The agent was administered daily for up to five consecutive days every other week for two to four courses. Doses of rTNF ranged from 5 to 200 micrograms/m2/d. Dose-limiting toxicities were encountered at doses greater than 100 micrograms/m2/d. Toxicities included tenderness, erythema and induration at the site of injection, fatigue, fever, chills, headache, anorexia, nausea, vomiting, and diarrhea. Moderate to marked reductions in WBC and platelet counts were observed regularly at the highest dose levels, but none were clinically significant. Hepatic enzyme elevation was seen frequently, and two patients developed hyperbilirubinemia. Only one of seven patients treated with doses greater than 100 micrograms/m2/d completed the planned course of therapy. Even at the highest dose levels, serum concentrations of rTNF could only rarely be detected in the serum. No therapeutic responses were observed. The maximal tolerated dose (MTD) of rTNF in this trial was 150 micrograms/m2/d, administered for two courses. PMID:2918329

  4. Role of tumor necrosis factor-alpha in lipopolysaccharide-induced pathologic alterations.

    PubMed Central

    Remick, D. G.; Strieter, R. M.; Eskandari, M. K.; Nguyen, D. T.; Genord, M. A.; Raiford, C. L.; Kunkel, S. L.

    1990-01-01

    Tumor necrosis factor-alpha (TNF) has been implicated strongly as a principal mediator in the pathogenesis of septic shock. The authors investigated the in vivo production of TNF in CBA/J and CD-1 mice that had been primed by an intraperitoneal injection of complete Freund's adjuvant followed 2 weeks later by an intraperitoneal injection of lipopolysaccharide (LPS). TNF bioactivity peaked in both the ascites and plasma one hour after challenge, and TNF mRNA expression in the ascites cells peaked 30 minutes after LPS. After the induction of bioactivity, an interstitial pulmonary neutrophilic infiltrate occurred that was quantitated both morphometrically and by a myeloperoxidase (MPO) assay. Peripheral blood neutrophilia and lymphopenia developed after the LPS injection (PMNs: control, 46 +/- 2%; LPS, 65 +/- 3%; Lymphs control, 53 +/- 2%; LPS, 37 +/- 3%). Treatment with dexamethasone (Dex) completely inhibited the pulmonary neutrophilic infiltrate as measured by the (MPO) assay. Because Dex will inhibit the production of several cytokines, anti-TNF antiserum was given to mice at the same time as the LPS challenge to assess specifically the role of TNF in inducing these changes. This antiserum partially blocked the pulmonary neutrophil infiltrate, and completely blocked the peripheral blood changes at one hour after LPS. These data demonstrate that TNF plays an important role in the early pathophysiologic alterations that occur after systemic exposure to LPS. Images Figure 3 Figure 4 Figure 6 Figure 11 PMID:2297050

  5. Wound healing potential of pterospermum acerifolium wild. With induction of tumor necrosis factor - α

    PubMed Central

    Senapati, Aswini Kumar; Giri, Ranjan Kumar; Panda, Dibya Sundar; Satyanarayan, Sremantula

    2011-01-01

    Pterospermum acerifolium, a well-known plant in Indian medicine possesses various therapeutic properties including healing properties and cytokine induction. Wound healing activity of ethanolic extract of P. acerifolium flower along with its effect on tumor necrosis factor-α (TNF-α) was assessed using excision model of wound repair in Wistar albino rats. After application of the P. acerifolium extract, rate of epithelization with an increase in wound contraction was observed. Animals tropically treated with 10% P. acerifolium extract in petroleum jelly, the wound healing process was observed faster as compared to control group which were treated with petroleum jelly alone. A significant accelerated healing was noticed in animals which were additionally prefed with 250mg/kg body weight of ethanolic P. acerifolium extract daily for 20 consecutive days along with the topical application 10% P. acerifolium extract. During wound healing phase TNF-α level was found to be up regulated by P. acerifolium treatment. Early wound healing may be pronounced due to P. acerifolium extract elevating TNF−α production PMID:24826024

  6. Modulation of transmembrane signalling in HL-60 granulocytes by tumour necrosis factor-alpha.

    PubMed Central

    McLeish, K R; Klein, J B; Schepers, T; Sonnenfeld, G

    1991-01-01

    Differentiated HL-60 granulocytes were used to study the mechanism by which tumour necrosis factor-alpha (TNF) enhances responses to N-formyl-methionyl-leucylphenylalanine (FMLP). Cultivation of differentiated HL-60 cells with 100 units of TNF/ml for 24 h resulted in a 3-fold increase in superoxide release and 4-fold increase in prostaglandin E2 production on stimulation with 1 microM-FMLP. On the other hand, cultivation with TNF failed to increase phorbol diester stimulation of superoxide release. Formyl-peptide-receptor expression determined on isolated membranes from cells cultivated with TNF (TNF-M) was increased by 50% compared with membranes from control cells (NM). Similarly, FMLP binding to intact HL-60 cells was increased by cultivation with TNF. Guanine-nucleotide-binding proteins (G-protein) levels were not different between TNF-M and NM, as determined by pertussis-toxin-catalysed ADP-ribosylation and by immunoblotting with antisera recognizing alpha i2 subunit. Binding of guanosine 5'-[gamma-thio]triphosphate and GTP hydrolysis stimulated by FMLP were enhanced by about 50% in TNF-M. The efficiency of G-protein activation by formyl-peptide receptors did not differ between TNF-M and NM. TNF regulates expression of formyl-peptide receptors independently of G-protein levels. The regulation of receptor expression is one mechanism by which TNF enhances cell responses to formylated peptides. Images Fig. 4. PMID:1659380

  7. Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans.

    PubMed

    Krishnadas, Rajeev; Nicol, Alice; Sassarini, Jen; Puri, Navesh; Burden, A David; Leman, Joyce; Combet, Emilie; Pimlott, Sally; Hadley, Donald; McInnes, Iain B; Cavanagh, Jonathan

    2016-01-01

    Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression. PMID:26255693

  8. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha.

    PubMed

    Moss, M L; Jin, S L; Milla, M E; Bickett, D M; Burkhart, W; Carter, H L; Chen, W J; Clay, W C; Didsbury, J R; Hassler, D; Hoffman, C R; Kost, T A; Lambert, M H; Leesnitzer, M A; McCauley, P; McGeehan, G; Mitchell, J; Moyer, M; Pahel, G; Rocque, W; Overton, L K; Schoenen, F; Seaton, T; Su, J L; Becherer, J D

    1997-02-20

    Tumour-necrosis factor-alpha (TNF-alpha) is a cytokine that contributes to a variety of inflammatory disease states. The protein exists as a membrane-bound precursor of relative molecular mass 26K which can be processed by a TNF-alpha-converting enzyme (TACE), to generate secreted 17K mature TNF-alpha. We have purified TACE and cloned its complementary DNA. TACE is a membrane-bound disintegrin metalloproteinase. Structural comparisons with other disintegrin-containing enzymes indicate that TACE is unique, with noteable sequence identity to MADM, an enzyme implicated in myelin degradation, and to KUZ, a Drosophila homologue of MADM important for neuronal development. The expression of recombinant TACE (rTACE) results in the production of functional enzyme that correctly processes precursor TNF-alpha to the mature form. The rTACE provides a readily available source of enzyme to help in the search for new anti-inflammatory agents that target the final processing stage of TNF-alpha production. PMID:9034191

  9. Tumor necrosis factor alpha regulates in vivo intrapulmonary expression of ICAM-1.

    PubMed Central

    Mulligan, M. S.; Vaporciyan, A. A.; Miyasaka, M.; Tamatani, T.; Ward, P. A.

    1993-01-01

    Lung injury following deposition of IgG immune complexes is neutrophil-dependent and requires both tumor necrosis factor alpha (TNF alpha) and CD18. In the current studies, we have evaluated the relationship between TNF alpha and expression of intracellular adhesion molecule-1 (ICAM-1) in vitro and in vivo. In both rat pulmonary artery endothelial cells and human umbilical vein endothelial cells, TNF alpha induced an early (within 60 minutes) increase in ICAM-1 expression, followed by a peak at 6 to 8 hours, with relatively stable expression at 24 hours. Expression of E-selectin did not show the early phase (within 60 minutes) of up-regulation, peaked at 4 hours, and then declined thereafter. Using a radioimmunochemical assay in vivo, it was demonstrated that intrapulmonary deposition of IgG immune complexes caused a progressive increase in ICAM-1 expression in lung over an 8-hour period. In animals pretreated with antibody to TNF alpha, the intrapulmonary expression of ICAM-1 was significantly reduced. These results were confirmed by immunoperoxidase analysis of lung tissue. It was also shown that airway instillation of TNF alpha caused up-regulation of ICAM-1 in lung. These data support the concept that deposition of IgG immune complexes in lung induces intrapulmonary up-regulation of ICAM-1 in a manner that is TNF alpha-dependent. Images Figure 2 Figure 7 PMID:7685152

  10. Tumour necrosis factor (TNF-alpha) in leishmaniasis. II. TNF-alpha-induced macrophage leishmanicidal activity is mediated by nitric oxide from L-arginine.

    PubMed Central

    Liew, F Y; Li, Y; Millott, S

    1990-01-01

    Peritoneal macrophages from CBA mice incubated with recombinant murine tumour necrosis factor (TNF-alpha) are effective in killing the protozoa parasite Leishmania major in vitro. The leishmanicidal activity is directly correlated with the level of nitrite (NO2-) in the culture supernatants. The killing of intracellular parasites can be completely inhibited by L-NG-monomethyl arginine (L-NMMA), a specific inhibitor of the L-arginine:nitric oxide (NO) pathway. The level of NO2-, which is also a measurement of NO production, in the culture supernatant of TNF-alpha-activated macrophages can be progressively decreased to basal level with increasing concentrations of L-NMMA, but not with its D-enantiomer, D-NMMA. These data demonstrate that NO is an important effector mechanism in the TNF-alpha-induced macrophage killing of intracellular protozoa. PMID:2279740

  11. Daidzein suppresses tumor necrosis factor-α induced migration and invasion by inhibiting hedgehog/Gli1 signaling in human breast cancer cells.

    PubMed

    Bao, Cheng; Namgung, Hyeju; Lee, Jaehoo; Park, Hyun-Chang; Ko, Jiwon; Moon, Heejung; Ko, Hyuk Wan; Lee, Hong Jin

    2014-04-30

    In breast cancer, the cytokine tumor necrosis factor-α (TNF-α) induces cell invasion, although the molecular basis of it has not been clearly elucidated. In this study, we investigated the role of daidzein in regulating TNF-α induced cell invasion and the underlying molecular mechanisms. Daidzein inhibited TNF-α induced cellular migration and invasion in estrogen receptor (ER) negative MCF10DCIS.com human breast cancer cells. TNF-α activated Hedgehog (Hh) signaling by enhancing Gli1 nuclear translocation and transcriptional activity, which resulted in increased invasiveness; these effects were blocked by daidzein and the Hh signaling inhibitors, cyclopamine and vismodegib. Moreover, these compounds suppressed TNF-α induced matrix metalloproteinase (MMP)-9 mRNA expression and activity. Taken together, mammary tumor cell invasiveness was stimulated by TNF-α induced activation of Hh signaling; these effects were abrogated by daidzein, which suppressed Gli1 activation, thereby inhibiting migration and invasion. PMID:24724627

  12. Tissue factor pathway inhibitor levels in patients with homocystinuria.

    PubMed

    Cella, G; Burlina, A; Sbarai, A; Motta, G; Girolami, A; Berrettini, M; Strauss, W

    2000-06-01

    Thrombotic events are a well-recognized complication of homocystinuria. However, the mechanisms involved in the atherogenic and thrombotic effects of homocyst(e)ine remain incompletely understood. The objective of this study was to determine the role of endothelial cell activation/damage as indicated by levels of thrombomodulin, tissue factor and tissue factor pathway inhibitor, and factor VII activity in patients with homocystinuria. Six patients with homocystinuria, nonresponsive to pyridoxine, treated only with trimethylglycine (betaine) were injected with a bolus of 20 IU/kg body weight of unfractionated commercial heparin to induce the release of tissue factor pathway inhibitor from the vascular endothelium. Tissue factor, thrombomodulin, and factor VII activity were measured by enzyme-linked immunosorbent assay and clotting assay before heparin administration. Tissue factor pathway inhibitor antigen and activity were measured before and 5 minutes after the bolus of heparin. Levels of homocyst(e)ine were elevated (patients: 144.2+/-19.2 micromol/L; controls: 10.2+/-0.9 micromol/L); however, levels of thrombomodulin, tissue factor, and tissue factor pathway inhibitor antigen were not statistically different from the control group. In contrast, tissue factor pathway inhibitor activity showed a significantly increased level (patients: 2.09+/-0.34 U/L; controls: 1.14+/-0.20 U/L; p<0.05) that was correlated with homocyst(e)ine. Factor VII activity was significantly decreased (patients: 64.7+/-5.1%; controls: 91.4+/-4.7%; p<0.05) and inversely correlated with homocyst(e)ine. After heparin the patients released higher amounts of tissue factor pathway inhibitor antigen and activity compared with the control group; however, the difference was not statistically significant. Although not treated with antithrombotic drugs, none of the patients had any thromboembolic complications after starting betaine. In addition to betaine treatment, the enhanced factor pathway

  13. Synergistic activation of NF-kappaB by nontypeable Haemophilus influenzae and tumor necrosis factor alpha.

    PubMed

    Watanabe, Takahiro; Jono, Hirofumi; Han, Jiahuai; Lim, David J; Li, Jian-Dong

    2004-03-01

    Nontypeable Haemophilus influenzae (NTHi) is an important human pathogen causing otitis media in children and exacerbation of chronic obstructive pulmonary disease in adults. Like most other bacterial infections, NTHi infections are also characterized by inflammation, which is mainly mediated by cytokines and chemokines such as tumor necrosis factor alpha (TNF-alpha). Among a variety of transcription regulators, NF-kappaB has been shown to play a critical role in regulating the expression of large numbers of genes encoding inflammatory mediators. In review of the current studies on NF-kappaB regulation, most of them have focused on investigating how NF-kappaB is activated by a single inducer at a time. However, in bacteria-induced inflammation in vivo, multiple inducers including both exogenous and endogenous mediators are present simultaneously. A key issue that has yet to be addressed is whether the exogenous inducers such as NTHi and the endogenous factors such as TNF-alpha activate NF-kappaB in a synergistic manner. We show that NTHi and TNF-alpha, when present together, synergistically induce NF-kappaB activation via two distinct signaling pathways: NF-kappaB translocation-dependent and -independent pathways. The NF-kappaB translocation-dependent pathway involves NF-kappaB-inducing kinase-IkappaB kinase beta/gamma-dependent phosphorylation and degradation of IkappaBalpha, whereas the NF-kappaB translocation-independent pathway involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase kinase 1-dependent activation of MAPK kinase 3/6-p38 MAPK pathway. In addition, the same signaling pathways are also involved in synergistic induction of TNF-alpha, IL-1beta, and IL-8. These studies should deepen our understanding of the molecular mechanisms underlying the combinatorial regulation of inflammation and lead to development of therapeutic strategies for NTHi-induced infections. PMID:14993593

  14. Disturbance of Tumor Necrosis Factor Alpha-Mediated Beta Interferon Signaling in Cervical Carcinoma Cells

    PubMed Central

    Bachmann, Anastasia; Hanke, Brigitte; Zawatzky, Rainer; Soto, Ubaldo; van Riggelen, Jan; zur Hausen, Harald; Rösl, Frank

    2002-01-01

    In the present study we show that malignant human papillomavirus (HPV)-positive cells lost their ability to synthesize endogenous beta interferon (IFN-β) upon tumor necrosis factor alpha (TNF-α) treatment. IFN-β transcription, however, was reinducible in nonmalignant HPV-positive cells, which was confirmed in functional protection assays against encephalomyocarditis virus or vesicular stomatitis virus infections. Addition of neutralizing antibodies against IFN-β blocked the antiviral effect, excluding the possibility that other IFN types were involved. Conversely, both malignant and immortalized cells could be protected against viral cytolysis when either IFN-β, IFN-α, or IFN-γ was added exogenously. This indicates that only the cross talk between TNF-α and the IFN-β pathways, and not IFN-α/β and IFN-γ signaling in general, is perturbed in cervical carcinoma cells. Notably, full virus protection was restricted exclusively to nonmalignant cells, indicating that the antiviral effect correlates with the growth-inhibitory and virus-suppressive properties of TNF-α. The IFN-regulatory factors IRF-1 and p48 (ISGF3γ) emerged as key regulatory molecules in the differential IFN-β response, since their transcription was either absent or only inefficiently enhanced in tumorigenic cells upon treatment with TNF-α. Inducibility of both genes, however, became reestablished in cervical carcinoma cells, which were complemented to nontumorigenicity after somatic cell hybridization. Complementation was paralleled by the entire reconstitution of cytokine-mediated IFN-β expression and the ability of TNF-α to exert an antiviral state. In contrast, under conditions where tumor suppression was not accomplished upon somatic cell hybridization, neither expression of IRF-1, p48, and IFN-β nor antiviral activity could be restored. PMID:11739693

  15. Adrenomedullin mediates tumor necrosis factor-α-induced responses in dorsal root ganglia in rats.

    PubMed

    Chen, Yajuan; Zhang, Yan; Huo, Yuanhui; Wang, Dongmei; Hong, Yanguo

    2016-08-01

    Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pain peptide. This study investigated the possible involvement of AM in tumor necrosis factor-alpha (TNF-α)-induced responses contributing to neuronal plasticity in the dorsal root ganglia (DRG). Exposure of the DRG explant cultures to TNF-α (5nM) for 48h upregulated the expression of AM mRNA. The treatment with TNF-α also increased the level of CGRP, CCL-2 and MMP-9 mRNA in the cultured DRG. This increase was attenuated by the co-treatment with the selective AM receptor antagonist AM22-52 (2μM). The blockade of AM receptors inhibited TNF-α-induced increase of the glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), phosphorylated cAMP response element binding protein (pCREB) and nuclear factor kappa B (pNF-κB) proteins. On the other hand, the treatment with the AM receptor agonist AM1-50 (10nM) for 96h induced an increase in the level of GFAP, IL-1β, pCREB and pNF-κB proteins. The inhibition of AM activity did not change TNF-α-induced phosphorylation of extracellular signal-related kinase (pERK) while the treatment with AM1-50 still increased the level of pERK in the cultured DRG. Immunofluorescence assay showed the colocalization of AM-like immunoreactivity (IR) with TNF-α-IR in DRG neurons. The present study suggests that the increased AM receptor signaling mediated the many, but not all, TNF-α-induced activities, contributing to peripheral sensitization in neuropathic pain. PMID:27184601

  16. Association of the tumor necrosis factor -308 A/G promoter polymorphism with Tourette syndrome.

    PubMed

    Keszler, G; Kruk, E; Kenezloi, E; Tarnok, Z; Sasvari-Szekely, M; Nemoda, Z

    2014-12-01

    Several lines of evidence suggest that certain subtypes of obsessive-compulsive and tic disorders might be paediatric manifestations of post-streptococcal autoimmunity caused by cross-reactive autoantibodies. As tumor necrosis factor (TNF) is known to play a seminal role in coordinating the humoral immune response, TNF gene polymorphisms have been proposed as genetic risk factors both in obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). The aim of this study was to investigate two TNF promoter polymorphisms (-238 A/G: rs361525 and -308 A/G: rs1800629) on the genetic susceptibility to OCD and TS in a child psychiatric sample (102 patients with OCD and 117 patients with TS). In the case-control set-up, the genotype and allele frequencies were compared to a control group from the general population (n = 405). As a control child psychiatric sample, 194 children with attention-deficit hyperactivity disorder were also genotyped. Our results revealed that the TNF -308 G-allele was more frequent in children with TS compared to controls (90.2% vs 84.8%, P = 0.037). For confirmation of this genetic association, a family-based analysis, the transmission disequilibrium test was used, which showed preferential transmission of the G-allele to patients with TS (nominal P-value 0.011). Moreover, this allele was also transmitted more frequently to children with tic symptoms (nominal P-value 0.039). No association was found between OCD or obsessive-compulsive symptoms and the studied TNF polymorphisms. Based on these findings, the TNF -308 G-allele can be associated with Tourette syndrome, highlighting the potential pathophysiological role of TNF dysregulation. PMID:25256363

  17. Risk factors for outbreaks of infectious pancreatic necrosis (IPN) and associated mortality in Norwegian salmonid farming.

    PubMed

    Bang Jensen, Britt; Kristoffersen, Anja B

    2015-06-01

    Infectious pancreatic necrosis (IPN) has for many years been considered one of the most important restraints to the production of salmonids in European aquaculture. In Norway, the disease is responsible for high losses in post-smolts in the first few weeks after sea transfer. Despite the importance of IPN, there are few epidemiological studies on risk factors and mitigation strategies. In this paper, we present analyses of data from all cohorts put to sea in 2009 to 2012 on Norwegian marine salmonid farms. The data used were obtained from national registers on salmonid production and disease outbreaks. The results showed that the risk of IPN outbreak was higher for spring versus autumn cohorts, Atlantic salmon versus rainbow trout and for cohorts on farms with previous history of IPN. The risk increased with increasing cohort size and infection pressure, whereas increasing temperature and weight at sea transfer decreased the risk. Estimations from a model of cumulative mortality within the first 6 mo after sea transfer showed that mortality in cohorts with IPN increased to approximately 7.2% as compared to a 'baseline' cohort with a mortality of 3.4%. If the cohort had both IPN and pancreas disease (PD), the estimated mortality increased to 12.9%, and cohorts with both IPN, PD and heart and skeletal muscle inflammation (HSMI) had an estimated mortality of 16.6%, when all other significant factors were kept constant (these were cohort type, year, temperature at sea transfer and weight at sea transfer). Our results provide valuable inputs for mitigation strategies and for economic modelling of consequences of disease. PMID:26036825

  18. Dendritic cell-derived tumor necrosis factor α modifies airway epithelial cell responses.

    PubMed

    Lutfi, R; Ledford, J R; Zhou, P; Lewkowich, I P; Page, K

    2012-01-01

    Mucosal dendritic cells (DC) are intimately associated with the airway epithelium and thus are ideally situated to be first responders to pathogens. We hypothesize that DC drive innate immune responses through early release of tumor necrosis factor (TNF) α, which drives airway epithelial cell responses. In a mouse model, TNFα release was significantly increased following a single exposure to German cockroach (GC) frass, an event independent of neutrophil recruitment into the airways. While lung epithelial cells and alveolar macrophages failed to release TNFα following GC frass exposure, bone marrow-derived DC (BMDC) produced substantial amounts of TNFα suggesting their importance as early responding cells. This was confirmed by flow cytometry of pulmonary myeloid DC. Addition of GC frass-pulsed BMDC or conditioned media from GC frass-pulsed BMDC to primary mouse tracheal epithelial cells (MTEC) or MLE-15 cells induced chemokine (C-C) motif ligand (CCL) 20 and granulocyte macrophage (GM) colony-stimulating factor (CSF), both of which are important for DC recruitment, survival and differentiation. Importantly, DC do not produce CCL20 or GM-CSF following allergen exposure. Blocking TNFα receptor 1 (TNFR1) completely abolished chemokine production, suggesting that BMDC-derived TNFα induced airway epithelial cell activation and enhancement of the innate immune response. Lastly, blocking TNFR1 in vivo resulted in significantly decreased CCL20 and GM-CSF production in the lungs of mice. Together, our data strongly suggest that DC-derived TNFα plays a crucial role in the initiation of innate immune responses through the modification of airway epithelial cell responses. PMID:22517116

  19. Effects of botulinum toxin type D on secretion of tumor necrosis factor from human monocytes

    SciTech Connect

    Imamura, K.; Spriggs, D.; Ohno, T.; Kufe, D.

    1989-05-01

    Botulinum toxins are potent neurotoxins which block the release of neurotransmitters. The effects of these toxins on hematopoietic cells, however, are unknown. Monocytes secrete a variety of polypeptide growth factors, including tumor necrosis factor (TNF). In the study reported here, the effects of botulinum toxin type D on the secretion of TNF from human monocytes were examined. The results demonstrate that biotulinum toxin type D inhibits the release of TNF from monocytes activated by lipopolysaccharide (LPS) but not by 12-O-tetradecanoylphorbol-13-acetate. Botulinum toxin type D had no detectable effect on intracellular TNF levels in LPS-treated monocytes, indicating that the effects of this toxin involve the secretory process. This inhibitory effect of botulinum toxin type D on TNF secretion from LPS-treated monocytes was partially reversed by treatment with 12-O-tetradecanoylphorbol-13-acetate or introduction of guanosine 5'-(/gamma/-thio)t-riphosphate into these cells. The results demonstrate that TNF secretion is regulated by at least two distinct guanine nucleotide-binding proteins, one responsible for the activation of phospholiphase C and another which acts as a substrate for botulinum toxin type D. ADP-ribosylation of monocyte membranes by botulinum toxin type D demonstrated the presence of three substrates with M/sub r/s of 45,000, 21,000, and 17,000. While the role of these substrates in exocytosis is unknown, the results suggest that the M/sub r/ 21,000 substrate is involved in a process other than TNF secretion.

  20. Induction of the E-selectin promoter by interleukin 1 and tumour necrosis factor alpha, and inhibition by glucocorticoids.

    PubMed Central

    Ray, K P; Farrow, S; Daly, M; Talabot, F; Searle, N

    1997-01-01

    Cytokine-induced expression of the endothelial cell surface adhesion molecule E-selectin is inhibited by glucocorticoids (GCs). To investigate possible mechanisms for steroid inhibition, a reporter gene (ESAP) was constructed, comprising the cytokine responsive region of the E-selectin gene (nt -383 to +81) coupled to alkaline phosphatase (AP). In A549 cells stably transfected with the ESAP gene, AP production was highly responsive to the cytokines interleukin 1beta (IL-1beta) and tumour necrosis factor alpha, with ED50 values of 3 pM and 1000 pM respectively. Furthermore the cytokine-induced AP responses were inhibited by GCs, indicating that both transcriptional activation and GC suppression of the E-selectin gene were mediated via regulatory elements within the same region of the promoter. The relative potencies of GC drugs as inhibitors of IL-1beta (10 pM)-stimulated ESAP-gene activation were fluticasone> beclomethasone>dexamethasone, with IC50 values of 0.13, 1.1 and 2.7 nM respectively. Inhibition by fluticasone was blocked by the GC receptor (GR) antagonist drug mifepristone (Ru486), which is consistent with the suppressive effects of GCs being mediated via the GR. However, because the E-selectin promoter lacks a consensus glucocorticoid responsive element, mechanisms for inhibition independent of GR-DNA binding were investigated. Evidence that GCs also inhibited cytokine activation of a synthetic nuclear factor kappaB (NFkappaB)-driven reporter gene transiently transfected into A549 cells suggested that interference with the activation and/or function of this transcription factor was important for GC inhibition of ESAP. However, in A549-ESAP cells, fluticasone (100 nM) did not affect IL-1beta (10 pM)-induced IkBalpha degradation, NFkappaB-p65 nuclear translocation or the DNA-binding capacity of nuclear NFkappaB complexes, over a period during which cytokine-induced ESAP-gene activation was inhibited. Finally, there was no evidence to suggest that GC

  1. HSP90 inhibitors enhance differentiation and MITF (microphthalmia transcription factor) activity in osteoclast progenitors.

    PubMed

    van der Kraan, A Gabrielle J; Chai, Ryan C C; Singh, Preetinder P; Lang, Benjamin J; Xu, Jiake; Gillespie, Matthew T; Price, John T; Quinn, Julian M W

    2013-04-15

    The HSP90 (heat-shock protein 90) inhibitor 17-AAG (17-allylamino-demethoxygeldanamycin) increases osteoclast formation both in vitro and in vivo, an action that can enhance cancer invasion and growth in the bone microenvironment. The cellular mechanisms through which 17-AAG exerts this action are not understood. Thus we sought to clarify the actions of 17-AAG on osteoclasts and determine whether other HSP90 inhibitors had similar properties. We determined that 17-AAG and the structurally unrelated HSP90 inhibitors CCT018159 and NVP-AUY922 dose-dependently increased RANKL [receptor activator of NF-κB (nuclear factor κB) ligand]-stimulated osteoclastogenesis in mouse bone marrow and pre-osteoclastic RAW264.7 cell cultures. Moreover, 17-AAG also enhanced RANKL- and TNF (tumour necrosis factor)-elicited osteoclastogenesis, but did not affect RANKL-induced osteoclast survival, suggesting that only differentiation mechanisms are targeted. 17-AAG affected the later stages of progenitor maturation (after 3 days of incubation), whereas the osteoclast formation enhancer TGFβ (transforming growth factor β) acted prior to this, suggesting different mechanisms of action. In studies of RANKL-elicited intracellular signalling, 17-AAG treatment did not increase c-Fos or NFAT (nuclear factor of activated T-cells) c1 protein levels nor did 17-AAG increase activity in luciferase-based NF-κB- and NFAT-response assays. In contrast, 17-AAG treatment (and RANKL treatment) increased both MITF (microphthalmia-associated transcription factor) protein levels and MITF-dependent vATPase-d2 (V-type proton ATPase subunit d2) gene promoter activity. These results indicate that HSP90 inhibitors enhance osteoclast differentiation in an NFATc1-independent manner that involves elevated MITF levels and activity. PMID:23379601

  2. Structural Insights into mitochondrial antiviral signaling protein (MAVS)-tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling.

    PubMed

    Shi, Zhubing; Zhang, Zhen; Zhang, Zhenzhen; Wang, Yanyan; Li, Chuanchuan; Wang, Xin; He, Feng; Sun, Lina; Jiao, Shi; Shi, Weiyang; Zhou, Zhaocai

    2015-10-30

    In response to viral infection, cytosolic retinoic acid-inducible gene I-like receptors sense viral RNA and promote oligomerization of mitochondrial antiviral signaling protein (MAVS), which then recruits tumor necrosis factor receptor-associated factor (TRAF) family proteins, including TRAF6, to activate an antiviral response. Currently, the interaction between MAVS and TRAF6 is only partially understood, and atomic details are lacking. Here, we demonstrated that MAVS directly interacts with TRAF6 through its potential TRAF6-binding motif 2 (T6BM2; amino acids 455-460). Further, we solved the crystal structure of MAVS T6BM2 in complex with the TRAF6 TRAF_C domain at 2.95 Å resolution. T6BM2 of MAVS binds to the canonical adaptor-binding groove of the TRAF_C domain. Structure-directed mutational analyses in vitro and in cells revealed that MAVS binding to TRAF6 via T6BM2 instead of T6BM1 is essential but not sufficient for an optimal antiviral response. Particularly, a MAVS mutant Y460E retained its TRAF6-binding ability as predicted but showed significantly impaired signaling activity, highlighting the functional importance of this tyrosine. Moreover, these observations were further confirmed in MAVS(-/-) mouse embryonic fibroblast cells. Collectively, our work provides a structural basis for understanding the MAVS-TRAF6 antiviral response. PMID:26385923

  3. Vascular endothelial growth factor promotes macrophage apoptosis through stimulation of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT).

    PubMed

    Petreaca, Melissa L; Yao, Min; Ware, Carl; Martins-Green, Manuela M

    2008-01-01

    Resolution of inflammation is critical for normal wound healing. Inflammation is prolonged and fails to resolve properly in chronic wounds. We used in vivo and in vitro approaches to show that vascular endothelial growth factor (VEGF) induces macrophage apoptosis and to delineate mechanisms involved in this process. VEGF inhibition during wound healing leads to an increased number of macrophages remaining in wounds, suggesting the involvement of VEGF in removal of these cells from the wound. If this effect has physiological relevance, it likely occurs via apoptosis. We show that VEGF increases apoptosis of macrophages in vitro using Annexin V-FITC staining and caspase activation. Microarray analysis, reverse transcription-polymerase chain reaction, and immunoblotting showed that VEGF increases the expression of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT) in macrophages. We also show that in macrophages LIGHT promotes apoptosis through the lymphotoxin beta receptor. Moreover, inhibition of LIGHT prevents VEGF-induced death, suggesting that LIGHT mediates VEGF-induced macrophage apoptosis. Taken together, our results identify a novel role for VEGF and for LIGHT in macrophage apoptosis during wound healing, an event critical in the resolution of inflammation. This finding may lead to the development of new strategies to improve resolution of inflammation in problematic wounds. PMID:19128255

  4. Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions

    PubMed Central

    Hildebrand, Joanne M.; Yi, Zuoan; Buchta, Claire M.; Poovassery, Jayakumar; Stunz, Laura L.; Bishop, Gail A.

    2011-01-01

    Summary A large and diverse group of receptors utilizes the family of cytoplasmic signaling proteins known as tumor necrosis factor receptor (TNFR)-associated factors (TRAFs). In recent years, there has been a resurgence of interest and exploration of the roles played by TRAF3 and TRAF5 in cellular regulation, particularly in cells of the immune system, the cell types of focus in this review. This work has revealed that TRAF3 and TRAF5 can play diverse roles for different receptors even in the same cell type, as well as distinct roles in different cell types. Evidence indicates that TRAF3 and TRAF5 play important roles beyond the TNFR-superfamily (SF) and viral mimics of its members, mediating certain innate immune receptor and cytokine receptor signals, and most recently, signals delivered by the T-cell receptor (TCR) signaling complex. Additionally, much research has demonstrated the importance of TRAF3-mediated cellular regulation via its cytoplasmic interactions with additional signaling proteins. In particular, we discuss below evidence for the participation by TRAF3 in a number of the regulatory post-translational modifications involving ubiquitin that are important in various signaling pathways. PMID:22017431

  5. Tumour necrosis factor-alpha up-regulates decay-accelerating factor gene expression in human intestinal epithelial cells.

    PubMed Central

    Andoh, A; Fujiyama, Y; Sumiyoshi, K; Sakumoto, H; Okabe, H; Bamba, T

    1997-01-01

    The increased expression of decay-accelerating factor (DAF) has been detected in intestinal epithelial cells at the inflamed mucosa. In this study, we examined the effects of tumour necrosis factor (TNF)-alpha on DAF expression in three intestinal epithelial cell lines. DAF mRNA expression was evaluated by Northern blot analysis, and DAF protein expression was analysed by biotin labelling and immunoprecipitation. TNF-alpha induced a marked increase in DAF mRNA and protein expression in HT-29, T84 and Caco-2 cells. In HT-29 cells, the effects of TNF-a on DAF mRNA accumulation were observed in a dose-dependent manner; DAF mRNA accumulation reached a maximum at 3-6 hr, and then gradually decreased. These effects of TNF-alpha required de novo protein synthesis. Messenger RNA stability studies suggested that TNF-alpha partially regulated DAF gene expression by a posttranscriptional mechanism. Moreover, the combination of TNF-alpha and interleukin (IL)-4 induced an additive increase in DAF mRNA accumulation in HT-29 and T84 cells. In human intestinal epithelial cells, TNF-alpha acts as a potent inducer of DAF mRNA expression, indicating an important role for TNF-alpha in the regulation of DAF expression at the inflamed mucosa. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 Figure 7 Figure 8 PMID:9155641

  6. Epidermal Platelet-activating Factor Receptor Activation and Ultraviolet B Radiation Result in Synergistic Tumor Necrosis Factor-alpha Production

    PubMed Central

    Wolverton, Jay E.; Al-Hassani, Mohammed; Yao, Yongxue; Zhang, Qiwei; Travers, Jeffrey B.

    2010-01-01

    Ultraviolet B radiation (UVB) is a potent stimulator of epidermal cytokine production which has been implicated in photoaggravated dermatoses. In addition to cytokines such as tumor necrosis factor-α (TNF-α), UVB generates bioactive lipids including platelet-activating factor (PAF). Our previous studies have demonstrated that UVB-mediated production of keratinocyte TNF-α is in part due to PAF. The current studies use a human PAF-receptor (PAF-R) negative epithelial cell line transduced with PAF-Rs and PAF–R-deficient mice to demonstrate that activation of the epidermal PAF-R along with UVB irradiation results in a synergistic production of TNF-α. It should be noted that PAF-R effects are mimicked by the protein kinase C (PKC) agonist phorbol myristic acetate, and are inhibited by pharmacological antagonists of the PKC gamma isoenzyme. These studies suggest that concomitant PAF-R activation and UVB irradiation results in a synergistic production of the cytokine TNF-α which is mediated in part via PKC. These studies provide a novel potential mechanism for photosensitivity responses. PMID:19769579

  7. Role of tumor necrosis factor-alpha in zebrafish retinal neurogenesis and myelination

    PubMed Central

    Lei, Xu-Dan; Sun, Yan; Cai, Shi-Jiao; Fang, Yang-Wu; Cui, Jian-Lin; Li, Yu-Hao

    2016-01-01

    AIM To investigate the role of tumor necrosis factor-alpha (TNF-α) in zebrafish retinal development and myelination. METHODS Morpholino oligonucleotides (MO), which are complementary to the translation start site of the wild-type embryonic zebrafish TNF-α mRNA sequence, were synthesized and injected into one- to four-cell embryos. The translation blocking specificity was verified by Western blotting using an anti-TNF-α antibody, whole-mount in situ hybridization using a hepatocyte-specific mRNA probe ceruloplasmin (cp), and co-injection of TNF-α MO and TNF-α mRNA. An atonal homolog 7 (atoh7) mRNA probe was used to detect neurogenesis onset. The retinal neurodifferentiation was analyzed by immunohistochemistry using antibodies Zn12, Zpr1, and Zpr3 to label ganglion cells, cones, and rods, respectively. Myelin basic protein (mbp) was used as a marker to track and observe the myelination using whole-mount in situ hybridization. RESULTS Targeted knockdown of TNF-α resulted in specific suppression of TNF-α expression and a severely underdeveloped liver. The co-injection of TNF-α MO and mRNA rescued the liver development. Retinal neurogenesis in TNF-α morphants was initiated on time. The retina was fully laminated, while ganglion cells, cones, and rods were well differentiated at 72 hours post-fertilization (hpf). mbp was expressed in Schwann cells in the lateral line nerves and cranial nerves from 3 days post-fertilization (dpf) as well as in oligodendrocytes linearly along the hindbrain bundles and the spinal cord from 4 dpf, which closely resembled its endogenous profile. CONCLUSION TNF-α is not an essential regulator for retinal neurogenesis and optic myelination. PMID:27366683

  8. Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis

    SciTech Connect

    Mulcahy, B.; Waldron-Lynch, F.; Adams, C.; O`Gara, F.

    1996-09-01

    The major histocompatibility complex class H1 tumor necrosis factor-tymphotoxin (TNF-LT) region (6p21.3) was investigated as a possible susceptibility locus for rheumatoid arthritis (RA). Inheritance of five TNF microsatellite markers was determined in 50 multiplex families. Overall, 47 different haplotypes were observed. One of these, the TNF a6, b5, c1, d3, e3 (H1) haplotype, was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P < .005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3 % not transmitted to affected offspring (P = .0003). The TNF a6 and TNF c1 alleles were individually associated with RA (P = .0005 and .0008, respectively), as were the HLA-DRB1 {open_quotes}shared epitope{close_quotes} (SE) (P = .0001) and HLA-DRB1*0401 (P = .0018). Both univariate and bivariate conditional logistic regression analysis showed significant effects of TNF c1 and SE in increasing risk to RA (P < .001). Stratification by the presence of SE indicated an independent effect of the TNFc1 allele (P = .0003) and the HLA A1, BS, DR3 extended haplotype (always TNFa2, b3, c1, d1, e3) (P = .0027) in SE heterozygotes, while the H1 haplotype was associated with RA in SE homozygotes (P = .0018). The TNF-LT region appears to influence susceptibility to RA, distinct from HLA-DR. 50 refs., 1 fig., 1 tab.

  9. Isolated guinea pig gastric chief cells express tumour necrosis factor receptors coupled with the sphingomyelin pathway.

    PubMed Central

    Fiorucci, S; Santucci, L; Migliorati, G; Riccardi, C; Amorosi, A; Mancini, A; Roberti, R; Morelli, A

    1996-01-01

    The tumour necrosis factor alpha (TNF), has been implicated in the pathogenesis of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy and Helicobacter pylori induced gastritis. Both conditions are characterised by high plasma pepsinogen concentrations, which are thought to reflect an increased rate of enzyme release by the pepsinogen secreting (chief) cells. The mechanisms responsible for this cell dysfunction are unknown. This study investigates whether chief cells express TNF receptors and, if so, whether their activation results in cell death. Immunohistochemical studies conducted with monoclonal antibodies (mAbs) directed against two TNF receptor associated proteins of 55 kDa (TNF-R1) and 75 kDa (TNF-R2) showed that TNF binding sites were expressed in approximately 100% gastric chief cells. Western blot analysis of whole chief cell lysates probed with the TNF-R1 and TNF-R2 mAbs gave two distinct bands of 55 and 75 kDa in the immunoprecipitate. Incubating chief cells with TNF caused concentration and time dependent cell death, which was prevented by pretreating the cells with anti-TNF receptor mAbs. Exposing the cells to TNF reduced sphingomyelin content by 25%. Sphingomyelinase (10(-6) to 10(-2) IU/ml) mimicked the effect of TNF in that it provoked a concentration and time dependent reduction in chief cell viability and increased pepsinogen release. In conclusion, gastric chief cells express two TNF receptors partially linked to the sphingomyelin pathway. TNF induced chief cell dysfunction might be responsible for the high plasma pepsinogen concentrations seen in patients with NSAID gastropathy or H pylori induced gastritis. Images Figure 1 Figure 2 PMID:8801194

  10. Estimation of salivary tumor necrosis factor-alpha in chronic and aggressive periodontitis patients

    PubMed Central

    Varghese, Sheeja S.; Thomas, Hima; Jayakumar, N. D.; Sankari, M.; Lakshmanan, Reema

    2015-01-01

    Introduction: Periodontitis is a chronic bacterial infection characterized by persistent inflammation, connective tissue breakdown and alveolar bone destruction mediated by pro-inflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is an important pro-inflammatory mediator that produced causes destruction of periodontal tissues. Objective: The aim of the study is to estimate the salivary TNF-α in chronic and aggressive periodontitis and control participants and further correlate the levels with clinical parameter such as gingival index (GI), plaque index (PI), probing pocket depth (PPD) and clinical attachment loss. Materials and Methods: The study population consisted of 75 subjects age ranging from 25 to 55 years attending the outpatient section of Department of Periodontics, Saveetha Dental College and Hospital. The study groups included Groups 1, 2, and 3 with participants with healthy periodontium (n = 25), generalized chronic periodontitis (n = 25) and generalized aggressive periodontitis (n = 25), respectively. Salivary samples from the participants were used to assess the TNF-α levels using enzyme-linked immunosorbent assay. Results: GI and PI were found to be significantly higher in chronic and aggressive periodontitis compared to the controls. The mean TNF-α value in chronic periodontitis patients (12.92 ± 17.21 pg/ml) was significantly higher than in control subjects (2.15 ± 3.60 pg/ml). Whereas, in aggressive periodontitis patients the mean TNF-α (7.23 ± 7.67) were not significantly different from chronic periodontitis or healthy subjects. Among periodontitis participants, aggressive periodontitis subjects exhibited a significant positive correlation between the salivary TNF-α and PPD. Conclusion: Salivary TNF-α levels are significantly higher in chronic periodontitis than in healthy subjects, but there was no significant correlation with the clinical parameters. PMID:26604566

  11. Increased tumour necrosis factor α production in mesenteric lymph nodes of cirrhotic patients with ascites

    PubMed Central

    Genescà, J; Martí, R; Rojo, F; Campos, F; Peribáñez, V; Gónzalez, A; Castells, L; Ruiz-Marcellán, C; Margarit, C; Esteban, R; Guardia, J; Segura, R

    2003-01-01

    Background: Cytokines produced in mesenteric lymph nodes of cirrhotic rats with bacterial translocation may participate in circulatory alterations of cirrhosis. Aim: To investigate whether cirrhotic patients present an increased local generation of cytokines in mesenteric lymph nodes. Methods: Mesenteric lymph nodes from 26 cirrhotic and 10 control patients were assessed for tumour necrosis factor α (TNF) and interleukin 6 mRNA and protein expression by competitive reverse transcription-polymerase chain reaction, and by enzyme immunoassay and immunohistochemistry, respectively. Results: Interleukin 6 levels were not different between cirrhotics and controls. Protein and mRNA TNF levels in mesenteric lymph nodes from cirrhotics were higher than in controls (p<0.05). Tissue expression of TNF by immunohistochemistry was more abundant in cirrhotics. Ascitic patients showed higher TNF levels (47 (34–54) pg/mg protein) than patients without ascites (18 (17–25) pg/mg protein) (p<0.001). Elevated TNF levels (>28 pg/mg protein) in cirrhotics were associated with a higher Child-Pugh score, the antecedent of ascites, a lower prothrombin rate, and higher bilirubin and blood TNF levels. The strongest association, confirmed by multivariate analysis, was with the presence of ascites (p<0.001). Bacterial infections after transplantation, mainly by enteric bacteria, were only detected in patients with high TNF levels in mesenteric lymph nodes (33% of patients; p=0.05). Conclusion: Patients with advanced liver cirrhosis, and especially with ascites, have increased local production of TNF in mesenteric lymph nodes that, in common with experimental cirrhosis, may also be induced by bacterial translocation. PMID:12801966

  12. Role of interleukin 1 and tumor necrosis factor on energy metabolism in rabbits

    SciTech Connect

    Tredget, E.E.; Yu, Y.M.; Zhong, S.; Burini, R.; Okusawa, S.; Gelfand, J.A.; Dinarello, C.A.; Young, V.R.; Burke, J.F.

    1988-12-01

    A study of the combined effects of intravenous infusion of the recombinant cytokines beta-interleukin 1 (IL-1) and alpha-tumor necrosis factor (TNF) on energy substrate metabolism in awake, conditioned, adult rabbits was performed. After a 2-h basal or control period, 48-h fasted rabbits were administered TNF and IL-1 as a bolus (5 micrograms/kg) followed by a continuous intravenous infusion (25 ng.kg-1.min-1) for 3 h. Significant increases in plasma lactate (P less than 0.01), glucose (P less than 0.01), and triglycerides (P less than 0.05) occurred during the combined infusion of IL-1 and TNF, whereas neither cytokine alone had no effect. There was a 33% increase in the rate of glucose appearance (P less than 0.05), but glucose clearance was not altered compared with the control period. Glucose oxidation increased during the combined cytokine infusion period and glucose recycling increased by 600% (P less than 0.002). Lactic acidosis and decreased oxygen consumption, as a result of the cytokine infusions, indicated development of anaerobic glycolytic metabolism. A reduction in the activity state of hepatic mitochondrial pyruvate dehydrogenase (65 vs. 82% in control animals, P less than 0.05) was consistent with the observed increase in anaerobic glycolysis. Thus the combined infusion of IL-1 and TNF in rabbits produces metabolic manifestations seen in severe injury and sepsis in human patients and, as such, may account for the profound alterations of energy metabolism seen in these conditions.

  13. Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence

    SciTech Connect

    Zheng, H.; Crowley, J.J.; Chan, J.C.; Hoffmann, H.; Hatherill, J.R.; Ishizaka, A.; Raffin, T.A. )

    1990-11-01

    Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents that attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.

  14. Tumor necrosis factor receptor-II nt587 polymorphism in Chinese Han patients with ankylosing spondylitis.

    PubMed

    Li, X; Wang, M; Ma, R; Zhang, T; Liu, J; Chen, J W; Peng, W

    2014-01-01

    We aimed to explore the association between the onset of ankylosing spondylitis (AS) and nt587 polymorphisms of the tumor necrosis factor receptor II (TNFRII) gene in the Han population of Hunan Province, China. Correlation analysis was performed in a case-control study involving 100 AS cases and 100 healthy controls. The nt587 single nucleotide polymorphism of the TNFRII gene was examined by polymerase chain reaction-restriction fragment length polymorphism. The relationship between AS and the frequencies of genotypes and alleles in TNFRII nt587 were analyzed using the SPSS software. There were 43 cases with the TNFRII nt587 T/T genotype, 32 cases with the TNFRII nt587 T/G genotype, and 25 cases with the TNFRII nt587 G/G genotype. In the 100 healthy controls, 56 subjects had the TNFRII nt587 T/T genotype, 34 had the TNFRII nt587 T/G genotype, and 10 had the TNFRII nt587 G/G genotype. The G allele frequency of the AS group was significantly higher (χ(2) = 8.734, P = 0.003) than that in the control group (41.0 vs 27.0%). The odds ratio (OR) in AS cases with the TNFRII nt587 G/G genotype was 3.256, which was obviously higher than in those with T/G (OR = 1.226) and T/T (OR = 1.0) genotype. The polymorphism at position nt587 of the TNFRII gene was found to be associated with AS, and the TNFRII nt587 G allele may play an important role in AS susceptibility. The TNFRII nt587 G/G genotype may increase the risk of developing AS in the Hunan population. PMID:25061744

  15. No impact of tumor necrosis-factor antagonists on the joint manifestations of sarcoidosis

    PubMed Central

    Banse, Christopher; Bisson-Vaivre, Aurélia; Kozyreff-Meurice, Marie; Vittecoq, Olivier; Goëb, Vincent

    2013-01-01

    Objective The use of anti-tumor necrosis factor (TNF) agents to treat joint manifestations of sarcoidosis has not been described. We evaluated the efficacy and safety of three such biologics in patients with these symptoms refractory to conventional therapy (nonsteroidal anti-inflammatory drugs, corticosteroids, and/or disease-modifying antirheumatic drugs). Methods This retrospective study, covering January 2001 to September 2011, examined clinical–biological parameters collected before anti-TNF treatment (age, sex, duration of disease evolution, drugs taken), and at introduction and under anti-TNF therapy (number of painful and swollen joints, visual analog scale score of global disease activity, disease-activity score of 28 joints with erythrocyte sedimentation rate or C-reactive protein, TNF-antagonist duration). At 3, 6, and 12 months, anti-TNF impact on joints and the therapeutic response according to European League Against Rheumatism criteria used for rheumatoid arthritis were assessed. Results Ten patients’ data were evaluated; some of them had received several anti-TNF agents (median [range] duration on each biotherapy was 10 [4–30] months), which enabled analysis of 19 prescriptions. The total duration of anti-TNF exposure was 17.6 patient-years, which was started a median of 3 (0.33–17) years after sarcoidosis diagnosis. The median numbers of painful and swollen joints were 1 (0–28) and 0 (0–9), respectively. Despite rapid efficacy, after 1 year of treatment, clinical (especially joint) and biological parameters were comparable to pretreatment, and only the corticosteroid dose was significantly lower (P=0.03). One case of mild skin toxicity was noted. Conclusion TNF antagonists allowed significant steroid sparing and were well tolerated, but do not seem to be effective against sarcoidosis joint involvement. PMID:23901289

  16. Different changes in cortical tumor necrosis factor-α-related pathways in schizophrenia and mood disorders.

    PubMed

    Dean, B; Gibbons, A S; Tawadros, N; Brooks, L; Everall, I P; Scarr, E

    2013-07-01

    The growing body of evidence implicating tumor necrosis factor-α (TNFα) in the pathophysiology of psychiatric disorders led us to measure levels of that protein in the cortex of subjects with major depressive disorders (MDD). Having reported an increase (458%) in the levels of the transmembrane (tmTNFα), but not the soluble (sTNFα), form of the protein in Brodmann's area (BA) 46, but not 24, in people with the disorder, we decided to examine additional components of TNFα-related pathways in the same regions in people with MDD and extend our studies to the same cortical regions of people with schizophrenia (Sz) and bipolar disorders (BD). Using postmortem tissue, western blots and quantitative PCR, we have now shown there is a significant increase (305%) in tmTNFα in Brodmann's area 24, but not 46, from subjects with BD, and that levels of the protein were not altered in Sz. Levels of sTNFα were not altered in BD or Sz. In addition, we have shown that levels of TNF receptor 1 (TNFR1) mRNA are increased in BA 24 (53%) and BA 46 (82%) in people with Sz, whereas levels of TNFR2 mRNA was decreased in BA 46 in people with mood disorders (MDD=-51%; BD=-67%). Levels of proteins frequently used as surrogate markers of neuronal, astrocytic and microglia numbers, as well as levels of the pro-inflammatory marker (interleukin 1β), were not changed in the cortex of people with mood disorders. Our data suggest there are differential changes in TNFα-related markers in the cortex of people with MDD, BD and Sz that may not be related to classical inflammation and may cause changes in different TNFα-related signaling pathways. PMID:22801413

  17. Effect of Tumour Necrosis Factor-Alpha on Estrogen Metabolic Pathways in Breast Cancer Cells

    PubMed Central

    Kamel, Marwa; Shouman, Samia; El-Merzebany, Mahmoud; Kilic, Gokhan; Veenstra, Timothy; Saeed, Muhammad; Wagih, Mohamed; Diaz-Arrastia, Concepcion; Patel, Deepa; Salama, Salama

    2012-01-01

    Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been linked to breast cancer development. Estrogen metabolic pathway is also involved in breast carcinogenesis and DNA adducts formation. In this study we investigated the effect of TNF-α on the estrogen metabolic pathway in MCF-7, a breast cancer cell line. Capillary liquid chromatography/mass spectrometry (LC/MS) and High performance liquid chromatography (HPLC) were used for analysis of estrogen metabolites and estrogen-DNA adducts levels respectively. Reporter gene assay, Real time reverse transcription polymerase chain reaction (real time RT-PCR) and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes. TNF-α significantly increased the total EM and decreased the estrone (E1) / 17-β estradiol (E2) ratio. Moreover, it altered the expression of genes and enzymes involved in E2 activation and deactivation pathways e.g. Cytochrome P-450 1A1 (CYP1A1), Cytochrome P-450 1B1 (CYP1B1), Catechol-O-methyl transferase (COMT) and Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1 (NQO1). In addition, there were increased levels of some catechol estrogens e.g. 4-hydroxy-estrone (4-OHE1) and 2-hydroxyestradiol (2-OHE2) with decreased levels of methylated catechols e.g. 2-methoxy estradiol (2-MeOE2). DNA adducts especially 4-OHE1-[2]-1-N3 Adenine was significantly increased. TNF-α directs the estrogen metabolism into more hormonally active and carcinogenic products in MCF-7. This may implicate a new possible explanation for inflammation associated breast cancer. PMID:22866165

  18. Tumor Necrosis Factor Alpha Promoter Polymorphism and Severity of Acute Kidney Injury

    PubMed Central

    Susantitaphong, Paweena; Perianayagam, Mary C.; Tighiouart, Hocine; Liangos, Orfeas; Bonventre, Joseph V.; Jaber, Bertrand L.

    2016-01-01

    Background Tumor necrosis factor-alpha is a proinflammatory cytokine that has been implicated in the pathobiology of acute kidney injury (AKI). Methods We explored the association of a functional polymorphism in the promoter region (rs1800629) of the TNFA gene with severity of AKI, as defined by level of glomerular filtration (serum cystatin C and creatinine) and tubular injury (urinary NAG, KIM-1, α-GST, and π-GST) markers, in 262 hospitalized adults. Results In unadjusted analyses, compared with the GG genotype, the TNFA GA and AA genotype groups tended to have higher enrollment (p = 0.08), peak (p = 0.004), and discharge (p = 0.004) serum creatinine levels, and the AA genotype tended to have a higher enrollment serum cystatin C level (p = 0.04). Compared with the GG genotype, the TNFA GA and AA genotype groups tended to have a higher urinary KIM-1 level (p = 0.03), and the AA genotype group tended to have a higher urinary π-GST level (p = 0.03). After adjustment for sex, race, age, baseline estimated glomerular filtration rate, sepsis, and dialysis requirement, compared with the GG genotype, the TNFA minor A-allele group had a higher peak serum creatinine of 1.03 mg/dl (0.43, 1.63; p = 0.001) and a higher urinary KIM-1 (relative ratio: 1.73; 95% CI: 1.16, 2.59; p = 0.008). The TNFA minor A-allele group also had a higher Multiple Organ Failure score of 0.26 (95% CI: 0.03, 0.49; p = 0.024) after adjustment for sex, race, age, and sepsis. Conclusions The TNFA rs1800629 gene polymorphism is associated with markers of kidney disease severity and distant organ dysfunction among patients with AKI. Larger studies are needed to confirm these relationships. PMID:23796916

  19. Comparative Biochemical and Functional Analysis of Viral and Human Secreted Tumor Necrosis Factor (TNF) Decoy Receptors.

    PubMed

    Pontejo, Sergio M; Alejo, Ali; Alcami, Antonio

    2015-06-26

    The blockade of tumor necrosis factor (TNF) by etanercept, a soluble version of the human TNF receptor 2 (hTNFR2), is a well established strategy to inhibit adverse TNF-mediated inflammatory responses in the clinic. A similar strategy is employed by poxviruses, encoding four viral TNF decoy receptor homologues (vTNFRs) named cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. These vTNFRs are differentially expressed by poxviral species, suggesting distinct immunomodulatory properties. Whereas the human variola virus and mouse ectromelia virus encode one vTNFR, the broad host range cowpox virus encodes all vTNFRs. We report the first comprehensive study of the functional and binding properties of these four vTNFRs, providing an explanation for their expression profile among different poxviruses. In addition, the vTNFRs activities were compared with the hTNFR2 used in the clinic. Interestingly, CrmB from variola virus, the causative agent of smallpox, is the most potent TNFR of those tested here including hTNFR2. Furthermore, we demonstrate a new immunomodulatory activity of vTNFRs, showing that CrmB and CrmD also inhibit the activity of lymphotoxin β. Similarly, we report for the first time that the hTNFR2 blocks the biological activity of lymphotoxin β. The characterization of vTNFRs optimized during virus-host evolution to modulate the host immune response provides relevant information about their potential role in pathogenesis and may be used to improve anti-inflammatory therapies based on soluble decoy TNFRs. PMID:25940088

  20. Regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor-α genetic variations

    PubMed Central

    LIU, YANGZHOU; HAN, NING; LI, QINCHUAN; LI, ZENGCHUN

    2016-01-01

    The present study aimed to investigate the regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor (TNF)-α genetic variations. The GSE5760 expression profile data, which was downloaded from the Gene Expression Omnibus database, contained 30 wild-type (WT) and 28 mutation (MUT) samples. Differentially expressed genes (DEGs) between the two types of samples were identified using the Student's t-test, and the corresponding microRNAs (miRNAs) were screened using WebGestalt software. An integrated miRNA-DEG network was constructed using the Cytoscape software, based on the interactions between the DEGs, as identified using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and the correlation between miRNAs and their target genes. Furthermore, Gene Ontology and pathway enrichment analyses were conducted for the DEGs using the Database for Annotation, Visualization and Integrated Discovery and the KEGG Orthology Based Annotation System, respectively. A total of 390 DEGS between the WT and MUT samples, along with 11 -associated miRNAs, were identified. The integrated miRNA-DEG network consisted of 38 DEGs and 11 miRNAs. Within this network, COPS2 was found to be associated with transcriptional functions, while FUS was found to be involved in mRNA metabolic processes. Other DEGs, including FBXW7 and CUL3, were enriched in the ubiquitin-mediated proteolysis pathway. In addition, miR-15 was predicted to target COPS2 and CUL3. The results of the present study suggested that COPS2, FUS, FBXW7 and CUL3 may be associated with sepsis in patients with TNF-α genetic variations. In the progression of sepsis, FBXW7 and CUL3 may participate in the ubiquitin-mediated proteolysis pathway, whereas COPS2 may regulate the phosphorylation and ubiquitination of the FUS protein. Furthermore, COPS2 and CUL3 may be novel targets of miR-15. PMID:27347057

  1. Increased serum concentrations of tumour necrosis factor in beta thalassaemia: effect of bone marrow transplantation.

    PubMed Central

    Meliconi, R; Uguccioni, M; Lalli, E; Nesci, S; Delfini, C; Paradisi, O; Lucarelli, G; Gasbarrini, G; Facchini, A

    1992-01-01

    AIMS: Serum concentrations of tumour necrosis factor-alpha (TNF) were determined in beta thalassemic patients before and after bone marrow transplantation (BMT) to evaluate whether changes in TNF concentrations after BMT were related to immune mediated complications. METHODS: Serum TNF concentrations were determined by enzyme linked immunoassay (EIA) in paired samples from 71 patients with beta thalassemia before and after BMT. Serial samples from 13 patients were also studied for up to six months after BMT. Forty one normal healthy children matched for sex and age were studied as controls. RESULTS: beta thalassemic patients had high serum TNF concentrations before transplantation compared with controls. These were not related to sex, age, duration of disease, number of blood transfusions, transferrin concentrations or splenectomy. DQw1 positive patients showed significantly lower TNF concentrations than non-DQw1 cases. Patients with severe liver fibrosis had significantly higher TNF concentrations. No correlation was found between TNF values and BMT outcome before transplantation but TNF alpha values fell significantly after BMT. The decrease persisted only in patients with successful engraftment. In serial samples studied for up to six months after BMT, TNF values decreased but in four out of five patients with graft rejection and in all five with acute graft versus host disease (GVHD) sharp increases occurred at the time of clinical symptoms. No correlation was found between the degree of GVHD and serum TNF-alpha concentrations nor between TNF-alpha concentrations after BMT and the presence of bacterial, viral, and fungal infections. CONCLUSIONS: About 50% of beta thalassemic patients have increased serum TNF, and the changes after BMT are related to the occurrence of immune mediate complications. The persistence of low TNF concentrations after successful engraftment may be due to the preparative regimen and the lack of adverse immune reactions. PMID:1740519

  2. The effect of diet on tumor necrosis factor stimulation of hepatic lipogenesis

    SciTech Connect

    Feingold, K.R.; Soued, M.; Serio, M.K.; Adi, S.; Moser, A.H.; Grunfeld, C. )

    1990-06-01

    In this study, we determined the effects of tumor necrosis factor (TNF) on serum lipid levels and hepatic lipid synthesis in animals whose diets and feeding conditions were varied to induce changes in baseline serum lipid levels and/or rates of hepatic lipid synthesis. In animals studied at both the nadir and peak of the diurnal cycle of hepatic lipid synthesis, TNF acutely increases serum triglyceride levels, stimulates hepatic fatty acid synthesis, and increases the quantity of newly synthesized fatty acids found in the serum. Similarly, in animals ingesting either high-sucrose or cholesterol-enriched diets, TNF induces the characteristic rapid increase in serum triglyceride levels, hepatic fatty acid synthesis, and quantity of labeled fatty acids in the serum. In animals fed a diet high in triglycerides, using either corn oil or lard, TNF stimulates hepatic fatty acid synthesis and increases the quantity of newly synthesized fatty acids in the serum, but serum triglyceride levels do not change. However, TNF inhibits gastric emptying, which results in a marked decrease in fat absorption in TNF-treated animals. It is likely that a decrease in the dietary contribution to serum triglyceride levels during high-triglyceride feeding counterbalances the increased hepatic contribution induced by TNF treatment. In animals fasted before TNF administration there was no acute change in either serum lipid levels, hepatic fatty acid synthesis, or the quantity of labeled fatty acids in the serum. Thus, TNF stimulates hepatic fatty acid synthesis and increases serum triglyceride levels under many diverse dietary conditions, suggesting that there is a strong linkage between the immune system and lipid metabolism that is independent of most dietary manipulations and may be of fundamental importance in the body's response to infection.

  3. Ultrasound-targeted antisense oligonucleotide attenuates ischemia/reperfusion-induced myocardial tumor necrosis factor-alpha.

    PubMed

    Erikson, John M; Freeman, Gregory L; Chandrasekar, Bysani

    2003-01-01

    Ultrasound contrast agents are now emerging as effective vehicles for delivering therapeutic agents to target tissues. In the present study, we used ultrasound-targeted, contrast-bound antisense oligonucleotides to inhibit the expression of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine with negative inotropic effects. We compared the efficacy of left ventricular vs. intravenous administration and determined the optimal time for delivery. WKY rats were treated with perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microspheres incubated with 100 microg of antisense oligonucleotide directed against TNF-alpha. Contrast was infused into either the superior vena cava or the left ventricular cavity along with simultaneous application of ultrasound. Twenty-four hours later, the animals underwent 15 min of ischemia and 2 h reperfusion. Control animals underwent sham operation only, ischemia/reperfusion only, or received PESDA only. A second group received treatment just prior to, or immediately after the onset of ischemia. At the end of the experimental period, hearts were removed and analyzed for TNF-alpha by northern and western blotting. While no TNF-alpha expression was detected in sham-operated animals, robust expression of TNF-alpha mRNA and protein was seen in controls treated with ultrasound and PESDA alone. In contrast, intravenous or left ventricular administration of antisense oligonucleotides significantly inhibited ischemia/reperfusion-induced TNF-alpha expression. Direct delivery into the left ventricular cavity was more effective than intravenous administration, and delivery just prior to ischemia was most effective in attenuating TNF-alpha expression. Furthermore, attenuation of TNF-alpha expression also significantly inhibited other post-ischemic inflammatory mediators including IL-1beta and intercellular adhesion molecule-1 (ICAM-1). Thus, ultrasound-targeted antisense oligonucleotides can effectively attenuate post

  4. A phase II trial of recombinant tumor necrosis factor in patients with advanced colorectal carcinoma.

    PubMed

    Kemeny, N; Childs, B; Larchian, W; Rosado, K; Kelsen, D

    1990-08-15

    Sixteen previously treated (with only one prior regimen) patients with histologically proven metastatic or locally recurrent colorectal carcinoma were treated with recombinant tumor necrosis factor (rTNF) administered by 30-minute i.v. infusions twice daily for 5 consecutive days every other week for 8 weeks. Patients received 100 micrograms/m2 twice daily on day 1 of cycle 1 with escalation to 150 micrograms/m2 twice daily thereafter. Patients were concomitantly treated with indomethacin 25 mg every 6 hours and acetaminophen 650 mg every 4 hours to obviate fever and chills. Toxicities included: nausea/vomiting (69%), headache (25%), chills (69%), pain at tumor sites (63%), hypotension (31%), and hypertension (38%). Hematologic toxicity included leukopenia less than 2000 cells/mm3 (38%) and thrombocytopenia less than 100,000 cells/mm3 (13%). Liver function abnormalities occurred independently of the site or extent of metastatic disease and inconsistently in each treatment cycle. Four patients developed bilirubinemia greater than 2.5 x baseline values (range, 2.5 to 10.3 U/L); five patients had greater than 2.5 x elevations in alkaline phosphatase (range, 624 to 1663 U/L). Two patients developed retinal vein thrombosis in the absence of hemostatic abnormalities. In both instances, this complication occurred several weeks after completion of therapy. No objective responses were noted in 14 evaluable patients (95% confidence interval: 0 to 0.23). Three patients had stable disease for a median duration of 4.5 months. In conclusion, i.v. rTNF at this dose and schedule has no demonstrable antitumor efficacy. Twice-daily i.v. administration of this agent is associated with more hepatotoxicity than previously reported in trials using subcutaneous or once daily i.v. administration. Retinal vein thrombosis may be a late complication of i.v. rTNF at this dose and schedule. PMID:2386895

  5. Claudin 1 mediates tumor necrosis factor alpha-induced cell migration in human gastric cancer cells

    PubMed Central

    Shiozaki, Atsushi; Shimizu, Hiroki; Ichikawa, Daisuke; Konishi, Hirotaka; Komatsu, Shuhei; Kubota, Takeshi; Fujiwara, Hitoshi; Okamoto, Kazuma; Iitaka, Daisuke; Nakashima, Shingo; Nako, Yoshito; Liu, Mingyao; Otsuji, Eigo

    2014-01-01

    AIM: To investigate the role of claudin 1 in the regulation of genes involved in cell migration and tumor necrosis factor alpha (TNF-α)-induced gene expression in human gastric adenocarcinoma cells. METHODS: Knockdown experiments were conducted with claudin 1 small interfering RNA (siRNA), and the effects on the cell cycle, apoptosis, migration and invasion were analyzed in human gastric adenocarcinoma MKN28 cells. The gene expression profiles of cells were analyzed by microarray and bioinformatics. RESULTS: The knockdown of claudin 1 significantly inhibited cell proliferation, migration and invasion, and increased apoptosis. Microarray analysis identified 245 genes whose expression levels were altered by the knockdown of claudin 1. Pathway analysis showed that the top-ranked molecular and cellular function was the cellular movement related pathway, which involved MMP7, TNF-SF10, TGFBR1, and CCL2. Furthermore, TNF- and nuclear frctor-κB were the top-ranked upstream regulators related to claudin 1. TNF-α treatment increased claudin 1 expression and cell migration in MKN28 cells. Microarray analysis indicated that the depletion of claudin 1 inhibited 80% of the TNF-α-induced mRNA expression changes. Further, TNF-α did not enhance cell migration in the claudin 1 siRNA transfected cells. CONCLUSION: These results suggest that claudin 1 is an important messenger that regulates TNF-α-induced gene expression and migration in gastric cancer cells. A deeper understanding of these cellular processes may be helpful in establishing new therapeutic strategies for gastric cancer. PMID:25548484

  6. Oxidative Stress Promotes Ligand-independent and Enhanced Ligand-dependent Tumor Necrosis Factor Receptor Signaling*

    PubMed Central

    Ozsoy, Hatice Z.; Sivasubramanian, Natarajan; Wieder, Eric D.; Pedersen, Steen; Mann, Douglas L.

    2008-01-01

    Tumor necrosis factor (TNF) receptor 1 (TNFR1, p55) and 2 (TNFR2, p75) are characterized by several cysteine-rich modules in the extracellular domain, raising the possibility that redox-induced modifications of these cysteine residues might alter TNFR function. To test this possibility, we examined fluorescence resonance energy transfer (FRET) in 293T cells transfected with CFP- and YFP-tagged TNFRs exposed to the thiol oxidant diamide. Treatment with high concentrations of diamide (1 mm) resulted in an increase in the FRET signal that was sensitive to inhibition with the reducing agent dithiothreitol, suggesting that oxidative stress resulted in TNFR self-association. Treatment of cells with low concentrations of diamide (1 μm) that was not sufficient to provoke TNFR self-association resulted in increased TNF-induced FRET signals relative to the untreated cells, suggesting that oxidative stress enhanced ligand-dependent TNFR signaling. Similar findings were obtained when the TNFR1- and TNFR2-transfected cells were pretreated with a cell-impermeable oxidase, DsbA, that catalyzes disulfide bond formation between thiol groups on cysteine residues. The changes in TNFR self-association were functionally significant, because pretreating the HeLa cells and 293T cells resulted in increased TNF-induced NF-κB activation and TNF-induced expression of IκB and syndecan-4 mRNA levels. Although pretreatment with DsbA did not result in an increase in TNF binding to TNFRs, it resulted in increased TNF-induced activation of NF-κB, consistent with an allosteric modification of the TNFRs. Taken together, these results suggest that oxidative stress promotes TNFR receptor self-interaction and ligand-independent and enhanced ligand-dependent TNF signaling. PMID:18544535

  7. Phase I evaluation of recombinant tumor necrosis factor given in combination with recombinant interferon-gamma.

    PubMed

    Smith, J W; Urba, W J; Clark, J W; Longo, D L; Farrell, M; Creekmore, S P; Conlon, K C; Jaffe, H; Steis, R G

    1991-10-01

    In light of in vitro and preclinical animal model data suggesting potential additive or synergistic antitumor effects from the combined use of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), we conducted a phase I study employing escalating doses of each agent in 36 patients with solid tumors to determine the maximum tolerated dose (MTD). Patients were given an intramuscular (i.m.) injection of IFN-gamma, followed 5 min later by an i.m. injection of TNF-alpha, each agent in different sites, every other day for ten doses over 20 days. Patients received 10, 50, or 100 micrograms/m2 of each agent throughout the treatment course. No dose modifications were made. Patients suffering serious toxicity had therapy stopped and were considered to be off-study. All patients experienced fatigue, and 36% spent over half their time in bed on treatment days. Fever and chills were nearly universal. Mild to moderate elevations in serum transaminase levels were noted in 44% of patients, and 44% developed transient microscopic hematuria. Although 81% of patients had anorexia, only 17% of patients lost more than 3 kg of body wt during the 3 weeks of therapy. Because two of three patients receiving 100 micrograms/m2 of both agents developed serious toxicity (one fever greater than 105 degrees F, one thrombocytopenia 43,000/mm3), the MTD was established to be 100 micrograms/m2 of IFN-gamma plus 50 micrograms/m2 of TNF-alpha. The use of aspirin did not significantly alter the toxic effects of the agents. One patient with melanoma had a mixed response and one patient with mesothelioma transiently cleared his ascites of malignant cells. PMID:1790143

  8. Targeting Mycobacterium tuberculosis Tumor Necrosis Factor Alpha-Downregulating Genes for the Development of Antituberculous Vaccines

    PubMed Central

    Olsen, Aaron; Chen, Yong; Ji, Qingzhou; Zhu, Guofeng; De Silva, Aruna Dharshan; Vilchèze, Catherine; Weisbrod, Torin; Li, Weimin; Xu, Jiayong; Larsen, Michelle; Zhang, Jinghang; Porcelli, Steven A.; Jacobs, William R.

    2016-01-01

    ABSTRACT Tumor necrosis factor alpha (TNF) plays a critical role in the control of Mycobacterium tuberculosis, in part by augmenting T cell responses through promoting macrophage phagolysosomal fusion (thereby optimizing CD4+ T cell immunity by enhancing antigen presentation) and apoptosis (a process that can lead to cross-priming of CD8+ T cells). M. tuberculosis can evade antituberculosis (anti-TB) immunity by inhibiting host cell TNF production via expression of specific mycobacterial components. We hypothesized that M. tuberculosis mutants with an increased capacity to induce host cell TNF production (TNF-enhancing mutants) and thus with enhanced immunogenicity can be useful for vaccine development. To identify mycobacterial genes that regulate host cell TNF production, we used a TNF reporter macrophage clone to screen an H37Rv M. tuberculosis cosmid library constructed in M. smegmatis. The screen has identified a set of TNF-downregulating mycobacterial genes that, when deleted in H37Rv, generate TNF-enhancing mutants. Analysis of mutants disrupted for a subset of TNF-downregulating genes, annotated to code for triacylglycerol synthases and fatty acyl-coenzyme A (acyl-CoA) synthetase, enzymes that concern lipid biosynthesis and metabolism, has revealed that these strains can promote macrophage phagolysosomal fusion and apoptosis better than wild-type (WT) bacilli. Immunization of mice with the TNF-enhancing M. tuberculosis mutants elicits CD4+ and CD8+ T cell responses that are superior to those engendered by WT H37Rv. The results suggest that TNF-upregulating M. tuberculosis genes can be targeted to enhance the immunogenicity of mycobacterial strains that can serve as the substrates for the development of novel anti-TB vaccines. PMID:27247233

  9. Evaluation of antitumor effects following tumor necrosis factor-α gene delivery using nanobubbles and ultrasound.

    PubMed

    Horie, Sachiko; Watanabe, Yukiko; Ono, Masao; Mori, Shiro; Kodama, Tetsuya

    2011-11-01

    The antitumor effects of tumor necrosis factor (TNF-α) were evaluated following transfection of TNF-α plasmid DNA into solid mouse tumors using the nanobubbles (NBs) and ultrasound (US) gene delivery system. Murine breast carcinoma (EMT6) cells expressing luciferase (1 × 10(6) cells) were injected intradermally into the flanks of 6-7-week-old male SCID mice on day 0. Ten microliters of TNF-α (5 μg/μL) or TNF-α mock plasmid DNA (5 μg/μL) with/without NBs (15 μL) and saline was injected intratumorally in a total volume of 30 μL, and tumors were exposed to US (frequency, 1 MHz; intensity, 3.0 W/cm(2); duty cycle, 20%; number of pulses, 200; and exposure time, 60 s) on days 2, 4, 7, and 9. Changes in tumor size were measured with an in vivo bioluminescent imaging system and a mechanical caliper. Changes in tumor vessel area were quantified using contrast-enhanced US imaging with Sonazoid and a high frequency US imaging system (40 MHz) and immunohistochemistry (CD31). At the mRNA level, expression of TNF-α, caspase-3, and p53 were quantified using real-time quantitative RT-PCR. At the protein level, expression of caspase-3 and p53 were confirmed by immunohistochemistry. We show that repeated TNF-α gene delivery using NBs and US can lead to the local production of TNF-α. This results in antitumor effects, including activation of p53-dependent apoptosis, decrease in tumor vessel density, and suppression of tumor size. In this study, we showed the effectiveness of using NBs and US for TNF-α gene delivery into tumor cells. PMID:21824220

  10. Trypanosoma cruzi Infection in Tumor Necrosis Factor Receptor p55-Deficient Mice

    PubMed Central

    Castaños-Velez, Esmeralda; Maerlan, Stephanie; Osorio, Lyda M.; Åberg, Frederik; Biberfeld, Peter; Örn, Anders; Rottenberg, Martín E.

    1998-01-01

    Tumor necrosis factor receptor p55 (TNFRp55) mediates host resistance to several pathogens by allowing microbicidal activities of phagocytes. In the studies reported here, TNFRp55−/− mice infected with the intracellular parasite Trypanosoma cruzi showed clearly higher parasitemia and cumulative mortality than wild-type (WT) controls did. However, gamma interferon (IFN-γ)-activated macrophages from TNFRp55−/− mice produced control levels of nitric oxide and killed the parasite efficiently in vitro. Trypanocidal mechanisms of nonphagocytic cells (myocardial fibroblasts) from both TNFRp55−/− and WT mice were also activated by IFN-γ in a dose-dependent way. However, IFN-γ-activated TNFRp55−/− nonphagocytes showed less effective killing of T. cruzi than WT control nonphagocytes, even when interleukin 1β (IL-1β) was added as a costimulator. In vivo, T. cruzi-infected TNFRp55−/− mice and WT mice released similar levels of NO and showed similar levels of IFN-γ mRNA and inducible nitric oxide synthase mRNA in their tissues. Instead, increased susceptibility to T. cruzi of TNFRp55−/− mice was associated with reduced levels of parasite-specific immunoglobulin G (IgG) (but not IgM) antibodies during infection, which is probably linked to abnormal B-cell differentiation in secondary lymphoid tissues of the mutant mice. Surprisingly, T. cruzi-infected TNFRp55−/− mice showed increased inflammatory and necrotic lesions in several tissues, especially in skeletal muscles, indicating that TNFRp55 plays an important role in controlling the inflammatory process. Accordingly, levels of Mn2+ superoxide dismutase mRNA, a TNF-induced enzyme which protects the cell from the toxic effects of superoxide, were lower in mutant than in WT infected mice. PMID:9596773

  11. Targeting the tumor necrosis factor-related apoptosis-inducing ligand path in neuroblastoma.

    PubMed

    Yang, Xuezhong; Thiele, Carol J

    2003-07-18

    The identification of the tumor necrosis factor (TNF) superfamily member TNF-related apoptosis-inducing ligand (TRAIL) a few years ago generated considerable enthusiasm for it as a potential cancer therapeutic agent. This is because TRAIL shows potent apoptosis inducing activity in a wide spectrum of transformed cell lines but not in cell lines derived from normal tissue origin. As the details in the signal transduction pathway of TRAIL-induced apoptosis are clarified, various defects of TRAIL pathway have been identified in TRAIL resistant cancer cells. Neuroblastoma is the most common extracranial solid tumor in children and those with a poor prognosis require more sensitive therapies. Unlike other cancer cells, most neuroblastoma cell lines are resistant to TRAIL induced apoptosis and the resistance correlates with caspase 8 deficiency, which is attributed to the methylation of the gene. Interferon (IFN)-gamma induces caspase 8 expression in most neuroblastoma cell lines regardless of the methylation status but fails to sensitize most NB to TRAIL. Further analysis indicates a TRAIL receptor deficiency contributes to TRAIL resistance in NB. Multiple lesions suggest that this path may play an important role in tumorigenesis and/ or evasion from therapies. Furthermore it indicates that the clinical application of TRAIL in NB will require a multi-modality approach. Important questions remain unanswered: How does IFN-gamma induce caspase 8 and why is the induction heterogeneous? How to stimulate the caspase 8 induction in cells that fail to respond to IFN-gamma? How to target other TRAIL pathway lesions with the clinically feasible approaches? PMID:12880973

  12. Original inhibition method of excessive synthesis of pro-inflammatory cytokine of tumour necrosis factor α

    PubMed Central

    Zinchuk, AleXander; Holubovska, Olga; Shkurba, Andrij; Hrytsko, Roman; Vorozhbyt, Olga; Richniak, Mykhailo

    2015-01-01

    Influence on pro- and anti-inflammatory cytokines of an ill person is an urgent aspect of treatment of many diseases. For inhibition of synthesis of a high level of pro-inflammatory cytokines, medications which are recombinant monoclonal antibodies, especially to tumour necrosis factor α (TNF-α), are used. However, these methods of treatment require further improvement by elaborating new approaches with a wider spectrum of influence on the immune system. A completely new method of reduction in high activity of TN F-α with the method of intradermal autoleukocyte immunization is presented in the article. Investigation was performed in a group of patients with psoriasis (24) with a high level of TNF-α in the blood (over 30 pg/ml). Simultaneously such investigation was performed on patients with psoriasis (9) without TNF-α detected (0 pg/ml). As a result of immunization, a significant reduction in TNF-α occurred in all patients with its high level, in 16 (66.7%) from 24 patients – to 0-5 pg/ml. The level of reduction and duration of the achieved effect was of an individual character and requires further investigation. However, the achieved results prove the expediency of administration of this immunization method for patients requiring reduction of TNF-α synthesis. However, the content of TNF-α in blood serum could not be detected in most patients with a low level of cytokine (in 6 from 9) after immunization (as well as before immunization), but an increase in its level from 0 to 5-8 pg/ml was observed in 3 patients. On the basis of the conducted research, the authors suggest that the influence of immunization on cytokine synthesis depends on the condition of immune cells and correlation of pro- and anti-inflammatory cytokines in a patient's skin. PMID:26648779

  13. Glycogen synthase kinase-3β regulates tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis via the NF-κB pathway in hepatocellular carcinoma

    PubMed Central

    FU, KAI; PAN, HUAZHENG; LIU, SHIHAI; LV, JING; WAN, ZHAOJUN; LI, JIAO; SUN, QING; LIANG, JUN

    2015-01-01

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for its ability to selectively induce apoptosis in malignant cells. However, human hepatocellular carcinoma (HCC) cells display resistance to TRAIL-induced cell death. The present study investigated whether TRAIL-induced apoptosis in HCC cells was enhanced by the administration of an inhibitor of glycogen synthase kinase-3β (GSK-3β) or by short hairpin RNA-mediated inhibition of GSK-3β. The results of the current study demonstrated that inhibition of GSK-3β significantly impairs the expression of the nuclear factor-κB (NF-κB) target genes Bcl-xL and clAP2 in HCC cells (P<0.05). This indicates that GSK-3β may regulate NF-κB target genes involved in cell survival. Furthermore, knockdown of Bcl-xL significantly enhanced the sensitizing effect of GSK-3β inhibitor on TRAIL-induced apoptosis (P<0.05). Overall, the present study provides a rationale for further exploration of GSK-3β inhibition combined with TRAIL as a novel treatment for HCC. PMID:26788169

  14. Impact of tumour necrosis factor-alpha and interferon-gamma on tetrahydrobiopterin synthesis in murine fibroblasts and macrophages.

    PubMed Central

    Werner, E R; Werner-Felmayer, G; Fuchs, D; Hausen, A; Reibnegger, G; Yim, J J; Wachter, H

    1991-01-01

    Tumour necrosis factor-alpha causes an up to 30-fold induction of GTP cyclohydrolase I (EC 3.5.4.16) activity in murine dermal fibroblasts in a dose-dependent manner. Owing to the high constitutive activities of 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase (EC 1.1.1.153), this potentiates biosynthesis of tetrahydrobiopterin. Murine macrophages already contain high activities of GTP cyclohydrolase I when unstimulated, and this is further augmented up to 4-fold by tumour necrosis factor-alpha/interferon-gamma. In Western blots an antiserum to murine liver GTP cyclohydrolase I does not stain cell extracts with high enzyme activities, suggesting that the cytokine induced peripheral form of GTP cyclohydrolase I might differ from the liver form. Images Fig. 2. PMID:1764035

  15. Interferon-gamma and tumor necrosis factor-alpha exert their antirickettsial effect via induction of synthesis of nitric oxide.

    PubMed Central

    Feng, H. M.; Walker, D. H.

    1993-01-01

    How the host defenses control rickettsiae in the cytosol of nonphagocytic host cells, where they are not exposed to antibodies or phagocytes, has posed a difficult question. Rickettsia conorii infection of a mouse fibroblast cell line was inhibited in a dose-dependent manner by nitrogen oxide synthesized by eukaryotic host cells stimulated by interferon-gamma or tumor necrosis factor-alpha. L-arginine was the source of the nitric oxide as demonstrated by competitive inhibition by NG-monomethyl-L-arginine. Nitric oxide synthesis required host cell protein synthesis and had an approximately 48-hour lag phase following cytokine stimulation. At low doses of interferon-gamma and tumor necrosis factor-alpha, which had no detectable response as single agents, dramatic synergistic nitric oxide synthesis and antirickettsial effects were observed. PMID:8213997

  16. Tetrandrine, a plant alkaloid, inhibits the production of tumour necrosis factor-alpha (cachectin) hy human monocytes.

    PubMed Central

    Ferrante, A; Seow, W K; Rowan-Kelly, B; Thong, Y H

    1990-01-01

    Human mononuclear leucocytes (MNL) or the adherent fraction (monocytes) produced tumour necrosis factor-alpha (TNF-alpha) (by ELISA) in culture when stimulated with killed Staphylococcus aureus. The bisbenzylisoquinoline alkaloid, tetrandrine inhibited the capacity of MNL and monocytes to produce TNF-alpha at a concentration range of 0.1 to 5 micrograms/ml. Tetrandrine may be potentially useful in the treatment of inflammatory diseases in which TNF-alpha plays a major role. PMID:2357850

  17. Association of tumor necrosis factor-α and -β gene polymorphisms in inflammatory bowel disease

    PubMed Central

    Al-Meghaiseeb, Ebtissam Saleh; Al-Robayan, Abdulrahman A; Al-Otaibi, Mulfi Mubarak; Arfin, Misbahul; Al-Asmari, Abdulrahman K

    2016-01-01

    Inflammatory bowel disease (IBD) is a complex, multifactorial, chronic inflammatory disorder of the gastrointestinal tract in which immune dysregulation caused by genetic and/or environmental factors plays an important role. The aim of this case–control study was to evaluate the association of tumor necrosis factor-alpha (TNF-α) (308) and -β (+252) polymorphisms with susceptibility of IBD. A total of 379 Saudi subjects including 179 IBD patients (ulcerative colitis (UC) =84 and Crohn’s disease (CD) =95) and 200 age- and sex-matched healthy controls were recruited. TNF-α and TNF-β genes were amplified using an amplification refractory mutation systems polymerase chain reaction methodology to detect TNF-α (−308) and -β (+252) polymorphisms. The frequency of the GA genotype of TNF-α (−308G/A) was higher, and the frequencies of the GG and AA genotypes were significantly lower in IBD patients compared with those in controls, indicating that genotype GA-positive individuals are susceptible to IBD and that the GG and AA genotypes exert a protective effect. The frequency of allele A of TNF-α (−308G/A) was significantly higher and that of allele G was lower in IBD patients compared with those in controls, indicating an association of allele A with IBD risk in Saudi patients. On stratification of IBD patients into UC and CD, an almost similar pattern was noticed in both the groups. The results of TNF-β (+252A/G) polymorphisms showed a significant increase in the frequency of the GG genotype in IBD patients, suggesting a positive association of GG genotype with IBD risk. On stratification of IBD patients into UC and CD, the genotype GG of TNF-β was associated with susceptibility risk to UC but not CD. The frequencies of alleles and genotypes of both TNF-α and-β polymorphisms are not affected by sex or type of IBD (familial or sporadic). TNF-α (−308G/A) and TNF-β (+252A/G) polymorphisms are associated with risk of developing IBD in Saudi population

  18. Serum and colostral antibody production in cows immunized with recombinant human tumor necrosis factor.

    PubMed

    Burton, Randall; Kim, Skaison; Patel, Rutvij; Scola, Michele; Hartman, Deborah; Tracey, Daniel; Fox, Barbara S

    2016-06-01

    The use of hyper-immune bovine colostrum as a human therapeutic platform is an emerging technology with potential to deliver the efficacy of antibody therapeutics with the convenience and safety of oral or topical application. It is necessary to understand how the bovine immune system responds to immunization with foreign proteins, both in terms of the serum antibody response and the transfer of antigen-specific antibodies into the colostrum to enable efficient large-scale production of therapeutic antibodies. We have immunized 25 cows with recombinant human tumor necrosis factor (rhTNF) and measured the levels of rhTNF-specific antibodies in the serum and colostrum of these animals. We observed a decline of 84±9% in serum IgG1 concentrations in the final weeks of pregnancy that presumably reflects rapid transport of IgG1 into colostrum. The serum IgG2 levels remained constant, such that the serum IgG1 to IgG2 ratio was 1:20 at parturition. We observed substantial animal-to-animal variability in the levels of anti-rhTNF antibodies in both serum and colostrum samples. In particular, a subset of 4 cows had extraordinarily high colostral anti-rhTNF antibody production. Only a weak correlation was found between the peak serum anti-rhTNF activity and the colostral anti-rhTNF activity in these animals. The 4 cows with high colostral anti-rhTNF activities trended toward higher serum IgG1 loss relative to average colostral anti-rhTNF producers, but this difference was not statistically significant in this small sample. The high-anti-rhTNF-producing cows also exhibited a greater proportion of rhTNF-specific antibodies that bound to bovine IgG1- and IgG2-specific detection antibodies relative to the total anti-rhTNF immunoglobulin population. This finding suggests that the isotype distribution of the anti-rhTNF response is varied between individuals and genetic or environmental factors may increase the yield of antigen-specific colostral antibodies. PMID:27040787

  19. Association of tumor necrosis factor-α and -β gene polymorphisms in inflammatory bowel disease.

    PubMed

    Al-Meghaiseeb, Ebtissam Saleh; Al-Robayan, Abdulrahman A; Al-Otaibi, Mulfi Mubarak; Arfin, Misbahul; Al-Asmari, Abdulrahman K

    2016-01-01

    Inflammatory bowel disease (IBD) is a complex, multifactorial, chronic inflammatory disorder of the gastrointestinal tract in which immune dysregulation caused by genetic and/or environmental factors plays an important role. The aim of this case-control study was to evaluate the association of tumor necrosis factor-alpha (TNF-α) (308) and -β (+252) polymorphisms with susceptibility of IBD. A total of 379 Saudi subjects including 179 IBD patients (ulcerative colitis (UC) =84 and Crohn's disease (CD) =95) and 200 age- and sex-matched healthy controls were recruited. TNF-α and TNF-β genes were amplified using an amplification refractory mutation systems polymerase chain reaction methodology to detect TNF-α (-308) and -β (+252) polymorphisms. The frequency of the GA genotype of TNF-α (-308G/A) was higher, and the frequencies of the GG and AA genotypes were significantly lower in IBD patients compared with those in controls, indicating that genotype GA-positive individuals are susceptible to IBD and that the GG and AA genotypes exert a protective effect. The frequency of allele A of TNF-α (-308G/A) was significantly higher and that of allele G was lower in IBD patients compared with those in controls, indicating an association of allele A with IBD risk in Saudi patients. On stratification of IBD patients into UC and CD, an almost similar pattern was noticed in both the groups. The results of TNF-β (+252A/G) polymorphisms showed a significant increase in the frequency of the GG genotype in IBD patients, suggesting a positive association of GG genotype with IBD risk. On stratification of IBD patients into UC and CD, the genotype GG of TNF-β was associated with susceptibility risk to UC but not CD. The frequencies of alleles and genotypes of both TNF-α and-β polymorphisms are not affected by sex or type of IBD (familial or sporadic). TNF-α (-308G/A) and TNF-β (+252A/G) polymorphisms are associated with risk of developing IBD in Saudi population. PMID:27382325

  20. Regulation of human lung fibroblast glycosaminoglycan production by recombinant interferons, tumor necrosis factor, and lymphotoxin.

    PubMed Central

    Elias, J A; Krol, R C; Freundlich, B; Sampson, P M

    1988-01-01

    Mononuclear cells may be important regulators of fibroblast glycosaminoglycan (GAG) biosynthesis. However, the soluble factors mediating these effects, the importance of intercytokine interactions in this regulation and the mechanisms of these alterations remain poorly understood. We analyzed the effect of recombinant (r) tumor necrosis factor (TNF), lymphotoxin (LT), and gamma, alpha, and beta 1 interferons (INF-gamma, -alpha and -beta 1), alone and in combination, on GAG production by normal human lung fibroblasts. rTNF, rLT, and rINF-gamma each stimulated fibroblast GAG production. In addition, rIFN-gamma synergized with rTNF and rLT to further augment GAG biosynthesis. In contrast, IFN-alpha A, -alpha D, and -beta 1 neither stimulated fibroblast GAG production nor interacted with rTNF or rLT to regulate GAG biosynthesis. The effects of the stimulatory cytokines and cytokine combinations were dose dependent and were abrogated by the respective monoclonal antibodies. In addition, these cytokines did not cause an alteration in the distribution of GAG between the fibroblast cell layer and supernatant. However, the stimulation was at least partially specific for particular GAG moieties with hyaluronic acid biosynthesis being markedly augmented without a comparable increase in the production of sulfated GAGs. Fibroblast prostaglandin production did not mediate these alterations since indomethacin did not decrease the stimulatory effects of the cytokines. In contrast, protein and mRNA synthesis appeared to play a role since the stimulatory effects of the cytokines were abrogated by cyclohexamide and actinomycin D, respectively. In addition, the cytokines and cytokine combinations increased cellular hyaluronate synthetase activity in proportion to their effects on hyaluronic acid suggesting that induction of this enzyme(s) is important in this stimulatory process. These studies demonstrate that IFN-gamma, TNF, and LT are important stimulators of fibroblast GAG

  1. Hypoxia inducible factor pathway inhibitors as anticancer therapeutics

    PubMed Central

    Burroughs, Sarah K; Kaluz, Stefan; Wang, Danzhu; Wang, Ke

    2013-01-01

    Hypoxia is a significant feature of solid tumor cancers. Hypoxia leads to a more malignant phenotype that is resistant to chemotherapy and radiation, is more invasive and has greater metastatic potential. Hypoxia activates the hypoxia inducible factor (HIF) pathway, which mediates the biological effects of hypoxia in tissues. The HIF complex acts as a transcription factor for many genes that increase tumor survival and proliferation. To date, many HIF pathway inhibitors indirectly affect HIF but there have been no clinically approved direct HIF inhibitors. This can be attributed to the complexity of the HIF pathway, as well as to the challenges of inhibiting protein–protein interactions. PMID:23573973

  2. Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis

    PubMed Central

    Herman, Michael P.; Sukhova, Galina K.; Kisiel, Walter; Foster, Don; Kehry, Marilyn R.; Libby, Peter; Schönbeck, Uwe

    2001-01-01

    Degradation of ECM, particularly interstitial collagen, promotes plaque instability, rendering atheroma prone to rupture. Previous studies implicated matrix metalloproteinases (MMPs) in these processes, suggesting that dysregulated MMP activity, probably due to imbalance with endogenous inhibitors, promotes complications of atherosclerosis. We report here that the serine proteinase inhibitor tissue factor pathway inhibitor-2 (TFPI-2) can function as an MMP inhibitor. TFPI-2 diminished the ability of the interstitial collagenases MMP-1 and MMP-13 to degrade triple-helical collagen, the primary load-bearing molecule of the ECM within human atheroma. In addition, TFPI-2 also reduced the activity of the gelatinases MMP-2 and MMP-9. In contrast to the “classical” tissue inhibitors of MMPs (TIMPs), TFPI-2 expression in situ correlated inversely with MMP levels in human atheroma. TFPI-2 colocalized primarily with smooth muscle cells in the normal media as well as the plaque’s fibrous cap. Conversely, the macrophage-enriched shoulder region, the prototypical site of matrix degradation and plaque rupture, stained only weakly for TFPI-2 but intensely for gelatinases and interstitial collagenases. Evidently, human mononuclear phagocytes, an abundant source of MMPs within human atheroma, lost their ability to express this inhibitor during differentiation in vitro. These findings establish a new, anti-inflammatory function of TFPI-2 of potential pathophysiological significance for human diseases, including atherosclerosis. PMID:11342575

  3. TUMOR NECROSIS FACTOR ALPHA DECREASES NOS3 EXPRESSION PRIMARILY VIA RHO/RHO KINASE IN THE THICK ASCENDING LIMB

    PubMed Central

    Ramseyer, Vanesa; Hong, Nancy; Garvin, Jeffrey L.

    2013-01-01

    Inappropriate Na+ reabsorption by thick ascending limbs (THALs) induces hypertension. Nitric oxide (NO) produced by NO synthase type 3 (NOS3 or eNOS) inhibits NaCl reabsorption by THALs. Tumor necrosis factor alpha (TNF-α) decreases NOS3 expression in endothelial cells and contributes to increases in blood pressure. However, the effects of TNF-α on THAL NOS3 and the signaling cascade are unknown. TNF-α activates several signaling pathways including Rho/Rho kinase (ROCK) which is known to reduce NOS3 expression in endothelial cells. Therefore, we hypothesized that TNF-α decreases NOS3 expression via Rho/ROCK in rat THAL primary cultures. THAL cells were incubated with either vehicle or 1 nmol/L TNF-α for 24 hrs and NOS3 expression was measured by Western blot. TNF-α decreased NOS3 expression by 51±6% (p<0.002) and blunted stimulus-induced NO production. A 10-minutes treatment with TNF-α stimulated RhoA activity by 60±23% (p<0.04). Inhibition of Rho GTPase with 0.05 μg/mL C3 exoenzyme blocked TNF-α-induced reductions in NOS3 expression by 30±8% (p<0.02). Inhibition of ROCK with 10 μmol/L H-1152 blocked TNF-α-induced decreases in NOS3 expression by 66±15 % (p<0.001). Simultaneous inhibition of Rho and ROCK had no additive effect. Myosin light chain kinase, NO, protein kinase C, mitogen-activated kinase kinase, c-Jun amino terminal kinases and Rac-1 were also not involved in TNF-α-induced decreases in NOS3 expression. We conclude that TNF-α decreases NOS3 expression primarily via Rho/ROCK in rat THALs. These data suggest that some of the beneficial effects of ROCK inhibitors in hypertension could be due to the mitigation of TNF-α-induced reduction in NOS3 expression. PMID:22566503

  4. Monocyte chemoattractant protein-1 but not tumor necrosis factor-alpha is correlated with monocyte infiltration in mouse lipid lesions

    SciTech Connect

    Reckless, Jill; Rubin, Edward M.; Verstuyft, Judy B.; Metcalfe, James C.; Grainger, David J.

    1999-01-11

    The infiltration of monocytes into the vascular wall and their transformation into lipid-laden foam cells characterize early atherogenesis. This focal accumulation of lipids, together with smooth muscle cell proliferation and migration, and the synthesis of extracellular matrix in the intima of large arteries result in the formation of an atherosclerotic plaque. The extent to which the plaque is infiltrated with monocytes appears to be an important determinant of plaque stability. It has been proposed that macrophages secrete an excess of matrix-degrading enzymes over their inhibitors, resulting in conversion of a stable plaque into anunstable plaque that is likely to rupture, resulting in acutemyocardial infarction. Macrophages and T cells constitute {approx}40 percent of the total population of cells in the lipid core region of atherosclerotic plaques. Their recruitment to the lesion may depend on alterations in the adhesive properties of the endothelial surface. Increased endothelial cell permeability and endothelial cell activation are among the earliest changes associated with developing lesions of atherosclerosis. Many of the cell adhesion molecules involved in monocyte recruitment are expressed at low or undetectable levels on normal endothelium but are substantially elevated on the endothelium overlaying atherosclerotic lesions In addition to endothelial cell activation, numerous chemotactic cytokines have also been postulated to be involved in monocyte recruitment. For example, interleukin (IL)-1 and tumor necrosis factor-a (TNF-a) are direct chemoattractants for human monocytes but additionally induce cytoskeletal changes in the endothelium that result in increased permeability. This increased permeability, together with stimulated expression of adhesion molecules such as E-selectin, plays an important part in the local inflammation mediated by TNF-a and IL-1. In addition, a large number of other proinflammatory cytokines, including macrophage

  5. Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain: inhibition by methylprednisolone and by rolipram

    PubMed Central

    Buttini, M; Mir, A; Appel, K; Wiederhold, K H; Limonta, S; Gebicke-Haerter, P J; Boddeke, H W G M

    1997-01-01

    We have investigated the effects of the phosphodiesterase (PDE) type IV inhibitor rolipram and of the glucocorticoid methylprednisolone on the induction of tumour necrosis factor alpha (TNF-α) mRNA and protein in brains of rats after peripheral administration of lipopolysaccharide (LPS).After intravenous administration of LPS, a similar time-dependent induction of both TNF-α mRNA and protein was observed in rat brain. Peak mRNA and protein levels were found 7 h after administration of LPS.In situ hybridization experiments with a specific antisense TNF-α riboprobe suggested that the cells responsible for TNF-α production in the brain were microglia.Intraperitoneal administration of methylprednisolone inhibited the induction of TNF-α protein in a dose-dependent manner. A maximal inhibition of TNF-α protein production by 42.9±10.2% was observed at a dose regimen consisting of two injections of each 30 mg kg−1 methylprednisolone.Intraperitoneal administration of rolipram also inhibited the induction of TNF-α protein in a dose-dependent manner. The maximal inhibition of TNF-α protein production was 96.1±12.2% and was observed at a dose regimen of three separate injections of each 3 mg kg−1 rolipram.In situ hybridization experiments showed that the level of TNF-α mRNA induced in rat brain by LPS challenge was reduced by intraperitoneal administration of methylprednisolone (2×15 mg kg−1) and of rolipram (3×3 mg kg−1).We suggest that peripheral administration of LPS induces a time-dependent expression of TNF-α in rat brain, presumably in microglial cells, and that methylprednisolone and rolipram inhibit LPS-induced expression of TNF-α in these cells via a decrease of TNF-α mRNA stability and/or TNF-α gene transcription. PMID:9421299

  6. Involvement of platelet-activating factor and tumour necrosis factor in the pathogenesis of joint inflammation in rabbits.

    PubMed Central

    Zarco, P; Maestre, C; Herrero-Beaumont, G; González, E; Garcia-Hoyo, R; Navarro, F J; Braquet, P; Egido, J

    1992-01-01

    We have studied the participation of platelet-activating factor (PAF) in antigen-induced arthritis in rabbits, as well as the possible co-operation between PAF and tumour necrosis factor (TNF) in their ability to induce joint inflammation when injected into the knees of healthy rabbits. The administration of two structurally different PAF receptor antagonists, BN52021 and Alprazolam, from 4 h before the intra-articular injection of ovalbumin in preimmunized rabbits, induced an important reduction in the synovial fluid volume, in the amount of cells infiltrating the articular cavity and the synovial membrane, as well as in the prostaglandin E2 (PGE2) concentration. Furthermore, proteoglycans of the articular cartilage, which were found diminished in animals with non-treated arthritis, were well preserved in rabbits treated with PAF antagonists. All the synovial fluids from joints with arthritis had detectable amounts of PAF. The injection of either TNF or PAF into the joints of normal rabbits induced a mild inflammation. When TNF was administered 1 h before PAF, a synergistic response was noted in the synovial fluid volume, in the accumulation of leucocytes, and in the amount of PGE2. The administration of BN50726, a hetrazepine with a potent PAF-receptor antagonist effect, induced a diminution in those parameters. Our results suggest that PAF may be an early and important mediator of joint damage, and that TNF can amplify the inflammatory response induced by PAF. PAF receptor antagonists could play some role in the treatment of inflammatory joint diseases. Images Fig. 2 Fig. 4 PMID:1315229

  7. Tumor necrosis factor-alpha induces nuclear factor-kappaB-dependent TRPC1 expression in endothelial cells.

    PubMed

    Paria, Biman C; Malik, Asrar B; Kwiatek, Angela M; Rahman, Arshad; May, Michael J; Ghosh, Sankar; Tiruppathi, Chinnaswamy

    2003-09-26

    We investigated the role of tumor necrosis factor-alpha (TNF-alpha) in activating the store-operated Ca2+ channels in endothelial cells via the expression of transient receptor potential channel (TRPC) isoforms. We observed that TNF-alpha exposure of human umbilical vein endothelial cells resulted in TRPC1 mRNA and protein expression, whereas it had no effect on TRPC3, TRPC4, or TRPC5 expression. The TRPC1 expression was associated with increased Ca2+ influx after intracellular Ca2+ store depletion with either thrombin or thapsigargin. We cloned the 5'-regulatory region of the human TRPC1 (hTRPC1) gene which contained a TATA box and CCAAT sequence close to the transcription initiation site. We also identified four nuclear factor-kappaB (NF-kappaB)-binding sites in the 5'-regulatory region. To address the contribution of NF-kappaB in the mechanism of TRPC1 expression, we determined the effects of TNF-alpha on expression of the reporter luciferase after transfection of hTRPC1 promoter-luciferase (hTRPC1-Pro-Luc) construct in the human dermal microvascular endothelial cell line. Reporter activity increased >4-fold at 4 h after TNF-alpha challenge. TNF-alpha-induced increase in reporter activity was markedly reduced by co-expression of either kinase-defective IKKbeta kinase mutant or non-phosphorylatable IkappaB mutant. Treatment with NEMO-binding domain peptide, which prevents NF-kappaB activation by selectively inhibiting IKKgamma interaction with IKK complex, also blocked the TNF-alpha-induced TRPC1 expression. Thus, TNF-alpha induces TRPC1 expression through an NF-kappaB-dependent pathway in endothelial cells, which can trigger augmented Ca2+ entry following Ca2+ store depletion. The augmented Ca2+ entry secondary to TRPC1 expression may be an important mechanism of endothelial injury induced by TNF-alpha. PMID:12855710

  8. Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction.

    PubMed

    Hayashi, Sachiko; Hatashita, Masanori; Matsumoto, Hideki; Shioura, Hiroki; Kitai, Ryuhei; Kano, Eiichi

    2006-11-01

    The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or AMROH. Sequential treatments with AMR or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and AMROH. Similar to AMR and AMROH, adriamycin and etoposide (VP-16) are DNA topoisomerase II inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments. PMID:17016621

  9. Effects of tumor necrosis factor-alpha on sexual activity of male patients with ankylosing spondylitis.

    PubMed

    Dong, Xin; Zheng, Yi; Shi, Tian-Yan; Liu, Hong-Yan

    2015-05-01

    The objective of this study was to investigate the therapeutic effect of a tumor necrosis factor-alpha (TNF-α) antagonist on the sexual quality of life of male patients with ankylosing spondylitis (AS). In this open-label study, 42 AS patients were grouped into the TNF-α antagonist treatment group and the non-TNF-α antagonist treatment group for 3 months. Clinical and laboratory indices and changes in the sexual quality of life were compared to assess the efficacy of TNF-α antagonists on sexual activity. The relationship between sexual quality and disease activity was analyzed. There were no significant differences in baseline data between the two groups. After treatment, disease activity and quality of life were improved in these two groups. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score (1.9 ± 1.6 vs. 3.0 ± 1.3, p = 0.020), erythrocyte sedimentation rate (ESR) (9 ± 7 mm/1 h vs. 18 ± 17 mm/1 h, p = 0.031), and C-reactive protein (CRP) levels (1.8 ± 2.1 mg/dl vs. 6.2 ± 8.5 mg/dl, p = 0.035) were significantly lower in the TNF-α antagonist treatment group than in the non-TNF-α antagonist treatment group. The extent of improvement in the quality of life was more evident in the TNF-α antagonist treatment group. The average degree of improvement in the quality of life was negatively related to the BASDAI score and the Bath Ankylosing Spondylitis Functional Index score in the TNF-α antagonist treatment group (r = -0.497, p = 0.018; r = -0.558, p = 0.007, respectively). Sexual quality of life and disease activity are improved after treatment with TNF-α antagonists in male patients with AS. The extent of improvement in sexual quality and disease activity are positively related. PMID:25064131

  10. Adverse Events of Anti-Tumor Necrosis Factor α Therapy in Ankylosing Spondylitis

    PubMed Central

    Tong, Qiang; Cai, Qing; de Mooij, Tristan; Xu, Xia; Dai, Shengming; Qu, Wenchun; Zhao, Dongbao

    2015-01-01

    Objective This study aims to investigate the prevalence of short-term and long-term adverse events associated with tumor necrosis factor-α (TNF-α) blocker treatment in Chinese Han patients suffering from ankylosing spondylitis (AS). Methods The study included 402 Chinese Han AS patients treated with TNF-α blockers. Baseline data was collected. All patients were monitored for adverse events 2 hours following administration. Long-term treatment was evaluated at 8, 12, 52 and 104 weeks follow-up for 172 patients treated with TNF-α blockers. Results Short-term adverse events occurred in 20.15% (81/402), including rash (3.5%; 14/402), pruritus (1.2%; 5/402), nausea (2.2%; 9/402), headache (0.7%; 3/402), skin allergies (4.0%; 16/402), fever (0.5%; 2/402), palpitations (3.0%; 12/402), dyspnea (0.5%; 2/402), chest pain (0.2%; 2/402), abdominal pain (1.0%; 4/402), hypertension (2.2%; 9/402), papilledema (0.5%; 2/402), laryngeal edema (0.2%; 1/402) and premature ventricular contraction (0.2%; 1/402). Long-term adverse events occurred in 59 (34.3%; 59/172) patients, including pneumonia (7.6%; 13/172), urinary tract infections (9.9%; 17/172), otitis media (4.7%; 8/172), tuberculosis (3.5%; 17/172), abscess (1.2%; 2/172), oral candidiasis (0.6%; 1/172), elevation of transaminase (1.7%; 3/172), anemia (1.2%; 2/172), hematuresis (0.6%; 1/172), constipation (2.3%; 4/172), weight loss (0.6%; 1/172), exfoliative dermatitis (0.6%; 1/172). CRP, ESR and disease duration were found to be associated with an increased risk of immediate and long-term adverse events (P<0.05). Long-term treatment with Infliximab was associated with more adverse events than rhTNFR-Fc (P<0.01). Conclusion This study reports on the prevalence of adverse events in short-term and long-term treatment with TNF-α blocker monotherapy in Chinese Han AS patients. Duration of disease, erythrocyte sedimentation rate, and c-reactive protein serum levels were found to be associated with increased adverse events with

  11. Interindividual concordance of methylation profiles in human genes for tumor necrosis factors alpha and beta.

    PubMed Central

    Kochanek, S; Toth, M; Dehmel, A; Renz, D; Doerfler, W

    1990-01-01

    The DNA in mammalian genomes is characterized by complex patterns of DNA methylation that reflect the states of all genetic activities of that genome. The modified nucleotide 5-methyldeoxycytidine (5mdC) can affect the interactions of specific proteins with DNA sequence motifs. The most extensively studied effect of sequence-specific methylations is that of the long-term silencing of eukaryotic (mammalian) promoters. We have initiated studies on the methylation status of parts of the human genome to view patterns of DNA methylation as indicators for genetic activities. In this report, analyses using both restriction enzyme--Southern blotting and the very precise genomic sequencing technique have been done. The genes for tumor necrosis factors (TNF) alpha and beta--in particular, their 5'-upstream and promoter regions--have been investigated in DNA isolated from human lymphocytes, granulocytes, and sperm. The results are characterized by a remarkable interindividual concordance of DNA methylation in specific human cell types. The patterns are identical in the DNA from one cell type for different individuals even of different genetic origins but different in the DNA from different cell types. As an example, in the DNA from human granulocytes of 15 different individuals (ages 20-48 yr, both sexes), 5mdC residues have been localized by the genomic sequencing technique in three identical sequence positions in the 5'-upstream region and in one downstream position of the gene encoding TNF-alpha. The promoter of this gene is free of 5mdC, and TNF-alpha is expressed in human granulocytes. The TNF-beta promoter is methylated in granulocytes from 9 different individuals, and TNF-beta is not expressed. In human lymphocytes, the main source of TNF-beta, the TNF-beta promoter is free of 5mdC residues. All 5'-CG-3' sites studied in the TNF-alpha and -beta genes are methylated in DNA from human sperm. In human cell lines HL-60, Jurkat, and RPMI 1788, the extent of DNA methylation

  12. Single nucleotide polymorphism in the tumor necrosis factor-alpha gene affects inflammatory bowel diseases risk

    PubMed Central

    Ferguson, Lynnette R; Huebner, Claudia; Petermann, Ivonne; Gearry, Richard B; Barclay, Murray L; Demmers, Pieter; McCulloch, Alan; Han, Dug Yeo

    2008-01-01

    AIM: To investigate the role that single nucleotide polymorphisms (SNPs) in the promoter of the tumour necrosis factor-alpha (TNF-α) gene play in the risk of inflammatory bowel diseases (IBDs) in a New Zealand population, in the context of international studies. METHODS: DNA samples from 388 patients with Crohn’s disease (CD), 405 ulcerative colitis (UC), 27 indeterminate colitis (IC) and 201 randomly selected controls, from Canterbury, New Zealand were screened for 3 common polymorphisms in the TNF-α receptor: -238 G→A, -308 G→A and -857C→T, using a TaqmanR assay. A meta-analysis was performed on the data obtained on these polymorphisms combined with that from other published studies. RESULTS: Individuals carrying the -308 G/A allele had a significantly (OR = 1.91, χ2 = 17.36, P < 0.0001) increased risk of pancolitis, and a 1.57-fold increased risk (OR = 1.57, χ2 = 4.34, P = 0.037) of requiring a bowel resection in UC. Carrying the -857 C/T variant decreased the risk of ileocolonic CD (OR = 0.56, χ2 = 4.32, P = 0.037), and the need for a bowel resection (OR = 0.59, χ2 = 4.85, P = 0.028). The risk of UC was reduced in individuals who were smokers at diagnosis, (OR = 0.48, χ2 = 4.86, P = 0.028). CONCLUSION: TNF-α is a key cytokine known to play a role in inflammatory response, and the locus for the gene is found in the IBD3 region on chromosome 6p21, known to be associated with an increased risk for IBD. The -308 G/A SNP in the TNF-α promoter is functional, and may account in part for the increased UC risk associated with the IBD3 genomic region. The -857 C/T SNP may decrease IBD risk in certain groups. Pharmaco- or nutrigenomic approaches may be desirable for individuals with such affected genotypes. PMID:18698679

  13. Iron-independent induction of ferritin H chain by tumor necrosis factor.

    PubMed Central

    Miller, L L; Miller, S C; Torti, S V; Tsuji, Y; Torti, F M

    1991-01-01

    Iron increases the synthesis of the iron-storage protein, ferritin, largely by promoting translation of preexisting mRNAs for both the H and L ferritin isoforms (H, heavy, heart, acidic; L, light, liver, basic). We have recently cloned and sequenced a full-length cDNA to murine ferritin H and identified ferritin H as a gene induced by tumor necrosis factor alpha (TNF-alpha, cachectin). Using primary human myoblasts, we have now examined the relationship between TNF-alpha and iron in regulating ferritin. Four lines of evidence suggest that TNF-alpha regulates ferritin independently of iron. First, evaluation of mRNA showed that TNF-alpha increased ferritin H chain specifically, provoking no change in steady-state levels of ferritin L mRNA; iron, in contrast, increased the mRNA of both isoforms. Second, the increase in ferritin H protein synthesis observed during TNF-alpha treatment was dependent on an increase in ferritin H mRNA: actinomycin D blocked the TNF-alpha-induced changes in ferritin H but did not inhibit the translational induction of ferritin seen with iron treatment. Third, equal ferritin mRNA induction was observed in iron-loaded cells and in cells depleted of iron by a permeant chelator, 2,2'-dipyridyl. Fourth, ferritin H induction by TNF-alpha and iron was additive over the entire range of iron concentrations, even at TNF-alpha doses known to maximally stimulate ferritin H mRNA levels. Nonetheless, the role of iron in translational regulation of ferritin was retained in TNF-alpha-treated cells; effective biosynthesis of TNF-alpha-induced, H-subunit-predominant ferritin protein required iron and could be enhanced by treatment of the cells with additional iron or blocked by 2,2'-dipyridyl. Finally, we observed that the TNF-alpha-mediated increase in ferritin synthesis peaked at 8 hr and was followed by a decrease in both H and L isoferritin synthesis; the addition of iron, however, reversed the late-occurring depression in ferritin synthesis. This

  14. Nitric oxide and tumour necrosis factor alpha in the process of pseudoexfoliation glaucoma

    PubMed Central

    Sarenac Vulovic, Tatjana S.; Pavlovic, Sladjana M.; Jakovljevic, Vladimir LJ.; Janicijevic, Katarina B.; Zdravkovic, Nemanja S.

    2016-01-01

    AIM To establish the role of nitric oxide (NO), ascorbic acid and tumour necrosis factor-α (TNF-α) in the pathogenesis of pseudoexfoliation glaucoma (XFG). METHODS Our study included 120 patients who were referred for cataract surgery. All patients were divided into four groups according to clinical findings: XFG, early and late pseudoexfoliation syndrome (XFS), and cataract (without pseudoexfoliation). Serum and aqueous humour levels of the ascorbic acid, NO and TNF-α were measured. The concentrations of the ascorbic acid and NO were measured by an appropriate spectrophotometric method. Enzyme-linked immunosorbent assay (ELISA) was used to determine TNF-α level. RESULTS Aqueous humour concentration of ascorbic acid was significantly lower in patients with late XFS (0.61±0.11 mmol/L) and XFG (0.48±0.15 mmol/L) compared to patients with early XFS (0.9±0.15 mmol/L) and cataract (1.16±0.22 mmol/L), while there was no difference in serum concentration in all examined groups. Aqueous humour concentration of NO was significantly higher in patients with XFG (77.7±11.4 µmol/L) compared to patients with early XFS (50.27±9.34 µmol/L) and cataract (49.77±7.1 µmol/L), while serum concentration was increased in the early stage of XFS (73.26±8.29 µmol/L). Aqueous humour level of proinflammatory cytokine TNF-α was increased in patients with XFS (early 460.04±18.32 pg/mL; late 502.42±53.23 pg/mL) and XFG (510.34±43.07 pg/mL), while there was no difference in serum level in all examined groups of patients. CONCLUSION Reduced ascorbic acid and elevated NO and inflammation related cytokine TNF-α level in aqueous humour of the patients with developed XFG suggest that oxidative stress induces local inflammation. PMID:27588268

  15. Binding of tumor necrosis factor alpha to activated forms of human plasma alpha 2 macroglobulin.

    PubMed Central

    Wollenberg, G. K.; LaMarre, J.; Rosendal, S.; Gonias, S. L.; Hayes, M. A.

    1991-01-01

    We tested the hypothesis that human plasma alpha 2 macroglobulin (alpha 2M) is a latent binding glycoprotein for human tumor necrosis factor alpha (TNF-alpha). Human recombinant 125I-TNF-alpha was incubated for 2 hours (37 degrees C) with purified native alpha 2M and with alpha 2M that was modified by reaction with methylamine or various proteinases. 125I-TNF-alpha/alpha 2M complexes were detected by nondenaturing polyacrylamide gel electrophoresis after autoradiography or by liquid chromatography on Superose-6. 125I-TNF-alpha bound strongly but noncovalently to alpha 2M-plasmin and alpha 2M-methylamine. There was minimal binding of 125I-TNF-alpha to native alpha 2M, alpha 2M-trypsin, or alpha 2M-thrombin. A 10(6) molar excess of porcine heparin did not reduce the binding of 125I-TNF-alpha to alpha 2M-methylamine or alpha 2M-plasmin. alpha 2M-plasmin or alpha 2M-methylamine added to human plasma or serum preferentially bound 125I-TNF-alpha in the presence of native alpha 2M. 125I-TNF-alpha also bound to 'fast' alpha-macroglobulins in methylamine-reacted human, rat, mouse, swine, equine, and bovine plasma. However, TNF-alpha, preincubated with either alpha 2M-plasmin or alpha 2M-methylamine, remained a potent necrogen for cultured L929 cells. Purified 125I-TNF-alpha/alpha 2M-plasmin complex injected intravenously in CD-1 mice rapidly cleared from the circulation, unless the alpha 2M-receptor pathway was blocked by coinjection of excess alpha 2M-trypsin. These findings demonstrate that alpha 2M is a latent plasmin-activated binding glycoprotein for TNF-alpha and that TNF-alpha/alpha 2M-plasmin complexes can be removed from the circulation by the alpha 2M-receptor pathway. This suggests that alpha 2M may be an important regulator of the activity and distribution of TNF-alpha in vivo. Images Figure 1 Figure 3 PMID:1704186

  16. Scopadulciol, Isolated from Scoparia dulcis, Induces β-Catenin Degradation and Overcomes Tumor Necrosis Factor-Related Apoptosis Ligand Resistance in AGS Human Gastric Adenocarcinoma Cells.

    PubMed

    Fuentes, Rolly G; Toume, Kazufumi; Arai, Midori A; Sadhu, Samir K; Ahmed, Firoj; Ishibashi, Masami

    2015-04-24

    Scopadulciol (1), a scopadulan-type diterpenoid, was isolated from Scoparia dulcis along with three other compounds (2-4) by an activity-guided approach using the TCF reporter (TOP) luciferase-based assay system. A fluorometric microculture cytotoxicity assay (FMCA) revealed that compound 1 was cytotoxic to AGS human gastric adenocarcinoma cells. The treatment of AGS cells with 1 decreased β-catenin levels and also inhibited its nuclear localization. The pretreatment of AGS cells with a proteasome inhibitor, either MG132 or epoxomicin, protected against the degradation of β-catenin induced by 1. The 1-induced degradation of β-catenin was also abrogated in the presence of pifithrin-α, an inhibitor of p53 transcriptional activity. Compound 1 inhibited TOP activity in AGS cells and downregulated the protein levels of cyclin D1, c-myc, and survivin. Compound 1 also sensitized AGS cells to tumor necrosis factor-related apoptosis ligand (TRAIL)-induced apoptosis by increasing the levels of the death receptors, DR4 and DR5, and decreasing the level of the antiapoptotic protein Bcl-2. Collectively, our results demonstrated that 1 induced the p53- and proteasome-dependent degradation of β-catenin, which resulted in the inhibition of TCF/β-catenin transcription in AGS cells. Furthermore, 1 enhanced apoptosis in TRAIL-resistant AGS when combined with TRAIL. PMID:25793965

  17. Apixaban, an oral, direct inhibitor of activated Factor Xa.

    PubMed

    Shantsila, Eduard; Lip, Gregory Y H

    2008-09-01

    Apixaban is an oral, direct Factor Xa inhibitor that is being developed by Bristol-Myers Squibb Co and Pfizer Inc. Apixaban is currently undergoing phase III clinical trials for cerebrovascular ischemia, deep vein thrombosis and lung embolism, and phase II clinical trials for coronary artery disease. PMID:18729009

  18. Tumor necrosis factor-{alpha} induces MMP-9 expression via p42/p44 MAPK, JNK, and nuclear factor-{kappa}B in A549 cells

    SciTech Connect

    Lin, C.-C.; Tseng, Hsiao-Wei; Hsieh, Hsi-Lung; Lee, Chiang-Wen; Wu, C.-Y.; Cheng, C.-Y.; Yang, C.-M.

    2008-06-15

    Matrix metalloproteinases (MMPs), in particular MMP-9, have been shown to be induced by cytokines including tumor necrosis factor-{alpha} (TNF-{alpha}) and contributes to airway inflammation. However, the mechanisms underlying MMP-9 expression induced by TNF-{alpha} in human A549 cells remain unclear. Here, we showed that TNF-{alpha} induced production of MMP-9 protein and mRNA is determined by zymographic, Western blotting, RT-PCR and ELISA assay, which were attenuated by inhibitors of MEK1/2 (U0126), JNK (SP600125), and NF-{kappa}B (helenalin), and transfection with dominant negative mutants of ERK2 ({delta}ERK) and JNK ({delta}JNK), and siRNAs for MEK1, p42 and JNK2. TNF-{alpha}-stimulated phosphorylation of p42/p44 MAPK and JNK were attenuated by pretreatment with the inhibitors U0126 and SP600125 or transfection with dominant negative mutants of {delta}ERK and {delta}JNK. Furthermore, the involvement of NF-{kappa}B in TNF-{alpha}-induced MMP-9 production was consistent with that TNF-{alpha}-stimulated degradation of I{kappa}B-{alpha} and translocation of NF-{kappa}B into the nucleus which were blocked by helenalin, but not by U0126 and SP600125, revealed by immunofluorescence staining. The regulation of MMP-9 gene transcription by MAPKs and NF-{kappa}B was further confirmed by gene luciferase activity assay. MMP-9 promoter activity was enhanced by TNF-{alpha} in A549 cells transfected with wild-type MMP-9-Luc, which was inhibited by helenalin, U0126, or SP600125. In contrast, TNF-{alpha}-stimulated MMP-9 luciferase activity was totally lost in cells transfected with mutant-NF-{kappa}B MMP-9-luc. Moreover, pretreatment with actinomycin D and cycloheximide attenuated TNF-{alpha}-induced MMP-9 expression. These results suggest that in A549 cells, phosphorylation of p42/p44 MAPK, JNK, and transactivation of NF-{kappa}B are essential for TNF-{alpha}-induced MMP-9 gene expression.

  19. Cutaneous adverse reactions specific to epidermal growth factor receptor inhibitors

    PubMed Central

    Lupu, I; Voiculescu, VM; Bacalbasa, N; Prie, BE; Cojocaru, I; Giurcaneanu, C

    2015-01-01

    Classical antineoplastic therapy is encumbered by extensively studied adverse reactions, most often of systemic nature. The emergence of new generations of anticancer treatments, including epidermal growth factor receptor inhibitors, besides improving the response to treatment and the survival rate, is accompanied by the occurrence of new specific side effects, incompletely studied. These side effects are most often cutaneous (hand foot syndrome, acneiform reactions), and in some cases are extremely severe, requiring dose reduction or drug discontinuation. The prevention of the cutaneous adverse effects and their treatment require a close collaboration between the oncologist and the dermatologist. The occurrence of some of these skin adverse effects may be a favorable prognostic factor for the response to the cancer treatment and the overall survival. Abbreviations: EGFR = epidermal growth factor receptors; EGFRI = epidermal growth factor receptors inhibitors PMID:26361513

  20. The first scintigraphic detection of tumor necrosis factor-alpha in patients with complex regional pain syndrome type 1.

    PubMed

    Bernateck, Michael; Karst, Matthias; Gratz, Klaus F; Meyer, Geerd J; Fischer, Michael J; Knapp, Wolfram H; Koppert, Wolfgang; Brunkhorst, Thomas

    2010-01-01

    Tumor necrosis factor (TNF)-alpha has been identified as a pathogenic factor in many immunologically based diseases and complex regional pain syndrome (CRPS). In this case series, we used radiolabeled technetium anti-TNF-alpha antibody to scintigraphically image TNF-alpha in 3 patients with type 1 CRPS. The results show that TNF-alpha was localized only in affected hands of patients with early-stage CRPS. No uptake was seen in clinically unaffected hands and late-stage CRPS. Our findings support the growing evidence for neuroimmune disturbance in patients with CRPS and may have important further implications for specific anticytokine treatment in patients with CRPS. PMID:19910617

  1. Paradoxical Autoinflammatory Skin Reaction to Tumor Necrosis Factor Alpha Blockers Manifesting as Amicrobial Pustulosis of the Folds in Patients With Inflammatory Bowel Diseases

    PubMed Central

    Marzano, Angelo V.; Tavecchio, Simona; Berti, Emilio; Gelmetti, Carlo; Cugno, Massimo

    2015-01-01

    Abstract The therapy of inflammatory bowel disease, particularly with tumor necrosis factor (TNF) blockers, may be associated with a number of cutaneous adverse effects, including psoriasis-like, eczema-like, and lichenoid eruptions. Other rare skin complications are neutrophilic dermatoses such as amicrobial pustulosis of the folds (APF), which is a chronic relapsing pustular disorder classified in this spectrum. The authors analyzed clinical, histopathologic, and cytokine expression profiles of 3 inflammatory bowel disease patients with APF triggered by adalimumab (patient 1) and infliximab (patients 2 and 3). All 3 patients presented with sterile pustules involving the cutaneous folds, genital regions, and scalp 6 months after starting adalimumab (patient 1) and 9 months after starting infliximab (patients 2 and 3). Histology was characterized by epidermal spongiform pustules with a dermal neutrophilic and lymphocytic infiltrate. Tumor necrosis factor blocker withdrawal associated with topical and systemic corticosteroids induced complete remission of APF in all 3 patients. The expressions of interleukin (IL)-1 beta and its receptors as well as TNF alpha and its receptors were significantly higher in APF than in controls. Also IL-17, leukocyte selectin, and chemokines, such as IL-8, [C-X-C motif] chemokine ligand 1/2/3 (C = cysteine, X = any amino acid), [C-X-C motif] chemokine ligand 16 (C = cysteine, X = any amino acid), and RANTES (regulated on activation, normal T cell expressed and secreted) were significantly overexpressed. Finally, the authors found significant overexpression of both metalloproteinases 2/9 and their inhibitors 1/2. The observation of 3 patients with APF following anti-TNF therapy expands not only the clinical context of APF but also the spectrum of anti-TNF side effects. Overexpression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that APF is autoinflammatory in origin. PMID

  2. Effects of Anti-Tumor Necrosis Factor α (anti-TNF) agents on Bone

    PubMed Central

    Kawai, Vivian K.; Stein, C. Michael; Perrien, Daniel S.; Griffin, Marie R.

    2013-01-01

    Purpose of the review TNF inhibitors are effective for achieving disease control in several inflammatory diseases. Although anti-TNF agents can inhibit bone loss in vitro, their role in the prevention of clinically relevant outcomes such as osteoporosis and fractures has not been clearly established. Recent findings There are many studies of the effects of TNF inhibitors on markers of bone turnover; however few have measured bone mineral density (BMD) or fractures. Most of these studies have small sample sizes and a minority had a placebo control group. Overall these studies suggest that the anti-resorptive effects of anti-TNF therapy are related to control of disease activity. Summary The antiresorptive effects of TNF inhibitors are likely related to their anti-inflammatory properties. Studies to date have not demonstrated any advantages of TNF inhibitors over traditional non biologic therapies in the prevention of bone loss and fractures. PMID:22810364

  3. Lack of the Transcription Factor Hypoxia-Inducible Factor 1α (HIF-1α) in Macrophages Accelerates the Necrosis of Mycobacterium avium-Induced Granulomas

    PubMed Central

    Cardoso, Marcos S.; Silva, Tânia M.; Resende, Mariana

    2015-01-01

    The establishment of mycobacterial infection is characterized by the formation of granulomas, which are well-organized aggregates of immune cells, namely, infected macrophages. The granuloma's main function is to constrain and prevent dissemination of the mycobacteria while focusing the immune response to a limited area. In some cases these lesions can grow progressively into large granulomas which can undergo central necrosis, thereby leading to their caseation. Macrophages are the most abundant cells present in the granuloma and are known to adapt under hypoxic conditions in order to avoid cell death. Our laboratory has developed a granuloma necrosis model that mimics the human pathology of Mycobacterium tuberculosis, using C57BL/6 mice infected intravenously with a low dose of a highly virulent strain of Mycobacterium avium. In this work, a mouse strain deleted of the hypoxia inducible factor 1α (HIF-1α) under the Cre-lox system regulated by the lysozyme M gene promoter was used to determine the relevance of HIF-1α in the caseation of granulomas. The genetic ablation of HIF-1α in the myeloid lineage causes the earlier emergence of granuloma necrosis and clearly induces an impairment of the resistance against M. avium infection coincident with the emergence of necrosis. The data provide evidence that granulomas become hypoxic before undergoing necrosis through the analysis of vascularization and quantification of HIF-1α in a necrotizing mouse model. Our results show that interfering with macrophage adaptation to hypoxia, such as through HIF-1α inactivation, accelerates granuloma necrosis. PMID:26099585

  4. Treatment of severe refractory erythema nodosum leprosum with tumor necrosis factor inhibitor Etanercept.

    PubMed

    Chowdhry, Sundeep; Shukla, Akhilesh; D'souza, Paschal; Dhali, Tapan; Jaiswal, Prashansa

    2016-06-01

    Erythema nodosum leprosum (ENL) is a common complication of lepromatous leprosy. Some patients unresponsive to conventional, first-line therapeutics develop recurrent, recalcitrant ENL. Here, we report a case of severe refractory ENL that was successfully treated with Etanercept. Biologics may be considered as therapeutic alternatives in management of severe, recalcitrant ENL. PMID:27242236

  5. Unexpected postpartum hemorrhage due to an acquired factor VIII inhibitor.

    PubMed

    Paidas, Michael J; Hossain, Nazli

    2014-09-01

    Unexplained postpartum hemorrhage (PPH) refractory to standard hemostatic measures should trigger a heightened clinical suspicion of an acquired bleeding disorder. When hemostatic medical interventions and surgical procedures fail to control the bleeding, then significant postoperative blood loss, debilitating morbidity, loss of fertility, and death may occur. In the setting of an autoantibody inhibitor to factor VIII (FVIII), control of life-threatening PPH and avoidance of subsequent bleeding episodes depends on a timely and accurate diagnosis, prompt hemostatic treatment and eradication of FVIII inhibitors, and appropriate long-term patient care and management. Acquired postpartum hemophilia due to a FVIII inhibitor is a rare cause of PPH; however, delayed treatment can lead to increased maternal morbidity and mortality. Acquired FVIII inhibitors also pose an emerging bleeding threat to the neonate as a result of possible transplacental transfer of FVIII autoantibodies to the fetus during the last trimester of pregnancy. The purpose of this review is to increase awareness among hematologists and obstetricians/gynecologists regarding the occurrence of FVIII neutralizing autoantibodies as a cause of PPH, and emphasize the importance of collaboration between obstetrician/gynecologists and hematology specialists to optimize the diagnostic evaluation, treatment, and long-term management of women who experience PPH due to an acquired FVIII inhibitor. PMID:24338123

  6. Tumor Necrosis Factor Alpha Inhibits L-Type Ca2+ Channels in Sensitized Guinea Pig Airway Smooth Muscle through ERK 1/2 Pathway

    PubMed Central

    Reyes-García, Jorge; Flores-Soto, Edgar; Solís-Chagoyán, Héctor; Sommer, Bettina; Díaz-Hernández, Verónica; García-Hernández, Luz María

    2016-01-01

    Tumor necrosis factor alpha (TNF-α) is a potent proinflammatory cytokine that plays a significant role in the pathogenesis of asthma by inducing hyperresponsiveness and airway remodeling. TNF-α diminishes the L-type voltage dependent Ca2+ channel (L-VDCC) current in cardiac myocytes, an observation that seems paradoxical. In guinea pig sensitized tracheas KCl responses were lower than in control tissues. Serum from sensitized animals (Ser-S) induced the same phenomenon. In tracheal myocytes from nonsensitized (NS) and sensitized (S) guinea pigs, an L-VDCC current (ICa) was observed and diminished by Ser-S. The same decrease was detected in NS myocytes incubated with TNF-α, pointing out that this cytokine might be present in Ser-S. We observed that a small-molecule inhibitor of TNF-α (SMI-TNF) and a TNF-α receptor 1 (TNFR1) antagonist (WP9QY) reversed ICa decrease induced by Ser-S in NS myocytes, confirming the former hypothesis. U0126 (a blocker of ERK 1/2 kinase) also reverted the decrease in ICa. Neither cycloheximide (a protein synthesis inhibitor) nor actinomycin D (a transcription inhibitor) showed any effect on the TNF-α-induced ICa reduction. We found that CaV1.2 and CaV1.3 mRNA and proteins were expressed in tracheal myocytes and that sensitization did not modify them. In cardiac myocytes, ERK 1/2 phosphorylates two sites of the L-VDCC, augmenting or decreasing ICa; we postulate that, in guinea pig tracheal smooth muscle, TNF-α diminishes ICa probably by phosphorylating the L-VDCC site that reduces its activity through the ERK1/2 MAP kinase pathway. PMID:27445440

  7. Tumor Necrosis Factor Alpha Inhibits L-Type Ca(2+) Channels in Sensitized Guinea Pig Airway Smooth Muscle through ERK 1/2 Pathway.

    PubMed

    Reyes-García, Jorge; Flores-Soto, Edgar; Solís-Chagoyán, Héctor; Sommer, Bettina; Díaz-Hernández, Verónica; García-Hernández, Luz María; Montaño, Luis M

    2016-01-01

    Tumor necrosis factor alpha (TNF-α) is a potent proinflammatory cytokine that plays a significant role in the pathogenesis of asthma by inducing hyperresponsiveness and airway remodeling. TNF-α diminishes the L-type voltage dependent Ca(2+) channel (L-VDCC) current in cardiac myocytes, an observation that seems paradoxical. In guinea pig sensitized tracheas KCl responses were lower than in control tissues. Serum from sensitized animals (Ser-S) induced the same phenomenon. In tracheal myocytes from nonsensitized (NS) and sensitized (S) guinea pigs, an L-VDCC current (ICa) was observed and diminished by Ser-S. The same decrease was detected in NS myocytes incubated with TNF-α, pointing out that this cytokine might be present in Ser-S. We observed that a small-molecule inhibitor of TNF-α (SMI-TNF) and a TNF-α receptor 1 (TNFR1) antagonist (WP9QY) reversed ICa decrease induced by Ser-S in NS myocytes, confirming the former hypothesis. U0126 (a blocker of ERK 1/2 kinase) also reverted the decrease in ICa. Neither cycloheximide (a protein synthesis inhibitor) nor actinomycin D (a transcription inhibitor) showed any effect on the TNF-α-induced ICa reduction. We found that CaV1.2 and CaV1.3 mRNA and proteins were expressed in tracheal myocytes and that sensitization did not modify them. In cardiac myocytes, ERK 1/2 phosphorylates two sites of the L-VDCC, augmenting or decreasing ICa; we postulate that, in guinea pig tracheal smooth muscle, TNF-α diminishes ICa probably by phosphorylating the L-VDCC site that reduces its activity through the ERK1/2 MAP kinase pathway. PMID:27445440

  8. A Novel Carboline Derivative Inhibits Nitric Oxide Formation in Macrophages Independent of Effects on Tumor Necrosis Factor α and Interleukin-1β Expression

    PubMed Central

    Poola, Bhaskar; Pasupuleti, Nagarekha; Nantz, Michael H.; Lein, Pamela J.; Gorin, Fredric

    2015-01-01

    Neuropathic pain is a maladaptive immune response to peripheral nerve injury that causes a chronic painful condition refractory to most analgesics. Nitric oxide (NO), which is produced by nitric oxide synthases (NOSs), has been implicated as a key factor in the pathogenesis of neuropathic pain. β-Carbolines are a large group of natural and synthetic indole alkaloids, some of which block activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), a predominant transcriptional regulator of NOS expression. Here, we characterize the inhibitory effects of a novel 6-chloro-8-(glycinyl)-amino-β-carboline (8-Gly carb) on NO formation and NF-κB activation in macrophages. 8-Gly carb was significantly more potent than the NOS inhibitor NG-nitro-l-arginine methyl ester in inhibiting constitutive and inducible NO formation in primary rat macrophages. 8-Gly carb interfered with NF-κB–mediated gene expression in differentiated THP1-XBlue cells, a human NF-κB reporter macrophage cell line, but only at concentrations severalfold higher than needed to significantly inhibit NO production. 8-Gly carb also had no effect on tumor necrosis factor α (TNFα)–induced phosphorylation of the p38 mitogen-activated protein kinase in differentiated THP1 cells, and did not inhibit lipopolysaccharide- or TNFα-stimulated expression of TNFα and interleukin-1β. These data demonstrate that relative to other carbolines and pharmacologic inhibitors of NOS, 8-Gly carb exhibits a unique pharmacological profile by inhibiting constitutive and inducible NO formation independent of NF-κB activation and cytokine expression. Thus, this novel carboline derivative holds promise as a parent compound, leading to therapeutic agents that prevent the development of neuropathic pain mediated by macrophage-derived NO without interfering with cytokine expression required for neural recovery following peripheral nerve injury. PMID:25538105

  9. Elevation of serum KL-6 in patients with psoriasis treated with anti-tumour necrosis factor-α therapy.

    PubMed

    Higashi, Y; Tada, K; Shimokawa, M; Kawai, K; Kanekura, T

    2016-01-01

    We report three patients with psoriasis whose serum level of Krebs Von Den Lungen (KL)-6 increased during therapy with anti-tumour necrosis factor (TNF)-α. A diagnosis of early-phase or subclinical interstitial pneumonia was made in two patients, and their KL-6 level decreased after anti-TNF-α discontinuation. The rise in KL-6 in the other patient was attributed to methotrexate. We propose that serum KL-6 should be monitored routinely in patients treated with anti-TNF agents. PMID:25557847

  10. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation.

    PubMed

    Schulze-Osthoff, K; Bakker, A C; Vanhaesebroeck, B; Beyaert, R; Jacob, W A; Fiers, W

    1992-03-15

    Structural mitochondrial damage accompanies the cytotoxic effects of several drugs including tumor necrosis factor (TNF). Using various inhibitors of mitochondrial electron transport we have investigated the mechanism of TNF-mediated cytotoxicity in L929 and WEHI 164 clone 13 mouse fibrosarcoma cells. Inhibitors with different sites of action modulated TNF cytotoxicity, however, with contrasting effects on final cell viability. Inhibition of mitochondrial electron transport at complex III (cytochrome c reductase) by antimycin A resulted in a marked potentiation of TNF-mediated injury. In contrast, when the electron flow to ubiquinone was blocked, either at complex I (NADH-ubiquinone oxidoreductase) with amytal or at complex II (succinate-ubiquinone reductase) with thenoyltrifluoroacetone, cells were markedly protected against TNF cytotoxicity. Neither uncouplers nor inhibitors of oxidative phosphorylation nor complex IV (cytochrome c oxidase) inhibitors significantly interfered with TNF-mediated effects, ruling out the involvement of energy-coupled phenomena. In addition, the toxic effects of TNF were counteracted by the addition of antioxidants and iron chelators. Furthermore, we analyzed the direct effect of TNF on mitochondrial morphology and functions. Treatment of L929 cells with TNF led to an early degeneration of the mitochondrial ultrastructure without any pronounced damage of other cellular organelles. Analysis of the mitochondrial electron flow revealed that TNF treatment led to a rapid inhibition of the mitochondria to oxidize succinate and NADH-linked substrates. The inhibition of electron transport was dose-dependent and became readily detectable 60 min after the start of TNF treatment, thus preceding the onset of cell death by at least 3-6 h. In contrast, only minor effects were observed on complex IV activity. The different effects observed with the mitochondrial respiratory chain inhibitors provide suggestive evidence that mitochondrial production

  11. The 55-kD tumor necrosis factor receptor on human keratinocytes is regulated by tumor necrosis factor-alpha and by ultraviolet B radiation.

    PubMed Central

    Trefzer, U; Brockhaus, M; Lötscher, H; Parlow, F; Budnik, A; Grewe, M; Christoph, H; Kapp, A; Schöpf, E; Luger, T A

    1993-01-01

    In previous studies we showed that cultured human keratinocytes expressed the 55-kD TNF receptor (TNFR) and that its expression the important for TNF alpha-mediated upregulation of intercellular adhesion molecule-1 (ICAM-1) expression on keratinocytes. Because factors that either reduce or enhance TNFR expression are likely to have a major impact on the biological effects of TNF alpha on keratinocytes, these studies were conducted to determine the factors that regulate its expression on keratinocytes. Using reverse transcriptase polymerase chain reaction, human keratinocytes were shown to lack 75-kD TNFR expression, indicating that TNF responsiveness of human keratinocytes critically depended on regulation of 55-kD TNFR expression. Human keratinocyte 55-kD TNFR surface and mRNA expression was found to be regulated in vitro by recombinant human (rh) TNF alpha. Stimulation of keratinocytes with rhTNF alpha initially decreased, but later increased, 55-kD TNFR surface expression. This biphasic modulation of 55-kD TNFR surface expression was associated with concomitant changes in 55-kD TNFR mRNA expression. Ultraviolet B (UVB) radiation, a well-known inducer of synthesis and secretion of TNF alpha by human keratinocytes, was found to mimic TNF alpha-induced modulation of 55-kD TNFR surface and mRNA expression via a TNF alpha-mediated autocrine regulatory mechanism. Production of soluble 55-kD TNFR by human keratinocytes remained unaffected by TNF alpha stimulation or UVB irradiation. These studies provide clear evidence that membrane expression of the human 55-kD TNFR may be regulated in human keratinocytes by the ligand itself: TNF alpha. Since in previous studies UVB irradiation transiently inhibited TNF alpha-induced human keratinocyte ICAM-1 expression, it is proposed that UVB radiation-induced biphasic modulation of human keratinocyte 55-kD TNFR expression may affect the capacity of these cells to respond to TNF alpha. Images PMID:8392091

  12. Simvastatin Inhibits Toll-like Receptor 8 (TLR8) Signaling in Primary Human Monocytes and Spontaneous Tumor Necrosis Factor Production from Rheumatoid Synovial Membrane Cultures

    PubMed Central

    Mullen, Lisa; Ferdjani, Jason; Sacre, Sandra

    2015-01-01

    Simvastatin has been shown to have antiinflammatory effects that are independent of its serum cholesterol lowering action, but the mechanisms by which these antiinflammatory effects are mediated have not been elucidated. To explore the mechanism involved, the effect of simvastatin on toll-like receptor (TLR) signaling in primary human monocytes was investigated. A short pretreatment with simvastatin dose-dependently inhibited the production of tumor necrosis factor (TNF)-α in response to TLR8 activation (but not TLR2, -4 or -5). Statins are known inhibitors of the cholesterol biosynthetic pathway, but, intriguingly, TLR8 inhibition could not be reversed by addition of mevalonate or geranylgeranyl pyrophosphate, downstream products of cholesterol biosynthesis. TLR8 signaling was examined in HEK 293 cells stably expressing TLR8, where simvastatin inhibited I kappa B kinase (IKK)α/β phosphorylation and subsequent nuclear factor (NF)-κB activation without affecting the pathway to activating protein-1 (AP-1). Because simvastatin has been reported to have antiinflammatory effects in RA patients and TLR8 signaling contributes to TNF production in human RA synovial tissue in culture, simvastatin was tested in these cultures. Simvastatin significantly inhibited the spontaneous release of TNF in this model, which was not reversed by mevalonate. Together, these results demonstrate a hitherto unrecognized mechanism of simvastatin inhibition of TLR8 signaling that may in part explain its beneficial antiinflammatory effects. PMID:26322850

  13. Down-regulation of protein kinase Ceta potentiates the cytotoxic effects of exogenous tumor necrosis factor-related apoptosis-inducing ligand in PC-3 prostate cancer cells.

    PubMed

    Sonnemann, Jürgen; Gekeler, Volker; Sagrauske, Antje; Müller, Cornelia; Hofmann, Hans-Peter; Beck, James F

    2004-07-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a highly promising candidate for the treatment of cancer because it elicits cell death in the majority of tumor cells while sparing most normal cells. Some cancers, however, display resistance to TRAIL, suggesting that treatment with TRAIL alone may be insufficient for cancer therapy. In the present study, we explored whether the apoptotic responsiveness of PC-3 prostate cancer cells to TRAIL could be enhanced by targeting the novel protein kinase C (PKC) isoform eta. Transfection of PC-3 cells with second-generation chimeric antisense oligonucleotides against PKCeta caused a time- and dose-dependent knockdown of PKCeta, as revealed by real-time RT-PCR and Western blot analyses. Knockdown of PKCeta resulted in a marked amplification of TRAIL's cytotoxic activity. Cell killing could be substantially prevented by the pan-caspase inhibitor z-VAD-fmk. In addition, PKCeta knockdown and administration of TRAIL significantly synergized in activation of caspase-3 and internucleosomal DNA fragmentation. Knockdown of PKCeta augmented TRAIL-induced dissipation of the mitochondrial transmembrane potential and release of cytochrome c from mitochondria into the cytosol, indicating that PKCeta acts upstream of mitochondria. We conclude that PKCeta represents a considerable resistance factor with respect to TRAIL and a promising target to exploit the therapeutic potential of TRAIL. PMID:15252138

  14. Enhancement by tumor necrosis factor alpha of dengue virus-induced endothelial cell production of reactive nitrogen and oxygen species is key to hemorrhage development.

    PubMed

    Yen, Yu-Ting; Chen, Hsuen-Chin; Chen, Hseun-Chin; Lin, Yang-Ding; Shieh, Chi-Chang; Wu-Hsieh, Betty A

    2008-12-01

    Hemorrhage is a severe manifestation of dengue disease. Virus strain and host immune response have been implicated as the risk factors for hemorrhage development. To delineate the complex interplay between the virus and the host, we established a dengue hemorrhage model in immune-competent mice. Mice inoculated intradermally with dengue virus develop hemorrhage within 3 days. In the present study, we showed by the presence of NS1 antigen and viral nuclei acid that dengue virus actively infects the endothelium at 12 h and 24 h after inoculation. Temporal studies showed that beginning at day 2, there was macrophage infiltration into the vicinity of the endothelium, increased tumor necrosis factor alpha (TNF-alpha) production, and endothelial cell apoptosis in the tissues. In the meantime, endothelial cells in the hemorrhage tissues expressed inducible nitric oxide synthase (iNOS) and nitrotyrosine. In vitro studies showed that primary mouse and human endothelial cells were productively infected by dengue virus. Infection by dengue virus induced endothelial cell production of reactive nitrogen and oxygen species and apoptotic cell death, which was greatly enhanced by TNF-alpha. N(G)-nitro-L-arginine methyl ester and N-acetyl cysteine reversed the effects of dengue virus and TNF-alpha on endothelial cells. Importantly, hemorrhage development and the severity of hemorrhage were greatly reduced in mice lacking iNOS or p47(phox) or treatment with oxidase inhibitor, pointing to the critical roles of reactive nitrogen and oxygen species in dengue hemorrhage. PMID:18842737

  15. Inhibition of p38 mitogen-activated protein kinase potentiates the apoptotic effect of berberine/tumor necrosis factor-related apoptosis-inducing ligand combination therapy

    PubMed Central

    REFAAT, ALAA; ABDELHAMED, SHERIF; SAIKI, IKUO; SAKURAI, HIROAKI

    2015-01-01

    It was previously reported that berberine (BBR) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) exhibited a synergistic apoptotic effect on triple negative breast cancer (TNBC) cells. In addition, the BBR/TRAIL combination treatment sensitized TRAIL-resistant TNBC cells to TRAIL. The aim of the present study was to investigate a novel pathway for enhancing the apoptotic effect of BBR/TRAIL through mitogen-activated protein kinases (MAPKs). Selective inhibitors and small interfering RNAs were utilized to understand the role of p38 MAPK in this pathway. The results demonstrated that p38 MAPK was activated in response to the combination therapy in TRAIL-resistant TNBC cells. In addition, it was revealed that the inhibition of p38 enhanced apoptosis in epidermal growth factor receptor (EGFR)-overexpressing MDA-MB-468 TNBC cells and EGFR-mutant PC-9 non-small-cell lung carcinoma cells, which was associated with the downregulation of EGFR serine phosphorylation. Viability assays for these two cell lines also confirmed the significant reduction of cell viability following p38 inhibition in BBR/TRAIL-treated cells. In conclusion, the present study provided novel evidence for the role of p38 in suppressing BBR/TRAIL-mediated apoptosis and its association with EGFR, which may explain the mechanism of treatment resistance in certain types of cancer. PMID:26622773

  16. Inhibition of expression of monocyte interleukin-1 by inhibitors of Hageman factor (factor XII).

    PubMed

    Ratnoff, O D; Voytus, J A; Toossi, Z

    1995-02-01

    In an earlier study, activated species of Hageman factor (factor XII) induced elaboration of interleukin-1 by human monocytes. These observations did not address whether Hageman factor participated in endotoxin-induced release of interleukin-1. To examine this question, the release of interleukin-1 by endotoxin-stimulated human mononuclear cells was measured in the presence of popcorn inhibitor, a specific inhibitor of Hageman factor. In the experiments herein described, popcorn inhibitor sharply decreased the release of interleukin-1 by human mononuclear cells that were incubated with endotoxin. This observation suggests that Hageman factor may play a role in the elaboration of interleukin-1 by human mononuclear cells. Conforming with this view, the addition of antiserum directed against Hageman factor inhibited the release of interleukin-1 from endotoxin-stimulated mononuclear cells. PMID:7844472

  17. The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation.

    PubMed Central

    Brown, Sharron A N; Richards, Christine M; Hanscom, Heather N; Feng, Sheau-Line Y; Winkles, Jeffrey A

    2003-01-01

    Fn14 is a growth-factor-inducible immediate-early-response gene encoding a 102-amino-acid type I transmembrane protein. The human Fn14 protein was recently identified as a cell-surface receptor for the tumour necrosis factor (TNF) superfamily member named TWEAK (TNF-like weak inducer of apoptosis). In the present paper, we report that the human TWEAK extracellular domain can also bind the murine Fn14 protein. Furthermore, site-specific mutagenesis and directed yeast two-hybrid interaction assays revealed that the TNFR-associated factor (TRAF) 1, 2, 3 and 5 adaptor molecules bind the murine Fn14 cytoplasmic tail at an overlapping, but non-identical, amino acid sequence motif. We also found that TWEAK treatment of quiescent NIH 3T3 cells stimulates inhibitory kappaBalpha phosphorylation and transcriptional activation of a nuclear factor-kappaB (NF-kappaB) enhancer/luciferase reporter construct. Fn14 overexpression in transiently transfected NIH 3T3 cells also promotes NF-kappaB activation, and this cellular response requires an intact TRAF binding site. These results indicate that Fn14 is a functional TWEAK receptor that can associate with four distinct TRAF family members and stimulate the NF-kappaB transcription factor signalling pathway. PMID:12529173

  18. Factor Xa inhibitors--new anticoagulants for secondary haemostasis.

    PubMed

    Perzborn, E

    2009-08-01

    Oral factor Xa (FXa) inhibitors are a promising alternative to current anticoagulants. This paper reviews the latest developments of oral direct FXa inhibitors and focuses on those which have been approved for the prevention of venous thromboembolism (VTE) after total hip or knee replacement or are in advanced development and have passed phase II (proof of principle) testing. The most advanced drugs are apixaban, betrixaban, edoxaban, eribaxaban, rivaroxaban, LY517717, TAK-442, and YM150. Rivaroxaban (Xareltoâ) is the first direct FXa inhibitor which has recently been approved for the prevention of VTE in adult patients after elective hip or knee replacement in several countries, including the European Union and Canada. Rivaroxaban has a flat dose-dependent anticoagulant response with a wide therapeutic window and low potential for drug-drug and drug-food interactions. Rivaroxaban can be given in fixed doses without coagulation monitoring. This review describes the pharmacodynamic and pharmacokinetic profiles and the results of clinical trials with FXa inhibitors in the prevention and treatment of thromboembolic disorders. PMID:19644596

  19. Tumor Necrosis Factor Related Apoptosis Inducing Ligand (Trail) in endothelial response to biomechanical and biochemical stresses in arteries.

    PubMed

    D'Auria, F; Centurione, L; Centurione, M A; Angelini, A; Di Pietro, R

    2015-11-01

    Shear stress is determined by three physical components described in a famous triad: blood flow, blood viscosity and vessel geometry. Through the direct action on endothelium, shear stress is able to radically interfere with endothelial properties and the physiology of the vascular wall. Endothelial cells (ECs) have also to sustain biochemical stresses represented by chemokines, growth factors, cytokines, complement, hormones, nitric oxide (NO), oxygen and reactive oxygen species (ROS). Many growth factors, cytokines, chemokines, hormones, and chemical substances, like NO, act and regulate endothelium functions and homeostasis. Among these cytokines Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) has been assigned a regulatory role in ECs physiology and physiopathology. Thus, the aim of this review is to provide a general overview of the endothelial response pathways after different types of biomechanical and biochemical stress in in vitro models and to analyze the crucial role of TRAIL under pathological conditions of the cardiocirculatory system like atherosclerosis, coronary artery disease, and diabetes. PMID:25974396

  20. Release of tumor necrosis factor alpha by human peritoneal macrophages in response to toxic shock syndrome toxin-1.

    PubMed

    Buyalos, R P; Rutanen, E M; Tsui, E; Halme, J

    1991-08-01

    We examined the release in vitro of tumor necrosis factor-alpha (TNF-alpha) by peritoneal macrophages and peripheral blood monocytes following incubation with toxic shock syndrome toxin-1 (TSST-1). We obtained peritoneal macrophages from 22 women at laparoscopy and peripheral blood monocytes from four healthy women during both the midfollicular and midluteal phases of the menstrual cycle. The samples were incubated for 24 hours at 37 C with 10(-2)-10(4) ng/mL of TSST-1 or 10(4) ng/mL of bacterial endotoxin. Tumor necrosis factor-alpha activity was determined with a bioassay using an actinomycin D-sensitized WEHI-164 murine fibrosarcoma cell line. Twenty-four-hour incubation with TSST-1 resulted in a dose-dependent release of TNF-alpha by both peritoneal macrophages (maximal response 554 +/- 97 U of activity) and peripheral blood monocytes (maximal response 478 +/- 81 U of activity). We observed enhanced TNF-alpha release by peritoneal macrophages from women with endometriosis, compared with those without endometriosis, at a concentration of 10(4) ng/mL of TSST-1 (704 +/- 134 versus 354 +/- 103 U of activity; P less than .05). These data support the theory that the metabolic and physiologic derangements of perimenstrual toxic shock syndrome may be partially mediated by TNF-alpha released by peritoneal macrophages as a result of exposure to TSST-1. PMID:2067760

  1. Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model.

    PubMed Central

    Costelli, P; Carbó, N; Tessitore, L; Bagby, G J; Lopez-Soriano, F J; Argilés, J M; Baccino, F M

    1993-01-01

    Rats bearing the Yoshida AH-130 ascites hepatoma showed enhanced fractional rates of protein degradation in gastrocnemius muscle, heart, and liver, while fractional synthesis rates were similar to those in non-tumor bearing rats. This hypercatabolic pattern was associated with marked perturbations of the hormonal homeostasis and presence of tumor necrosis factor in the circulation. The daily administration of a goat anti-murine TNF IgG to tumor-bearing rats decreased protein degradation rates in skeletal muscle, heart, and liver as compared with tumor-bearing rats receiving a nonimmune goat IgG. The anti-TNF treatment was also effective in attenuating early perturbations in insulin and corticosterone homeostasis. Although these results suggest that tumor necrosis factor plays a significant role in mediating the changes in protein turnover and hormone levels elicited by tumor growth, the inability of such treatment to prevent a reduction in body weight implies that other mediators or tumor-related events were also involved. PMID:8254032

  2. A Novel Allosteric Inhibitor of Macrophage Migration Inhibitory Factor (MIF)*

    PubMed Central

    Bai, Fengwei; Asojo, Oluwatoyin A.; Cirillo, Pier; Ciustea, Mihai; Ledizet, Michel; Aristoff, Paul A.; Leng, Lin; Koski, Raymond A.; Powell, Thomas J.; Bucala, Richard; Anthony, Karen G.

    2012-01-01

    Macrophage migration inhibitory factor (MIF) is a catalytic cytokine and an upstream mediator of the inflammatory pathway. MIF has broad regulatory properties, dysregulation of which has been implicated in the pathology of multiple immunological diseases. Inhibition of MIF activity with small molecules has proven beneficial in a number of disease models. Known small molecule MIF inhibitors typically bind in the tautomerase site of the MIF trimer, often covalently modifying the catalytic proline. Allosteric MIF inhibitors, particularly those that associate with the protein by noncovalent interactions, could reveal novel ways to block MIF activity for therapeutic benefit and serve as chemical probes to elucidate the structural basis for the diverse regulatory properties of MIF. In this study, we report the identification and functional characterization of a novel allosteric MIF inhibitor. Identified from a high throughput screening effort, this sulfonated azo compound termed p425 strongly inhibited the ability of MIF to tautomerize 4-hydroxyphenyl pyruvate. Furthermore, p425 blocked the interaction of MIF with its receptor, CD74, and interfered with the pro-inflammatory activities of the cytokine. Structural studies revealed a unique mode of binding for p425, with a single molecule of the inhibitor occupying the interface of two MIF trimers. The inhibitor binds MIF mainly on the protein surface through hydrophobic interactions that are stabilized by hydrogen bonding with four highly specific residues from three different monomers. The mode of p425 binding reveals a unique way to block the activity of the cytokine for potential therapeutic benefit in MIF-associated diseases. PMID:22782901

  3. Identification of the major fibroblast growth factors released spontaneously in inflammatory arthritis as platelet derived growth factor and tumour necrosis factor-alpha.

    PubMed Central

    Thornton, S C; Por, S B; Penny, R; Richter, M; Shelley, L; Breit, S N

    1991-01-01

    Rheumatoid arthritis is characterized by chronic inflammation and proliferation of a number of important elements within the joint including the synovial fibroblasts. Elevated levels of a number of cytokines such as Il-1, IL-2, IL-6, interferon-gamma (IFN-gamma), transforming growth factor-beta and tumour necrosis factor-alpha (TNF-alpha) have been detected in the synovial fluid of patients with rheumatoid arthritis and other inflammatory arthritides. It seems likely that local release of such mediators may be responsible for the proliferation and overgrowth of connective tissue elements in these disorders. In order to ascertain whether there was evidence to suggest local production or release of fibroblast growth factors in the joint in inflammatory arthritis, and to determine their identity, cells were obtained from the synovial fluid of 15 patients with chronic inflammatory arthritides. All subjects' synovial fluid cells spontaneously released growth factor activity for fibroblasts. This was present in large amounts, being detectable in culture supernatants diluted to a titre of at least 1/625. By a series of depletion experiments using solid-phase bound antibodies to cytokines, it was possible to demonstrate that this activity was due to TNF-alpha and platelet-derived growth factor (PDGF). Thus, this study showed for the first time that functionally active PDGF was released from synovial fluid cells. Both PDGF and TNF-alpha appeared to contribute in approximately equal amounts to this fibroblast growth factor activity, and were synergistic in effect. Thus this study provides evidence for the local production and release of these two cytokines and suggests that together they are the dominant factors in fibroblast proliferation within the synovial cavity. PMID:1914237

  4. Involvement of oxidants and oxidant-generating enzyme(s) in tumour-necrosis-factor-alpha-mediated apoptosis: role for lipoxygenase pathway but not mitochondrial respiratory chain.

    PubMed

    O'Donnell, V B; Spycher, S; Azzi, A

    1995-08-15

    Cellular signalling by the inflammatory cytokine tumour necrosis factor alpha (TNF alpha) has been suggested to involve generation of low levels of reactive oxygen species (ROS). Certain antioxidants and metal chelators can inhibit cytotoxicity and gene expression in response to TNF alpha in numerous cell types. However, neither the source nor function of TNF alpha-induced oxidant generation is known. Using specific inhibitors, we ruled out involvement of several oxidant-generating enzymes [cyclo-oxygenase (indomethacin), cytochrome P-450 (metyrapone), nitric oxide synthase (NG-methyl-L-arginine), NADPH oxidase (iodonium diphenyl), xanthine oxidase (allopurinol), ribonucleotide reductase (hydroxyurea)] in TNF alpha-mediated apoptosis of the murine fibrosarcoma line, L929. We also demonstrated no role for mitochondrial-derived radicals/respiratory chain in the lytic pathway using specific inhibitors/uncouplers (rotenone, KCN, carboxin, fluoroacetate, antimycin, malonate, carbonyl cyanide p-trifluoromethoxyphenylhydrazone) and chloramphenicol-derived respiration-deficient cells. Significant ROS (H2O2, O2-.) generation was not observed in response to TNF alpha in L929 cells using four separate assays. Also, prevention of intracellular H2O2 removal by inhibition of catalase did not potentiate TNF alpha-mediated cell death. These data suggest that neither H2O2 nor O2-. plays a direct role in TNF alpha cytotoxicity. Finally, we suggest a central role for lipoxygenase in TNF alpha-mediated lysis. Three inhibitors of this radical-generating signalling pathway, including an arachidonate analogue (5,8,11,14-eicosatetraynoic acid), could protect cells against TNF alpha. The inhibitor nordihydroguaiaretic acid is also a radical scavenger, but it could not protect cells from ROS toxicity at concentrations that effectively prevented TNF alpha killing. Therefore protection by nordihydroguaiaretic acid cannot be due to scavenging of cytotoxic H2O or O2-.. The lipoxygenase product

  5. Studies on the biological effects of ozone: 2. Induction of tumor necrosis factor (TNF-alpha) on human leucocytes

    SciTech Connect

    Paulesu, L.; Luzzi, E.; Bocci, V. )

    1991-10-01

    The effect of ozone as a probable inducer of tumor necrosis factor (TNF-alpha) has been investigated on human blood and on Ficoll-purified blood mononuclear cells (PBMC). Samples were exposed at different ozone concentrations ranging from 2.2 to 108 micrograms/ml and incubated at 37 degrees C in an 95% air-5% CO2 atmosphere. At predetermined times, all cell supernatants were tested for TNF activity and some PBMC cultures were examined for DNA synthesis. The authors have shown that ozone concentration is critical in terms of TNF production and of cell mitogenesis and that, owing to the presence of erythrocytes, higher ozone concentrations are required to be effective in blood than in PBMC. Because ozonization of blood is a procedure followed in several European countries for the treatment of viral diseases and tumors, the release of factors with antiviral and immunomodulatory activities by leukocytes may explain the mechanism of action of ozone and of autohemotherapy.

  6. Tumor necrosis factor α induces epithelial-mesenchymal transition and promotes metastasis via NF-κB signaling pathway-mediated TWIST expression in hypopharyngeal cancer.

    PubMed

    Yu, Liang; Mu, Yakui; Sa, Na; Wang, Haibo; Xu, Wei

    2014-01-01

    Epithelial-mesenchymal transition (EMT) is an important mechanism in cancer metastasis. Tumor necrosis factor α (TNFα) can induce cancer invasion and metastasis associated with EMT. However, the underlying mechanisms are not entirely clear. Therefore, we investigated whether TNFα has an effect on EMT and invasion and metastasis in human hypopharyngeal cancer FaDu cells, and further explored the potential mechanisms. In the present study, we demonstrated that TNFα induced EMT in FaDu cells and promoted FaDu cell migration and invasion. TNFα-induced EMT was characterized by a change from well organized cell-cell adhesion and cell polarity to loss of cell-cell contacts, cell scattering and increased expression of vimentin and N-cadherin accompanied by a decrease in E-cadherin. Furthermore, we found that p65 translocated to the nucleus after TNFα stimulation and increased the nuclear expression of TWIST. We demonstrated that TNFα treatment also increased the expression of TWIST by activating the NF-κB signaling pathway. While p65 was inhibited by siRNA-65 or BAY11-7082 (inhibitor of NF-κB), TWIST expression was also decreased. Therefore, we conclude that TNFα induces EMT and promotes metastasis via NF-κB signaling pathway-mediated TWIST expression in hypopharyngeal cancer. PMID:24220622

  7. Tumor necrosis factor-α-induced colitis increases NADPH oxidase 1 expression, oxidative stress, and neutrophil recruitment in the colon: preventive effect of apocynin.

    PubMed

    Mouzaoui, Souad; Djerdjouri, Bahia; Makhezer, Nesrine; Kroviarski, Yolande; El-Benna, Jamel; Dang, Pham My-Chan

    2014-01-01

    Reactive oxygen species- (ROS-) mediated injury has been implicated in several inflammatory disorders, including inflammatory bowel disease (IBD). NADPH oxidases (NOXs) are the major source of endogenous ROS. Here, we investigated the role of NOXs derived-ROS in a mouse model of colitis induced by the proinflammatory cytokine, tumor necrosis factor-α (TNF-α). Intraperitoneal injection of TNFα (10 μg · kg(-1)) induced an acute inflammation of the colon and a marked increase in expression of NADPH oxidase 1 (NOX1), a colon specific NADPH oxidase isoform. TNFα-induced colitis was also characterized by high production of keratinocyte-derived chemokine (KC) and mucosal infiltration of neutrophils, NOX2-expressing cells. Concomitantly, ROS production and lipid peroxidation were significantly enhanced while catalase activity and glutathione level were reduced indicating a redox imbalance in the colon. Furthermore, the redox-sensitive MAP kinases, ERK1/2 and p38 MAPK, were activated during TNFα-induced colitis. Pretreatment of mice with apocynin, an NADPH oxidase inhibitor with antioxidant properties, before TNFα challenge, prevented all these events. These data suggest that ROS derived from NADPH oxidases (mainly NOX1 and NOX2) and MAP kinase pathways could contribute to the induction and expansion of oxidative lesions characteristics of IBD and that apocynin could potentially be beneficial in IBD treatment. PMID:25276054

  8. Molecular characterization and expression analysis of the first Porifera tumor necrosis factor superfamily member and of its putative receptor in the marine sponge Chondrosia reniformis.

    PubMed

    Pozzolini, Marina; Scarfì, Sonia; Ghignone, Stefano; Mussino, Francesca; Vezzulli, Luigi; Cerrano, Carlo; Giovine, Marco

    2016-04-01

    Here we report the molecular cloning and characterization of the first Tumor Necrosis Factor homologous and of its putative receptor in the marine sponge Chondrosia reniformis: chTNF and chTNFR, respectively. The deduced chTNF amino acid sequence is a type II transmembrane protein containing the typical TNFSF domain. Phylogenetic analysis reveals that chTNF is more related to Chordata TNFs rather than to other invertebrates. chTNF and chTNFR are constitutively expressed both in the ectosome and in the choanosome of the sponge, with higher levels in the ectosome. chTNF and chTNFR mRNAs were monitored in sponge fragmorphs treated with Gram(+) or Gram(-) bacteria. chTNF was significantly upregulated in Gram(+)-treated fragmorphs as compared to controls, while chTNFR was upregulated by both treatments. Finally, the possible chTNF fibrogenic role in sponge fragmorphs was studied by TNF inhibitor treatment measuring fibrillar and non fibrillar collagen gene expression; results indicate that the cytokine is involved in sponge collagen deposition and homeostasis. PMID:26705701

  9. Luteinizing hormone induces ovulation via tumor necrosis factor α-dependent increases in prostaglandin F2α in a nonmammalian vertebrate

    PubMed Central

    Crespo, Diego; Goetz, Frederick W.; Planas, Josep V.

    2015-01-01

    Ovulation is induced by the preovulatory surge of luteinizing hormone (LH) that acts on the ovary and triggers the rupture of the preovulatory ovarian follicle by stimulating proteolysis and apoptosis in the follicle wall, causing the release of the mature oocyte. The pro-inflammatory cytokine tumor necrosis factor α (TNFα) and prostaglandin (PG) F2α (PGF2α) are involved in the control of ovulation but their role mediating the pro-ovulatory actions of LH is not well established. Here we show that Lh induces PGF2α synthesis through its stimulation of Tnfα production in trout, a primitive teleost fish. Recombinant trout Tnfα (rTnfα) and PGF2α recapitulate the stimulatory in vitro effects of salmon Lh (sLh) on contraction, proteolysis and loss of cell viability in the preovulatory follicle wall and, finally, ovulation. Furthermore, all pro-ovulatory actions of sLh are blocked by inhibition of Tnfα secretion or PG synthesis and all actions of rTnfα are blocked by PG synthesis inhibitors. Therefore, we provide evidence that the Tnfα–dependent increase in PGF2α production is necessary for the pro-ovulatory actions of Lh. The results from this study shed light onto the mechanisms underlying the pro-ovulatory actions of LH in vertebrates and may prove important in clinical assessments of female infertility. PMID:26374476

  10. Tumor Necrosis Factor-α-Induced Colitis Increases NADPH Oxidase 1 Expression, Oxidative Stress, and Neutrophil Recruitment in the Colon: Preventive Effect of Apocynin

    PubMed Central

    Mouzaoui, Souad; Djerdjouri, Bahia; Makhezer, Nesrine; Kroviarski, Yolande; El-Benna, Jamel; Dang, Pham My-Chan

    2014-01-01

    Reactive oxygen species- (ROS-) mediated injury has been implicated in several inflammatory disorders, including inflammatory bowel disease (IBD). NADPH oxidases (NOXs) are the major source of endogenous ROS. Here, we investigated the role of NOXs derived-ROS in a mouse model of colitis induced by the proinflammatory cytokine, tumor necrosis factor-α (TNF-α). Intraperitoneal injection of TNFα (10 μg · kg−1) induced an acute inflammation of the colon and a marked increase in expression of NADPH oxidase 1 (NOX1), a colon specific NADPH oxidase isoform. TNFα-induced colitis was also characterized by high production of keratinocyte-derived chemokine (KC) and mucosal infiltration of neutrophils, NOX2-expressing cells. Concomitantly, ROS production and lipid peroxidation were significantly enhanced while catalase activity and glutathione level were reduced indicating a redox imbalance in the colon. Furthermore, the redox-sensitive MAP kinases, ERK1/2 and p38 MAPK, were activated during TNFα-induced colitis. Pretreatment of mice with apocynin, an NADPH oxidase inhibitor with antioxidant properties, before TNFα challenge, prevented all these events. These data suggest that ROS derived from NADPH oxidases (mainly NOX1 and NOX2) and MAP kinase pathways could contribute to the induction and expansion of oxidative lesions characteristics of IBD and that apocynin could potentially be beneficial in IBD treatment. PMID:25276054

  11. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa.

    PubMed

    Harenberg, Job; Wehling, Martin

    2008-02-01

    Indirect systemic and direct oral factor Xa and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed. PMID:18393142

  12. Liver Failure Impairs the Intrahepatic Elimination of Interleukin-6, Tumor Necrosis Factor-Alpha, Hepatocyte Growth Factor, and Transforming Growth Factor-Beta.

    PubMed

    Porowski, Dawid; Wirkowska, Agnieszka; Hryniewiecka, Ewa; Wyzgał, Janusz; Pacholczyk, Marek; Pączek, Leszek

    2015-01-01

    The strategic location of the liver and its metabolic activity make it a key organ regulating homeostasis. Our purpose was to examine its participation in removal of cytokines: interleukin-6 (Il-6), tumor necrosis factor-alpha (TNF-α), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGF-β) from the portal circulation in human. 20 liver donors and 20 patients with end-stage liver failure were included in the study. Their blood was collected during liver transplantation from the portal, hepatic, and peripheral vein, and the hepatic artery and cytokines' concentrations were determined. Using the results the mathematical model of cytokine elimination by the liver was developed. In donors significantly lower levels of IL-6, TNF-α, HGF, and TGF-β were detected in portal blood compared to hepatic vein. In patients with cirrhosis there were no significant differences of IL-6, TNF-α, and TGF-β levels between portal and hepatic veins. Significantly higher level of HGF in hepatic compared to portal vein was observed. In healthy liver elimination of the cytokines prevailed over their synthesis, as reflected by the positive values of the elimination ratios. In the cirrhotic liver elimination ratios of Il-6, HGF, and TGF-β were negative indicating the prevalence of intrahepatic synthesis of cytokines over their removal. PMID:26090463

  13. Xylosyltransferase-1 Expression Is Refractory to Inhibition by the Inflammatory Cytokines Tumor Necrosis Factor α and IL-1β in Nucleus Pulposus Cells

    PubMed Central

    Ye, Wei; Zhou, Jie; Markova, Dessislava Z.; Tian, Ye; Li, Jun; Anderson, D. Greg; Shapiro, Irving M.; Risbud, Makarand V.

    2016-01-01

    We investigated whether expression of xylosyltransferase-1 (XT-1), a key enzyme in glycosaminoglycan biosynthesis, is responsive to disk degeneration and to inhibition by the inflammatory cytokines tumor necrosis factor α and IL-1β in nucleus pulposus (NP) cells. Analysis of human NP tissues showed that XT-1 expression is unaffected by degeneration severity; XT-1 and Jun, Fos, and Sp1 mRNA were positively correlated. Cytokines failed to inhibit XT-1 promoter activity and expression. However, cytokines decreased activity of XT-1 promoters containing deletion and mutation of the –730/–723 bp AP-1 motif, prompting us to investigate the role of AP-1 and Sp1/Sp3 in the regulation of XT-1 in healthy NP cells. Overexpression and suppression of AP-1 modulated XT-1 promoter activity. Likewise, treatment with the Sp1 inhibitors WP631 and mithramycin A or cotransfection with the plasmid DN-Sp1 decreased XT-1 promoter activity. Inhibitors of AP-1 and Sp1 and stable knockdown of Sp1 and Sp3 resulted in decreased XT-1 expression in NP cells. Genomic chromatin immunoprecipitation analysis showed AP-1 binding to motifs located at –730/–723 bp and –684/–677 bp and Sp1 binding to –227/–217 bp and –124/–114 bp in XT-1 promoter. These results suggest that XT-1 expression is refractory to the disease process and to inhibition by inflammatory cytokines and that signaling through AP-1, Sp1, and Sp3 is important in the maintenance of XT-1 levels in NP cells. PMID:25476526

  14. Hypothermia-induced neurite outgrowth is mediated by tumor necrosis factor-alpha.

    PubMed

    Schmitt, Katharina R L; Boato, Francesco; Diestel, Antje; Hechler, Daniel; Kruglov, Andrei; Berger, Felix; Hendrix, Sven

    2010-07-01

    Systemic or brain-selective hypothermia is a well-established method for neuroprotection after brain trauma. There is increasing evidence that hypothermia exerts beneficial effects on the brain and may also support regenerative responses after brain damage. Here, we have investigated whether hypothermia influences neurite outgrowth in vitro via modulation of the post-injury cytokine milieu. Organotypic brain slices were incubated: deep hypothermia (2 h at 17 degrees C), rewarming (2 h up to 37 degrees C), normothermia (20 h at 37 degrees C). Neurite density and cytokine release (IL 1beta, IL-6, IL-10, and TNF-alpha) were investigated after 24 h. For functional analysis mice deficient in NT-3/NT-4 and TNF-alpha as well as the TNF-alpha inhibitor etanercept were used. Hypothermia led to a significant increase of neurite outgrowth, which was independent of neurotrophin signaling. In contrast to other cytokines investigated, TNF-alpha secretion by organotypic brain slices was significantly increased after deep hypothermia. Moreover, hypothermia-induced neurite extension was abolished after administration of the TNF-alpha inhibitor and in TNF-alpha knockout mice. We demonstrate that TNF-alpha is responsible for inducing neurite outgrowth in the context of deep hypothermia and rewarming. These data suggest that hypothermia not only exerts protective effects in the CNS but may also support neurite outgrowth as a potential mechanism of regeneration. PMID:20070303

  15. Targeting of Tumor Necrosis Factor Receptor 1 to Low Density Plasma Membrane Domains in Human Endothelial Cells*

    PubMed Central

    D'Alessio, Alessio; Kluger, Martin S.; Li, Jie H.; Al-Lamki, Rafia; Bradley, John R.; Pober, Jordan S.

    2010-01-01

    TNFR1 (tumor necrosis factor receptor 1) localizes to caveolae of human endothelial-derived EA.hy926 cells. Transduced TNFR1 molecules lacking amino acid residues 229–244 (spanning the transmembrane/intercellular boundary) are expressed on the cell surface equivalently to full-length TNFR1 molecules but incompletely localize to caveolae. A peptide containing this sequence pulls down CAV-1 (caveolin-1) and TNFR1 from cell lysates but fails to do so following disruption of caveolae with methyl-β-cyclodextrin. We previously reported that methyl-β-cyclodextrin eliminates caveolae and blocks tumor necrosis factor (TNF)-induced internalization of TNFR1 but not TNF-induced activation of NF-κB in EA.hy926 cells. Both CAV-1 and FLOT-2 (flotillin-2), organizing proteins of caveolae and lipid rafts, respectively, associate with caveolae in EA.hy926 cells. Small interfering RNA-mediated knockdown of CAV-1 but not FLOT-2 strikingly reduces caveolae number. Both knockdowns reduce total TNFR1 protein expression, but neither prevents TNFR1 localization to low density membrane domains, TNF-induced internalization of TNFR1, or NF-κB activation by TNF. Both CAV-1 and FLOT-2 knockdowns reduce TNF-mediated activation of stress-activated protein kinase (SAPK). However, both knockdowns reduce expression of TRAF2 (TNF receptor-associated factor-2) protein, and small interfering RNA targeting of TRAF2 also selectively inhibits SAPK activation. We conclude that TNFR1 contains a membrane-proximal sequence that targets the receptor to caveolae/lipid rafts. Neither TNFR1 targeting to nor internalization from these low density membrane domains depends upon CAV-1 or FLOT-2. Furthermore, both NF-κB and SAPK activation appear independent of both TNFR1 localization to low density membrane domains and to TNF-induced receptor internalization. PMID:20511226

  16. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis.

    PubMed Central

    Yoshida, S; Ono, M; Shono, T; Izumi, H; Ishibashi, T; Suzuki, H; Kuwano, M

    1997-01-01

    Tumor necrosis factor alpha (TNF-alpha) is a macrophage/monocyte-derived polypeptide which modulates the expression of various genes in vascular endothelial cells and induces angiogenesis. However, the underlying mechanism by which TNF-alpha mediates angiogenesis is not completely understood. In this study, we assessed whether TNF-alpha-induced angiogenesis is mediated through TNF-alpha itself or indirectly through other TNF-alpha-induced angiogenesis-promoting factors. Cellular mRNA levels of interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors were increased after the treatment of human microvascular endothelial cells with TNF-alpha (100 U/ml). TNF-alpha-dependent tubular morphogenesis in vascular endothelial cells was inhibited by the administration of anti-IL-8, anti-VEGF, and anti-bFGF antibodies, and coadministration of all three antibodies almost completely abrogated tubular formation. Moreover, treatment with Sp1, NF-kappaB, and c-Jun antisense oligonucleotides inhibited TNF-alpha-dependent tubular morphogenesis by microvascular endothelial cells. Administration of a NF-kappaB antisense oligonucleotide almost completely inhibited TNF-alpha-dependent IL-8 production and partially abrogated TNF-alpha-dependent VEGF production, and an Sp1 antisense sequence partially inhibited TNF-alpha-dependent production of VEGF. A c-Jun antisense oligonucleotide significantly inhibited TNF-alpha-dependent bFGF production but did not affect the production of IL-8 and VEGF. Administration of an anti-IL-8 or anti-VEGF antibody also blocked TNF-alpha-induced neovascularization in the rabbit cornea in vivo. Thus, angiogenesis by TNF-alpha appears to be modulated through various angiogenic factors, both in vitro and in vivo, and this pathway is controlled through paracrine and/or autocrine mechanisms. PMID:9199336

  17. Potent inhibitors of anthrax lethal factor from green tea

    PubMed Central

    Dell'Aica, Isabella; Donà, Massimo; Tonello, Fiorella; Piris, Alejandro; Mock, Michèle; Montecucco, Cesare; Garbisa, Spiridione

    2004-01-01

    The anthrax lethal factor (LF) has a major role in the development of anthrax. LF is delivered by the protective antigen (PA) inside the cell, where it exerts its metalloprotease activity on the N-terminus of MAPK-kinases. PA+LF are cytotoxic to macrophages in culture and kill the Fischer 344 rat when injected intravenously. We describe here the properties of some polyphenols contained in green tea as powerful inhibitors of LF metalloproteolytic activity, and how the main catechin of green tea, (−)epigallocatechin-3-gallate, prevents the LF-induced death of macrophages and Fischer 344 rats. PMID:15031715

  18. New Insights into the Mechanisms of Action of Anti-Tumor Necrosis Factor-α Monoclonal Antibodies in Inflammatory Bowel Disease.

    PubMed

    Slevin, Stephanie M; Egan, Laurence J

    2015-12-01

    Tumor necrosis factor alpha (TNF-α) has been widely accepted as a therapeutic target for inflammatory disorders including inflammatory bowel disease. Anti-TNF-α monoclonal antibodies (mAbs) including infliximab, adalimumab, golimumab, and certolizumab pegol have revolutionized therapy for these chronic inflammatory disorders. These agents are potent inhibitors of TNF-α, but significant evidence points to the fact that their actions extend beyond simple neutralization of the cytokine. Recent advances in understanding the mechanism of action of anti-TNF-α mAbs has discovered a number of previously unrecognized actions that are likely to be relevant in mediating their anti-inflammatory effects. Many of those actions are mediated by the binding of the antibodies to transmembrane TNF-α (tmTNF-α) and involve complex interactions with other molecular factors and cells. In this review, we have highlighted new information on the mechanism of actions of anti-TNF-α mAbs, from in vitro and in vivo studies. Despite obvious benefits in many patients, the clinical use of these antibodies are hampered by the fact that some patients do not respond to them, and among patients who do respond, many will develop recurrent disease despite continued dosing. Although pharmacokinetic factors explain some of the observed cases of partial or complete resistance to the effects of anti-TNF-α mAbs, other nonresponder patients may be resistant to those agents mechanism of action. A more thorough understanding of the mechanism of action of anti-TNF-α mAbs may allow the development of strategies to individualize therapy and to overcome resistance. PMID:26348448

  19. Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype

    PubMed Central

    Jin, Ping; Zhao, Yuanlong; Liu, Hui; Chen, Jinguo; Ren, Jiaqiang; Jin, Jianjian; Bedognetti, Davide; Liu, Shutong; Wang, Ena; Marincola, Francesco; Stroncek, David

    2016-01-01

    Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-α and IFN-γ stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-γ and TNF-α was synergistic and induced a transcriptome most similar to that found in MSCs stimulated with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-γ and TNF-α polarized uniformly to this phenotype. The combination of IFN-γ and TNF-α results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-γ and TNF-α released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment. PMID:27211104

  20. Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype.

    PubMed

    Jin, Ping; Zhao, Yuanlong; Liu, Hui; Chen, Jinguo; Ren, Jiaqiang; Jin, Jianjian; Bedognetti, Davide; Liu, Shutong; Wang, Ena; Marincola, Francesco; Stroncek, David

    2016-01-01

    Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-α and IFN-γ stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-γ and TNF-α was synergistic and induced a transcriptome most similar to that found in MSCs stimulated with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-γ and TNF-α polarized uniformly to this phenotype. The combination of IFN-γ and TNF-α results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-γ and TNF-α released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment. PMID:27211104

  1. Benefits and risks of combining anti-tumor necrosis factor with immunomodulator therapy in pediatric inflammatory bowel disease.

    PubMed

    Cozijnsen, Martinus A; Escher, Johanna C; Griffiths, Anne; Turner, Dan; de Ridder, Lissy

    2015-04-01

    Since the introduction of anti-tumor necrosis factor (TNF) therapy as treatment of inflammatory bowel disease (IBD), care of pediatric and adult patients with IBD has significantly improved. To further improve treatment efficacy and durability, multiple trials have compared the efficacy of combination therapy, using anti-TNF therapy combined with an immunomodulator (a thiopurine or methotrexate), with that of anti-TNF monotherapy with contradicting results. The safety of combined therapy has been questioned after several reported cases of hepatosplenic T-cell lymphoma in young patients with IBD so treated. Physicians prescribing anti-TNF therapy to patients with IBD are required to weigh the benefits of combined therapy with its risks. To inform physicians treating children with IBD of these benefits and risks, we reviewed studies in pediatric and adult patients with IBD comparing efficacy, durability, and/or safety of combined therapy with anti-TNF monotherapy. PMID:25723615

  2. Characterization of a Canine Tetranucleotide Microsatellite Marker Located in the First Intron of the Tumor Necrosis Factor Alpha Gene

    PubMed Central

    WATANABE, Masashi; TANAKA, Kazuaki; TAKIZAWA, Tatsuya; SEGAWA, Kazuhito; NEO, Sakurako; TSUCHIYA, Ryo; MURATA, Michiko; MURAKAMI, Masaru; HISASUE, Masaharu

    2013-01-01

    ABSTRACT A polymorphic tetranucleotide (GAAT)n microsatellite in the first intron of the canine tumor necrosis factor alpha (TNFA) gene was characterized in this study; 139 dogs were analyzed: 22 Beagles, 26 Chihuahuas, 20 Miniature Dachshunds, 24 Miniature Poodles, 22 Pembroke Welsh Corgis and 25 Shiba Inus. We detected the presence of the 4 alleles (GAAT)5, (GAAT)6, (GAAT)7 and (GAAT)8, including 9 of the 10 expected genotypes. The expected heterozygosity (He) and the polymorphic information content (PIC) value of this microsatellite locus varied from 0.389 to 0.749 and from 0.333 to 0.682, respectively, among the 6 breeds. The allelic frequency differed greatly among breeds, but this microsatellite marker was highly polymorphic and could be a useful marker for the canine TNFA gene. PMID:24042337

  3. Inhibitory effects of Turkish folk remedies on inflammatory cytokines: interleukin-1alpha, interleukin-1beta and tumor necrosis factor alpha.

    PubMed

    Yeşilada, E; Ustün, O; Sezik, E; Takaishi, Y; Ono, Y; Honda, G

    1997-09-01

    In this study, in vitro inhibitory effects of 55 extracts or fractions obtained from 10 plant species on interleukin-1 (IL-1alpha, IL-1beta) and tumor necrosis factor (TNF-alpha) biosynthesis were studied. The following plant materials from Turkish folk medicine for the treatment of various diseases which are thought to be inflammatory in nature e.g. rheumatism, fever, infections, edemas or related inflammatory diseases were selected as the subject of this study: Cistus laurifolius leaves, Clematis flammna flowering herbs, Crataegus orientalis roots, Daphne oleoides ssp. oleoides whole plant, Ecbalium elaterium roots, Rosa canina roots, Rubus discolor roots, Rubus hirtus roots, Sambucus ebulus flowers and leaves, Sambucus nigra flowers and leaves. All plants showed inhibitory activity against at least one of these models in various percentages depending upon the concentration, thus supporting the folkloric utilization. Daphne oleoides was found to be the most active plant against the test models. PMID:9324006

  4. Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection.

    PubMed

    Beyer, Marc; Abdullah, Zeinab; Chemnitz, Jens M; Maisel, Daniela; Sander, Jil; Lehmann, Clara; Thabet, Yasser; Shinde, Prashant V; Schmidleithner, Lisa; Köhne, Maren; Trebicka, Jonel; Schierwagen, Robert; Hofmann, Andrea; Popov, Alexey; Lang, Karl S; Oxenius, Annette; Buch, Thorsten; Kurts, Christian; Heikenwalder, Mathias; Fätkenheuer, Gerd; Lang, Philipp A; Hartmann, Pia; Knolle, Percy A; Schultze, Joachim L

    2016-05-01

    Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity-infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)-we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection. PMID:26950238

  5. Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation

    PubMed Central

    Mahmud, Shawn A.; Manlove, Luke S.; Schmitz, Heather M.; Xing, Yan; Wang, Yanyan; Owen, David L.; Schenkel, Jason M.; Boomer, Jonathan S.; Green, Jonathan M.; Yagita, Hideo; Chi, Hongbo; Hogquist, Kristin A.; Farrar, Michael A.

    2014-01-01

    Regulatory T (Treg) cells express tumor necrosis factor receptor superfamily (TNFRSF) members, but their role in thymic Treg development is undefined. We demonstrate that Treg progenitors highly express the TNFRSF members GITR, OX40, and TNFR2. Expression of these receptors correlates directly with T cell receptor (TCR) signal strength, and requires CD28 and the kinase TAK1. Neutralizing TNFSF ligands markedly reduced Treg development. Conversely, TNFRSF agonists enhanced Treg differentiation by augmenting IL-2R/STAT5 responsiveness. GITR-ligand costimulation elicited a dose-dependent enrichment of lower-affinity cells within the Treg repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated Treg development. Thus TNFRSF expression on Treg progenitors translates strong TCR signals into molecular parameters that specifically promote Treg differentiation and shape the Treg repertoire. PMID:24633226

  6. Perioperative management of tumor necrosis factor-alpha blocker-treated psoriatic patients: Case reports and review.

    PubMed

    Kawakami, Hiroshi; Matsumoto, Yuka; Abe, Namiko; Katori, Youich; Takahashi, Kousuke; Tsuboi, Ryoji; Okubo, Yukari

    2016-02-01

    Regarding appropriate timings of discontinuation and resumption of biologics for psoriasis patients before and after elective surgeries, an international consensus has yet to be reached. The Japanese Dermatological Association of Guideline and Safety Manual for the use of Biologic Agents in Psoriasis 2013 states that infliximab (IFX) and adalimumab (ADA) should be withheld at least 4 and 2 weeks, respectively, before surgery and can be restarted as neither postoperative infection nor delayed wound healing is recognized. We experienced three generalized pustular psoriasis (GPP) patients and one plaque-type psoriasis patient undergoing surgeries during tumor necrosis factor (TNF)-α blocker therapy. Three GPP cases experienced uneventful post-surgical course. One psoriasis vulgaris patient on IFX had a wound healing delay with deterioration of psoriatic plaques which was restored by restarting IFX. The timing of suspension and resumption of TNF-α blockers in all cases were determined following the Japanese guideline. PMID:26346621

  7. Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1.

    PubMed Central

    Walsh, L J; Trinchieri, G; Waldorf, H A; Whitaker, D; Murphy, G F

    1991-01-01

    Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that mediates endothelial leukocyte interactions by inducing expression of adhesion molecules. In this report, we demonstrate that human dermal mast cells contain sizeable stores of immunoreactive and biologically active TNF-alpha within granules, which can be released rapidly into the extracellular space upon degranulation. Among normal human dermal cells, mast cells are the predominant cell type that expresses both TNF-alpha protein and TNF-alpha mRNA. Moreover, induction of endothelial leukocyte adhesion molecule 1 expression is a direct consequence of release of mast cell-derived TNF-alpha. These findings establish a role for human mast cells as "gatekeepers" of the dermal microvasculature and indicate that mast cell products other than vasoactive amines influence endothelium in a proinflammatory fashion. Images PMID:1709737

  8. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone.

    PubMed Central

    Folks, T M; Clouse, K A; Justement, J; Rabson, A; Duh, E; Kehrl, J H; Fauci, A S

    1989-01-01

    Tumor necrosis factor alpha (TNF-alpha), also known as cachectin, was demonstrated to induce the expression of human immunodeficiency virus (HIV) in a chronically infected T-cell clone (ACH-2). Concentrations of recombinant TNF-alpha as low as 50 pg/ml induced a significant increase over background of HIV expression in the ACH-2 cells as determined by supernatant reverse transcriptase activity. The HIV-inducing effects of TNF-alpha could not be explained by toxic effects on the cells. In addition, both the uninfected parental cell line (A3.01) and the infected ACH-2 cells were shown to have high-affinity receptors for TNF-alpha. Transient-transfection experiments demonstrated that the inductive effects of TNF-alpha were due to specific activation of the HIV long terminal repeat. These studies provide evidence that TNF-alpha may play a role in the mechanisms of pathogenesis of HIV infection. Images PMID:2784570

  9. Pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis: efficacy of anti-tumor necrosis factor α therapy.

    PubMed

    Bruzzese, Vincenzo

    2012-12-01

    We report the case of a patient with a simultaneous presence of pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis. This condition differs from both the PASH (pyoderma gangrenosum, acne, and suppurative hidradenitis) syndrome, in which arthritis is absent, and the PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, in which suppurative hidradenitis is lacking. Our patient failed to respond to etanercept therapy, whereas all dermatologic and rheumatic manifestations completely regressed following infliximab infusion. We therefore propose that simultaneous presence of pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis might represent a distinct syndrome that could be termed the PASS syndrome. Tumor necrosis factor α therapies seem to play selective roles. PMID:23188209

  10. An extraordinary form of the Melkersson-Rosenthal syndrome successfully treated with the tumour necrosis factor-α blocker adalimumab

    PubMed Central

    Stein, Juergen; Paulke, Alexander; Schacher, Beate; Noehte, Matthias

    2014-01-01

    Melkersson-Rosenthal syndrome (MRS) is a rare granulomatous inflammatory disease characterised by the triad of orofacial oedema, facial nerve palsy and furrowed tongue. We describe the case of a 29-year-old patient suffering from an oligosymptomatic form of the disease with orofacial oedema, cobblestone pattern on the buccal mucosa and swelling of the tongue, accompanied by intermittent fatigue, influenza-like symptoms, intermittent tinnitus and acute hearing loss. An increase of several autoimmune-associated antibodies was also detected. Treatment with prednisolone, azathioprine or methotrexate failed to adequately control all symptoms in the long term. In the absence of a specific and well-established therapy for MRS, treatment with adalimumab was administered. Under adalimumab, total remission of all symptoms was achieved, indicating that tumour necrosis factor-α blockers are a promising therapeutic option for patients with Melkersson-Rosenthal syndrome. PMID:24827666

  11. Synergistic effects of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha: central monoamine, corticosterone, and behavioral variations.

    PubMed

    Brebner, K; Hayley, S; Zacharko, R; Merali, Z; Anisman, H

    2000-06-01

    The proinflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) influence neuroendocrine activity, promote central neurotransmitter alterations, and induce a constellation of symptoms collectively referred to as sickness behaviors. These cytokines may also elicit anxiety and anhedonia, and have been associated with psychological disturbances in humans. In the present investigation, systemic IL-1beta and TNF-alpha dose-dependently and synergistically disrupted consumption of a highly palatable food source (chocolate milk), possibly reflecting anorexia or anhedonia engendered by the treatments. As well, these cytokines synergistically increased plasma corticosterone levels. Although IL-1beta and TNF-alpha provoked variations of amine turnover in the hypothalamus, locus coeruleus, and central amygdala, synergistic effects were not evident in this respect. Nevertheless, in view of the central amine variations induced by the cytokines, it is suggested that immune activation may come to influence complex behavioral processes, as well as affective state. PMID:10788757

  12. Tumor necrosis factor-α driven inflammation in alpha-1 antitrypsin deficiency: a new model of pathogenesis and treatment.

    PubMed

    Hurley, Killian; Reeves, Emer P; Carroll, Tomás P; McElvaney, Noel G

    2016-02-01

    Alpha-1 antitrypsin (AAT) deficiency (AATD) has traditionally been thought of as a genetic disorder characterized by lung destruction and early emphysema in a low AAT, and high neutrophil elastase (NE) environment in the lungs of affected individuals. Recently, a growing body of evidence has emerged to support the hypothesis that tumor necrosis factor alpha (TNF-α) is essential in the pathogenesis of both genetic AATD and non-genetic chronic obstructive pulmonary disease (COPD). Reports have highlighted the importance of TNF-α driven immune cell dysfunction in the development of lung disease in AATD. The authors discuss the role of AAT as a key modulator of TNF-α signaling firstly in the setting of AATD and secondly in other conditions where AAT augmentation therapy has potential utility as a novel therapy. PMID:26634397

  13. Immunomodulatory parasites and toll-like receptor-mediated tumour necrosis factor alpha responsiveness in wild mammals

    PubMed Central

    Jackson, Joseph A; Friberg, Ida M; Bolch, Luke; Lowe, Ann; Ralli, Catriona; Harris, Philip D; Behnke, Jerzy M; Bradley, Janette E

    2009-01-01

    Background Immunological analyses of wild populations can increase our understanding of how vertebrate immune systems respond to 'natural' levels of exposure to diverse infections. A major recent advance in immunology has been the recognition of the central role of phylogenetically conserved toll-like receptors in triggering innate immunity and the subsequent recruitment of adaptive response programmes. We studied the cross-sectional associations between individual levels of systemic toll-like receptor-mediated tumour necrosis factor alpha responsiveness and macro- and microparasite infections in a natural wood mouse (Apodemus sylvaticus) population. Results Amongst a diverse group of macroparasites, only levels of the nematode Heligmosomoides polygyrus and the louse Polyplax serrata were correlated (negatively) with innate immune responsiveness (measured by splenocyte tumour necrosis factor alpha responses to a panel of toll-like receptor agonists). Polyplax serrata infection explained a strikingly high proportion of the total variation in innate responses. Contrastingly, faecal oocyst count in microparasitic Eimeria spp. was positively associated with innate immune responsiveness, most significantly for the endosomal receptors TLR7 and TLR9. Conclusion Analogy with relevant laboratory models suggests the underlying causality for the observed patterns may be parasite-driven immunomodulatory effects on the host. A subset of immunomodulatory parasite species could thus have a key role in structuring other infections in natural vertebrate populations by affecting the 'upstream' innate mediators, like toll-like receptors, that are important in initiating immunity. Furthermore, the magnitude of the present result suggests that populations free from immunosuppressive parasites may exist at 'unnaturally' elevated levels of innate immune activation, perhaps leading to an increased risk of immunopathology. PMID:19386086

  14. Lysosomal serine protease CLN2 regulates tumor necrosis factor-alpha-mediated apoptosis in a Bid-dependent manner.

    PubMed

    Autefage, Hélène; Albinet, Virginie; Garcia, Virginie; Berges, Hortense; Nicolau, Marie-Laure; Therville, Nicole; Altié, Marie-Françoise; Caillaud, Catherine; Levade, Thierry; Andrieu-Abadie, Nathalie

    2009-04-24

    Apoptosis is a highly organized, energy-dependent program by which multicellular organisms eliminate damaged, superfluous, and potentially harmful cells. Although caspases are the most prominent group of proteases involved in the apoptotic process, the role of lysosomes has only recently been unmasked. This study investigated the role of the lysosomal serine protease CLN2 in apoptosis. We report that cells isolated from patients affected with late infantile neuronal ceroid lipofuscinosis (LINCL) having a deficient activity of CLN2 are resistant to the toxic effect of death ligands such as tumor necrosis factor (TNF), CD95 ligand, or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not to receptor-independent stress agents. CLN2-deficient cells exhibited a defect in TNF-induced Bid cleavage, release of cytochrome c, and caspase-9 and -3 activation. Moreover, extracts from CLN2-overexpressing cells or a CLN2 recombinant protein were able to catalyze the in vitro cleavage of Bid. Noteworthy, correction of the lysosomal enzyme defect of LINCL fibroblasts using a medium enriched in CLN2 protein enabled restoration of TNF-induced Bid and caspase-3 processing and toxicity. Conversely, transfection of CLN2-corrected cells with small interfering RNA targeting Bid abrogated TNF-induced cell death. Altogether, our study demonstrates that genetic deletion of the lysosomal serine protease CLN2 and the subsequent loss of its catalytic function confer resistance to TNF in non-neuronal somatic cells, indicating that CLN2 plays a yet unsuspected role in TNF-induced cell death. PMID:19246452

  15. Tumor necrosis factor α-induced protein-3 protects zinc transporter 8 against proinflammatory cytokine-induced downregulation

    PubMed Central

    Cheng, Liqing; Zhang, Dongmei; Chen, Bing

    2016-01-01

    Zinc transporter 8 (ZnT8) is exclusively expressed in the pancreatic islet and is essential for insulin crystallization, hexamerization and secretion. Tumor necrosis factor α-induced protein-3 (TNFAIP3) is a zinc finger protein that serves a major role in the negative feedback regulation of NF-κB signaling in response to multiple stimuli, and is a central regulator of immunopathology. Although the role of TNFAIP3 in diabetes has been extensively studied, its effect on ZnT8 has not been fully elucidated. The present study aimed to verify whether proinflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), are able to affect ZnT8 expression in islet cells. In addition, the study aimed to determine the effect of TNFAIP3 overexpression on cytokine-altered ZnT8 activity, considering its effect on NF-κB signaling. Cell-based studies using NIT-1 cells overexpressing TNFAIP3 were used to assess the effect of cytokines on ZnT8 and NF-κB activation, as well as the effect of TNFAIP3 on ZnT8 expression. Western blot analysis and immunofluorescence staining were employed to determine the protein expression and NF-κB activation, respectively. The results indicated that cytokine stimulation led to TNFAIP3 upregulation, ZnT8 downregulation and NF-κB activation. Furthermore, TNFAIP3 overexpression protected ZnT8 from cytokine-induced downregulation. In conclusion, the current results suggest that inflammation or TNFAIP3 dysfunction may be involved in the pathogenesis of diabetes via ZnT8 expression, besides from islet cell apoptosis. In addition, restricting inflammation and enhancing TNFAIP3 expression may exert a positive effect in diabetes prevention, treatment and pancreatic cell transplantation. PMID:27588072

  16. Effect of interleukin-1β and tumor necrosis factor α gene silencing on mouse gastric cancer cell proliferation and migration

    PubMed Central

    SUN, ZHONGWEI; MENG, YAN; LIU, GUOQIN; JIANG, YONGSHENG; MENG, QINGHUA; HU, SANYUAN

    2016-01-01

    The aim of the present study was to investigate the effect of interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) gene co-silencing in mouse gastric cancer (GC) cells. Respectively, three pairs of liposome-encapsulated IL-1β and TNFα small interfering RNA (siRNA) were transfected into the mouse GC cell line MFC. The most effective siRNA, as identified by reverse transcription-polymerase chain reaction, was used for co-suppression of IL-1β and TNFα genes. The activities of cell proliferation, colony formation and migration were determined by the Cell Counting Kit 8 method, colony formation assay and Transwell assay, respectively. Protein array analysis was performed to identify the differentially expressed factors. The possible signaling pathways of the various factors targeting the genes were identified by pathway enrichment analysis using KOBAS 2.0. siRNA1 and siRNAc were the most effective interference sequences for IL-1β and TNFα, respectively. Following co-transfection of siRNA1 and siRNAc, the expression of IL-1β and TNFα was inhibited at the mRNA and protein levels, and the cell proliferation, colony forming and migration abilities were reduced (P<0.05). The expression of inflammatory factors, including chemokine ligand 5, cyclooxygenase-2, IL-6, transforming growth factor β, IL-17A, matrix metallopeptidase 9 and stromal cell-derived factor 1α were also inhibited (P<0.05). These factors are mainly involved in the rheumatoid arthritis pathway, the intestinal immune network for IgA production, the TNF signaling pathway and the inflammatory bowel disease pathway. IL-1β and TNFα gene silencing inhibits the proliferation and migration of MFC. The mechanisms may involve multiple inflammatory factors that participate in the signaling pathways of tumor tissue inflammation, the immune network and TNF. PMID:27073517

  17. Drug modulation of antigen-induced paw oedema in guinea-pigs: effects of lipopolysaccharide, tumour necrosis factor and leucocyte depletion.

    PubMed

    da Motta, J I; Cunha, F Q; Vargaftig, B B; Ferreira, S H

    1994-05-01

    1. In guinea-pigs previously sensitized with ovalbumin, the intra-plantar administration of the antigen induced dose-dependent and sustained oedema. An intense infiltrate of neutrophils and eosinophils was observed at the peak of the oedema (4 h). 2. Oedema induced by ovalbumin at the doses of 50 or 200 micrograms/paw was not inhibited by antihistamines (meclizine and cetirizine), a PAF antagonist (BN 50730), a cyclo-oxygenase inhibitor (indomethacin), a lipoxygenase inhibitor (MK-886), a dual type lipo- and cyclo-oxygenase inhibitor (NDGA), a bradykinin antagonist (Hoe 140) or the combination of cetirizine, MK-886, indomethacin and BN 50730. These drugs did inhibit paw oedema induced by their specific agonists or by carrageenin. These results suggest that histamine, PAF, prostaglandins, leukotrienes or bradykinin are not important in the development of immune paw oedema in guinea-pigs. 3. Dexamethasone (10 mg kg-1) inhibited oedema induced by ovalbumin (50 or 200 micrograms/paw, P < 0.05). This effect apparently does not result from inhibition of arachidonate metabolism, since indomethacin, MK-886 and NDGA were without effect. 4. Oedema induced by ovalbumin (50 or 200 micrograms/paw) was also inhibited by azelastine. This effect was not due to the anti-histaminic property of azelastine since two other potent-antihistamines, meclizine and cetirizine, were ineffective. 5. Intravenous injection of lipopolysaccharide (LPS) dose-dependently inhibited the oedema induced by ovalbumin (200 micrograms/paw). This effect could not be attributed to hypotension or leucopenia since the maximal dose applied (81 micrograms kg-1) did not induce significant changes in the blood pressure or in the white blood cell levels of the animals. It is suggested that the effect of LPS is mediated by the endogenous release of cytokines, including tumour necrosis factor (TNF alpha). Murine TNF alpha dose dependently(9-81 microg kg-1) inhibited the paw oedema induced by ovalbumin.7. The anti

  18. Identification of inflammatory factor TNFα inhibitor from medicinal herbs.

    PubMed

    Ye, Hong; Wang, Yali; Bennett Jenson, A; Yan, Jun

    2016-04-01

    The inflammatory response is one of the first defenses our body has to fight against potential endangerments. It plays a critical role in host defense, clearing and slowing the infection in the case of microbial invasion. During an inflammatory response, a variety of cytokines are produced by cells and trigger or enhance the specific inflammation response. TNFα, one of these factors, plays a crucial role in many immune and inflammatory processes, such as proliferation, apoptosis, necrosis, and cell survival. It acts in orchestrating the cytokine cascade and the major regulator of inflammatory cytokine production. Abnormality of TNFα signaling leads to many diseases, including rheumatoid arthritis, psoriasis, Crohn's disease, atherosclerosis, and cancer. Due to the importance of TNFα, regulating TNFα activity is a key to treat the related diseases. There is a long history of using medicinal herbs to treat diseases related to inflammation. We searched for an ingredient that has the ability to inhibit TNFα, we examined AO herbal extract, containing 10 individual herbs and most of these herbs have anti-inflammatory activity within humans. We have tested the anti-inflammatory ability of AO herbal extract on mice. Furthermore, we used macrophage cell from young mice and found that AO extract has the ability to reduce the inflammation by inhibiting TNFα level. PMID:26778692

  19. Cyanidin-3-O-glucoside Induces Apoptosis and Inhibits Migration of Tumor Necrosis Factor-α-Treated Rat Aortic Smooth Muscle Cells.

    PubMed

    Yan, Xuerui; Wu, Lin; Li, Bin; Meng, Xianjun; Dai, Hanping; Zheng, Yanan; Fu, Junfan

    2016-07-01

    Blueberries are rich in anthocyanins (ACNs), which have recently been noted to protect against atherosclerosis development in mice. Cyanidin-3-O-glucoside (C3G), a member of blueberry ACN family, can inhibit the tumor necrosis factor-α (TNF-α)-induced proliferation of vascular smooth muscle cells (VSMCs). However, the effects of C3G on VSMC apoptosis and migration remain unclear. This study was thus conducted to examine whether and how C3G affected the apoptosis and migration of rat aortic smooth muscle cells (RASMCs) challenged by TNF-α. Primary cultured RASMCs were pretreated with C3G (25, 50 or 100 μM) for 2 h and then stimulated with TNF-α (10 ng/ml) for additional 24 h. Our results illustrated that C3G pretreatment induced significant apoptosis in TNF-α-stimulated RASMCs in a dose-dependent way, which was accompanied with increased cleaved caspase-3, caspase-9 and Bax and decreased Bcl-2. Moreover, RASMC migration was enhanced by TNF-α, but markedly suppressed by C3G pretreatment. The expressions and activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 were inhibited by C3G. In addition, TNF-α-enhanced nuclear translocation of nuclear factor kappa B (NF-κB) subunit p65 and phosphorylation of NF-κB inhibitor α (IκBα) in RASMCs were attenuated by C3G. In summary, our study reveals that C3G can induce significant apoptosis in TNF-α-treated RASMCs and markedly inhibit their migration. PMID:26138096

  20. Trichostatin A modulates thiazolidinedione-mediated suppression of tumor necrosis factor α-induced lipolysis in 3T3-L1 adipocytes.

    PubMed

    Lu, Juu-Chin; Chang, Yu-Tzu; Wang, Chih-Tien; Lin, Yu-Chun; Lin, Chun-Ken; Wu, Zhong-Sheng

    2013-01-01

    In obesity, high levels of tumor necrosis factor α (TNFα) stimulate lipolysis in adipocytes, leading to hyperlipidemia and insulin resistance. Thiazolidinediones (TZDs), the insulin-sensitizing drugs, antagonize TNFα-induced lipolysis in adipocytes, thereby increasing insulin sensitivity in diabetes patients. The cellular target of TZDs is peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that controls many adipocyte functions. As a transcription factor, PPARγ is closely modulated by coregulators, which include coactivators and corepressors. Previous studies have revealed that in macrophages, the insulin-sensitizing effect of PPARγ may involve suppression of proinflammatory gene expression by recruiting the corepressor complex that contains corepressors and histone deacetylases (HDACs). Therefore, we investigated whether the corepressor complex is involved in TZD-mediated suppression of TNFα-induced lipolysis in 3T3-L1 adipocytes. Trichostatin A (TSA), a pan HDAC inhibitor (HDACI) that inhibits class I and II HDACs, was used to examine the involvement of HDACs in the actions of TZDs. TSA alone increased basal lipolysis and attenuated TZD-mediated suppression of TNFα-induced lipolysis. Increased basal lipolysis may in part result from class I HDAC inhibition because selective class I HDACI treatment had similar results. However, attenuation of TZD-mediated TNFα antagonism may be specific to TSA and related hydroxamate-based HDACI rather than to HDAC inhibition. Consistently, corepressor depletion did not affect TZD-mediated suppression. Interestingly, TSA treatment greatly reduced PPARγ levels in differentiated adipocytes. Finally, extracellular signal-related kinase 1/2 (ERK1/2) mediated TNFα-induced lipolysis, and TZDs suppressed TNFα-induced ERK phosphorylation. We determined that TSA increased basal ERK phosphorylation, and attenuated TZD-mediated suppression of TNFα-induced ERK phosphorylation, consistent with TSA's effects

  1. Benzo[a]pyrene and tumor necrosis factor-α coordinately increase genotoxic damage and the production of proinflammatory mediators in alveolar epithelial type II cells.

    PubMed

    Umannová, Lenka; Machala, Miroslav; Topinka, Jan; Schmuczerová, Jana; Krčmář, Pavel; Neča, Jiří; Šujanová, Klára; Kozubík, Alois; Vondráček, Jan

    2011-10-10

    Alveolar type II epithelial (AEII) cells regulate lung inflammatory response and, simultaneously, they are a target of environmental carcinogenic factors. We employed an in vitro model of rat AEII cells, the RLE-6TN cell line, in order to analyze the interactive effects of tumor necrosis factor-α (TNF-α), a cytokine which plays a key role in the initiation of inflammatory responses in the lung, and benzo[a]pyrene (BaP), a highly carcinogenic polycyclic aromatic hydrocarbon. TNF-α strongly augmented the formation of stable BaP diol epoxide-DNA adducts in AEII cells, which was associated with enhanced p53-Ser15 phosphorylation and decreased cell survival. The increased genotoxicity of BaP was associated with altered expression of cytochrome P450 (CYP) enzymes involved in its bioactivation, a simultaneous suppression of CYP1A1 and enhancement of CYP1B1 expression. Importantly, BaP and TNF-α acted synergistically to upregulate key inflammatory regulators in AEII cells, including the expression of inducible NO synthase and cyclooxygenase-2 (COX-2), and enhanced prostaglandin E2 production and expression of proinflammatory cytokines, such as TNF-α, interleukin-1β and interleukin-6. We observed that BaP and TNF-α together strongly activated p38 kinase, a principal regulator of inflammatory response. SB202190, a specific p38 inhibitor, prevented induction of both COX-2 and proinflammatory cytokines, thus confirming that p38 activity was crucial for the observed inflammatory reaction. Taken together, our data demonstrated, for the first time, that a proinflammatory cytokine and an environmental PAH may interact to potentiate both DNA damage and the inflammatory response in AEII cells, which may occur through coordinated upregulation of p38 activity. PMID:21745554

  2. Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells.

    PubMed

    Morioka, Norimitsu; Tomori, Mizuki; Zhang, Fang Fang; Saeki, Munenori; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

    2016-01-01

    Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. PMID:26616049

  3. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis.

    PubMed Central

    Tramontana, J. M.; Utaipat, U.; Molloy, A.; Akarasewi, P.; Burroughs, M.; Makonkawkeyoon, S.; Johnson, B.; Klausner, J. D.; Rom, W.; Kaplan, G.

    1995-01-01

    BACKGROUND: The monocyte-derived cytokine, tumor necrosis factor alpha (TNF alpha), is essential for host immunity, but overproduction of this cytokine may have serious pathologic consequences. Excess TNF alpha produced in pulmonary tuberculosis may cause fevers, weakness, night sweats, necrosis, and progressive weight loss. Thalidomide (alpha-N-phthalimidoglutarimide) has recently been shown to suppress TNF alpha production by human monocytes in vitro and to reduce serum TNF alpha in leprosy patients. We have therefore conducted a two-part placebo-controlled pilot study of thalidomide in patients with active tuberculosis to determine its effects on clinical response, immune reactivity, TNF alpha levels, and weight. MATERIALS AND METHODS: 30 male patients with active tuberculosis, either human immunodeficiency virus type 1 positive (HIV-1+) or HIV-1-, received thalidomide or placebo for single or multiple 14 day cycles. Toxicity of the study drug, delayed type hypersensitivity (DTH), cytokine production, and weight gain were evaluated. RESULTS: Thalidomide treatment was well tolerated, without serious adverse events. The drug did not adversely affect the DTH response to purified protein derivative (PPD), total leukocyte, or differential cell counts. TNF alpha production was significantly reduced during thalidomide treatment while interferon-gamma (IFN gamma) production was enhanced. Daily administration of thalidomide resulted in a significant enhancement of weight gain. CONCLUSIONS: The results indicate that thalidomide is well tolerated by patients receiving anti-tuberculosis therapy. Thalidomide treatment reduces TNF alpha production both in vivo and in vitro and is associated with an accelerated weight gain during the study period. PMID:8521296

  4. Generation and Characterization of Small Single Domain Antibodies Inhibiting Human Tumor Necrosis Factor Receptor 1*

    PubMed Central

    Steeland, Sophie; Puimège, Leen; Vandenbroucke, Roosmarijn E.; Van Hauwermeiren, Filip; Haustraete, Jurgen; Devoogdt, Nick; Hulpiau, Paco; Leroux-Roels, Geert; Laukens, Debby; Meuleman, Philip; De Vos, Martine; Libert, Claude

    2015-01-01

    The cytokine TNF is a well known drug target for several inflammatory diseases such as Crohn disease. Despite the great success of TNF blockers, therapy could be improved because of high costs and side effects. Selective inhibition of TNF receptor (TNFR) 1 signaling holds the potential to greatly reduce the pro-inflammatory activity of TNF, thereby preserving the advantageous immunomodulatory signals mediated by TNFR2. We generated a selective human TNFR1 inhibitor based on Nanobody (Nb) technology. Two anti-human TNFR1 Nbs were linked with an anti-albumin Nb to generate Nb Alb-70-96 named “TNF Receptor-One Silencer” (TROS). TROS selectively binds and inhibits TNF/TNFR1 and lymphotoxin-α/TNFR1 signaling with good affinity and IC50 values, both of which are in the nanomolar range. Surface plasmon resonance analysis reveals that TROS competes with TNF for binding to human TNFR1. In HEK293T cells, TROS strongly reduces TNF-induced gene expression, like IL8 and TNF, in a dose-dependent manner; and in ex vivo cultured colon biopsies of CD patients, TROS inhibits inflammation. Finally, in liver chimeric humanized mice, TROS antagonizes inflammation in a model of acute TNF-induced liver inflammation, reflected in reduced human IL8 expression in liver and reduced IL6 levels in serum. These results demonstrate the considerable potential of TROS and justify the evaluation of TROS in relevant disease animal models of both acute and chronic inflammation and eventually in patients. PMID:25538244

  5. Characterization of specific high affinity receptors for human tumor necrosis factor on mouse fibroblasts

    SciTech Connect

    Hass, P.E.; Hotchkiss, A.; Mohler, M.; Aggarwal, B.B.

    1985-10-05

    Mouse L-929 fibroblasts, an established line of cells, are very sensitive to lysis by human lymphotoxin (hTNF-beta). Specific binding of a highly purified preparation of hTNF-beta to these cells was examined. Recombinant DNA-derived hTNF-beta was radiolabeled with (TH)propionyl succinimidate at the lysine residues of the molecule to a specific activity of 200 microCi/nmol of protein. (TH)hTNF-beta was purified by high performance gel permeation chromatography and the major fraction was found to be monomeric by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The labeled hTNF-beta was fully active in causing lysis of L-929 fibroblasts and bound specifically to high affinity binding sites on these cells. Scatchard analysis of the binding data revealed the presence of a single class of high affinity receptors with an apparent Kd of 6.7 X 10(-11) M and a capacity of 3200 binding sites/cell. Unlabeled recombinant DNA-derived hTNF-beta was found to be approximately 5-fold more effective competitive inhibitor of binding than the natural hTNF-beta. The binding of hTNF-beta to these mouse fibroblasts was also correlated with the ultimate cell lysis. Neutralizing polyclonal antibodies to hTNF-beta efficiently inhibited the binding of (TH)hTNF-beta to the cells. The authors conclude that the specific high affinity binding site is the receptor for hTNF-beta and may be involved in lysis of cells.

  6. RAC1 regulate tumor necrosis factor-α-mediated impaired osteogenic differentiation of dental pulp stem cells.

    PubMed

    Feng, Guijuan; Shen, Qijie; Lian, Min; Gu, Zhifeng; Xing, Jing; Lu, Xiaohui; Huang, Dan; Li, Liren; Huang, Shen; Wang, Yi; Zhang, Jinlong; Shi, Jiahai; Zhang, Dongmei; Feng, Xingmei

    2015-09-01

    Human dental pulp contains a rapidly proliferative subpopulation of precursor cells termed dental pulp stem cells (DPSCs) that show self-renewal and multilineage differentiation, including neurogenic, chondrogenic, osteogenic and adipogenic. We previously reported that tomuor necrosis factor-α (TNF-α) (10 ng/mL) triggered osteogenic differentiation of human DPSCs via the nuclear factor-κB (NF-κB) signaling pathway. While previous studies showed that cells treated with TNF-α at higher concentrations showed decreased osteogenic differentiation capability. In this study we analyze the function of TNF-α (100 ng/mL) on osteogenic differentiation of human DPSCs for the first time and identify the underlying molecule mechanisms. Our data revealed that TNF-α with higher concentration significantly reduced mineralization and the expression of bone morphogenetic protein 2 (BMP2), alkaline phosphatase (ALP) and runt-related transcription factor 2 (RUNX2). Further, we revealed that TNF-α could suppress the osteogenic differentiation of DPSCs via increasing the expression of RAC1, which could activate the Wnt/β-catenin signaling pathway and liberate β-catenin to translocate into the nucleus. Genetic silencing of RAC1 expression using siRNA restored osteogenic differentiation of DPSCs. Our findings may provide a potential approach to bone regeneration in inflammatory microenvironments. PMID:26219349

  7. Propanil inhibits tumor necrosis factor-alpha production by reducing nuclear levels of the transcription factor nuclear factor-kappab in the macrophage cell line ic-21.

    PubMed

    Frost, L L; Neeley, Y X; Schafer, R; Gibson, L F; Barnett, J B

    2001-05-01

    Tumor necrosis factor-alpha (TNF-alpha) is an essential proinflammatory cytokine whose production is normally stimulated by bacterial cell wall components, such as lipopolysaccharide (LPS), during an infection. Macrophages stimulated with LPS in vitro produce several cytokines, including TNF-alpha. LPS-stimulated primary mouse macrophages produced less TNF-alpha protein and message after treatment with the herbicide propanil (Xie et al., Toxicol. Appl. Pharmacol. 145, 184-191, 1997). Nuclear factor-kappaB (NF-kappaB) tightly regulates TNF-alpha transcription. Therefore, as a step toward understanding the mechanism of the effect of propanil on TNF-alpha transcription, IC-21 cells were transfected with a TNF-alpha promoter-luciferase construct, and the effect of propanil on luciferase activity was measured. Cells transfected with promoter constructs containing a kappaB site showed decreased luciferase activity relative to controls after propanil treatment. These observations implicated NF-kappaB binding as an intracellular target of propanil. Further studies demonstrated a marked reduction in the nuclear levels of the stimulatory p65 subunit of NF-kappaB after propanil treatment, as measured by fluorescence confocal microscopy and Western blot analysis. The p50 subunit of NF-kappaB was not found to be reduced after propanil exposure by Western blot. Electrophoretic mobility gel shift assays showed decreased DNA binding of both p65/p50 heterodimers and p50/p50 homodimers to the kappaB3 site of the TNF-alpha promoter of propanil-treated cells. The marked reduction in nuclear p65/p50 NF-kappaB levels and diminished binding to the TNF-alpha promoter in propanil-treated cells are consistent with reduced TNF-alpha levels induced by LPS. PMID:11312646

  8. Regulation of platelet-activating factor receptor gene expression in vivo by endotoxin, platelet-activating factor and endogenous tumour necrosis factor.

    PubMed Central

    Wang, H; Tan, X; Chang, H; Gonzalez-Crussi, F; Remick, D G; Hsueh, W

    1997-01-01

    A competitive PCR assay was developed to quantify platelet-activating factor (PAF) receptor (PAF-R) transcripts in rat tissues using a synthetic RNA as a competitor. We found PAF-R mRNA constitutively expressed in the eight organs tested, with the ileum containing the highest concentration [(3.49+/-0.15) x 10(7) molecules/microg of RNA]. Significant but lower levels were also detected in the jejunum, spleen, lungs, kidneys, heart, stomach and liver. Furthermore we defined the regulatory role of inflammatory mediators in ileal PAF-R gene expression using a rat model of intestinal injury induced by PAF or lipopolysaccharide (LPS). Injection of LPS or low-dose PAF resulted in a marked increase in ileal PAF-R mRNA within 30 min. The up-regulation on PAF-R elicited by PAF was biphasic, peaking first at 90 min, then again at 6 h. In contrast, LPS elicited a weak monophasic response. The second phase of PAF-R mRNA increase after PAF administration was completely abolished by WEB 2170, a PAF antagonist, and partially inhibited by antitumour necrosis factor (TNF) antibody. These observations indicate the involvement of endogenous PAF and TNF in this event. In conclusion, we found: (a) preferential PAF-R expression in the ileum, suggesting a role for PAF in intestinal inflammation; (b) induction of PAF-R expression in vivo by its own agonist; (c) a complex regulation of PAR-R gene expression in vivo involving a network of various pro-inflammatory mediators. PMID:9065783

  9. Apixaban, an oral direct Factor Xa inhibitor: awaiting the verdict.

    PubMed

    Carreiro, Jennifer; Ansell, Jack

    2008-12-01

    For the last half-century, despite its many limitations warfarin has been the mainstay of treatment for patients with venous and arterial thromboembolic disease. During the past decade, a number of new oral anticoagulant agents have been developed that may offer an alternative to warfarin. Emerging data suggest that Factor Xa may be a target for inhibition. Apixaban is one such agent. It is a potent, selective, reversible, and orally bioavailable FXa inhibitor that demonstrates antithrombotic efficacy, with a favorable pharmacokinetic profile. At present, the safety and efficacy of apixaban for the prophylaxis and treatment of venous thromboembolism is being evaluated in Phase II and Phase III trials involving nearly 25,000 patients. Trials are also underway involving over 20,000 patients for secondary prevention after acute coronary syndromes and the prevention of stroke in patients with non-valvular atrial fibrillation. This review article discusses the discovery, pharmacokinetics, attributes, and current clinical trials of this emerging drug. PMID:19012508

  10. Distinct mechanisms for induction and tolerance regulate the immediate early genes encoding interleukin 1β and tumor necrosis factor α.

    PubMed

    Adamik, Juraj; Wang, Kent Z Q; Unlu, Sebnem; Su, An-Jey A; Tannahill, Gillian M; Galson, Deborah L; O'Neill, Luke A; Auron, Philip E

    2013-01-01

    Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. PMID:23936458

  11. A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease.

    PubMed

    Haw, T J; Starkey, M R; Nair, P M; Pavlidis, S; Liu, G; Nguyen, D H; Hsu, A C; Hanish, I; Kim, R Y; Collison, A M; Inman, M D; Wark, P A; Foster, P S; Knight, D A; Mattes, J; Yagita, H; Adcock, I M; Horvat, J C; Hansbro, P M

    2016-07-01

    Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy. PMID:26555706

  12. Cloning of Human Tumor Necrosis Factor (TNF) Receptor cDNA and Expression of Recombinant Soluble TNF-Binding Protein

    NASA Astrophysics Data System (ADS)

    Gray, Patrick W.; Barrett, Kathy; Chantry, David; Turner, Martin; Feldmann, Marc

    1990-10-01

    The cDNA for one of the receptors for human tumor necrosis factor (TNF) has been isolated. This cDNA encodes a protein of 455 amino acids that is divided into an extracellular domain of 171 residues and a cytoplasmic domain of 221 residues. The extracellular domain has been engineered for expression in mammalian cells, and this recombinant derivative binds TNFα with high affinity and inhibits its cytotoxic activity in vitro. The TNF receptor exhibits similarity with a family of cell surface proteins that includes the nerve growth factor receptor, the human B-cell surface antigen CD40, and the rat T-cell surface antigen OX40. The TNF receptor contains four cysteine-rich subdomains in the extra-cellular portion. Mammalian cells transfected with the entire TNF receptor cDNA bind radiolabeled TNFα with an affinity of 2.5 x 10-9 M. This binding can be competitively inhibited with unlabeled TNFα or lymphotoxin (TNFβ).

  13. Significance of Tumor necrosis factor α-308 (G/A) gene polymorphism in the development of prostate cancer.

    PubMed

    Berhane, Nega; Sobti, Rabinder Chandera; Melesse, Shiferaw; Mahdi, Salih Abdul; Kassu, Afework

    2012-12-01

    Prostate cancer (PCa) is the most common noncutaneous cancer among men, accounting for 10 % of male cancer-related deaths worldwide. The etiology of PCa is largely unknown, although multiple environmental and lifestyle factors such as ultraviolet irradiation, smoking, and diet might increase the risk of the disease. Risk of disease varies most prominently with age, ethnicity, family history, and diet. The multifunctional cytokine tumor necrosis factor alpha (TNF-α) has an important role in the pathogenesis of inflammatory, autoimmune and malignant diseases. In this case control study 150 Prostate cancer patients and 150 age matched benign prostate hyperplasia (BPH) and equal number of healthy control groups were involved. The aim of this study was to analyze the effect of TNF-α-308 (G/A) polymorphism on risk of prostate cancer on north Indian prostate cancer patients. The polymerase chain reaction (PCR) technique was utilized to genotype TNF-α-308 (G/A) polymorphism. The present study showed statistically significant increased risk of prostate cancer among individuals that carried the A allele of TNF-α-308 gene (OR = 1.81, 95 % CI 1.00-3.481, p = 0.03). PMID:23065208

  14. Elevated CO2 selectively inhibits interleukin-6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage.

    PubMed

    Wang, Naizhen; Gates, Khalilah L; Trejo, Humberto; Favoreto, Silvio; Schleimer, Robert P; Sznajder, Jacob I; Beitel, Greg J; Sporn, Peter H S

    2010-07-01

    Elevated blood and tissue CO(2), or hypercapnia, is common in severe lung disease. Patients with hypercapnia often develop lung infections and have an increased risk of death following pneumonia. To explore whether hypercapnia interferes with host defense, we studied the effects of elevated P(CO2) on macrophage innate immune responses. In differentiated human THP-1 macrophages and human and mouse alveolar macrophages stimulated with lipopolysaccharide (LPS) and other Toll-like receptor ligands, hypercapnia inhibited expression of tumor necrosis factor and interleukin (IL)-6, nuclear factor (NF)-kappaB-dependent cytokines critical for antimicrobial host defense. Inhibition of IL-6 expression by hypercapnia was concentration dependent, rapid, reversible, and independent of extracellular and intracellular acidosis. In contrast, hypercapnia did not down-regulate IL-10 or interferon-beta, which do not require NF-kappaB. Notably, hypercapnia did not affect LPS-induced degradation of IkappaB alpha, nuclear translocation of RelA/p65, or activation of mitogen-activated protein kinases, but it did block IL-6 promoter-driven luciferase activity in mouse RAW 264.7 macrophages. Elevated P(CO2) also decreased phagocytosis of opsonized polystyrene beads and heat-killed bacteria in THP-1 and human alveolar macrophages. By interfering with essential innate immune functions in the macrophage, hypercapnia may cause a previously unrecognized defect in resistance to pulmonary infection in patients with advanced lung disease. PMID:20181940

  15. Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

    PubMed Central

    Orihara, Kanami; Matsuda, Akio

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) and bronchial asthma are common respiratory diseases that are caused by chronic inflammation of the airways. Although these diseases are mediated by substantially distinct immunological reactions, especially in mild cases, they both show increased numbers of neutrophils, increased production of tumor necrosis factor-alpha (TNF-α) and poor responses to corticosteroids, particularly in patients with severe diseases. These immunological alterations may contribute strongly to airway structural changes, commonly referred to as airway remodeling. Microvascular alterations, a component of airway remodeling and caused by chronic inflammation, are observed and appear to be clinically involved in both diseases. It has been well established that vascular endothelial growth factor (VEGF) plays important roles in the airway microvascular alterations in mild and moderate cases of both diseases, but any role that VEGF might play in severe cases of these diseases remains unclear. Here, we review recent research findings, including our own data, and discuss the possibility that TNF-α and its associated CXC chemokines play roles in microvascular alterations that are even more crucial than those of VEGF in patients with severe COPD or asthma. PMID:19281078

  16. Legionella pneumophila EnhC is required for efficient replication in tumor necrosis factor α-stimulated macrophages

    PubMed Central

    Liu, Mingyu; Conover, Gloria M.; Isberg, Ralph R.

    2008-01-01

    Legionella pneumophila enhC− mutants were originally identified as being defective for uptake into host cells. In this work, we found that the absence of EnhC resulted in defective intracellular growth when dissemination of intracellular bacteria to neighboring cells was expected to occur. No such defect was observed during growth within the amoeba Dictyostelium discoideum Culture supernatants containing the secreted products of infected macrophages added to host cells restricted the growth of the ΔenhC strain, while tumor necrosis factor α (TNF-α), at concentrations similar to those found in macrophage culture supernatants, could reproduce the growth restriction exerted by culture supernatants on L. pneumophila ΔenhC. The absence of EnhC also caused defective trafficking of the Legionella-containing vacuole in TNF-α treated macrophages. EnhC was shown to be an envelope-associated protein largely localized to the periplasm, with its expression induced in post-exponential phase, as is true for many virulence-associated proteins. Furthermore, the absence of EnhC appeared to affect survival under stress conditions, as the ΔenhC mutant was more susceptible to H2O2 treatment than the wild type strain. EnhC, therefore, is a unique virulence factor that is required for growth specifically when macrophages have heightened potential to restrict microbial replication. PMID:18549456

  17. Tumor necrosis factor alpha -308 gene locus promoter polymorphism: an analysis of association with health and disease.

    PubMed

    Elahi, Maqsood M; Asotra, Kamlesh; Matata, Bashir M; Mastana, Sarabjit S

    2009-03-01

    Tumor necrosis factor-alpha (TNF-alpha) is a potent immunomediator and proinflammatory cytokine that has been implicated in the pathogenesis of a large number of human diseases. The location of its gene within major histocompatibility complex and biological activities has raised the possibility that polymorphisms within this locus may contribute to the pathogenesis of wide range of autoimmune and infectious diseases. For example, a bi-allelic single nucleotide substitution of G (TNFA1 allele) with A (TNFA2 allele) polymorphism at -308 nucleotides upstream from the transcription initiation site in the TNF-alpha promoter is associated with elevated TNF-alpha levels and disease susceptibilities. However, it is still unclear whether TNF-alpha -308 polymorphism plays a part in the disease process, in particular whether it could affect transcription factor binding and in turn influence TNF-alpha transcription and synthesis. Several studies have suggested that TNFA2 allele is significantly linked with the high TNF-alpha-producing autoimmune MHC haplotype HLA-A1, B8, DR3, with elevated serum TNF-alpha levels and a more severe outcome in diseases. This review discusses the genetics of the TNF-alpha -308 polymorphism in selected major diseases and evaluates its common role in health and disease. PMID:19708125

  18. In vitro production of tumour necrosis factor and prostaglandin E2 by peripheral blood mononuclear cells from tuberculosis patients.

    PubMed Central

    Cadranel, J; Philippe, C; Perez, J; Milleron, B; Akoun, G; Ardaillou, R; Baud, L

    1990-01-01

    We investigated the production of tumour necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2) by peripheral blood mononuclear cells (PBMC) from tuberculosis patients and healthy controls. PBMC from tuberculosis patients generated constitutively more TNF-alpha than did control PBMC. This production was significantly higher for patients with high-grade fever and cachexia. The increase of TNF-alpha production by PBMC from tuberculosis patients was associated with a comparatively weaker elevation of PGE2 synthesis which did not parallel fever or weight loss. In vitro treatment of control PBMC with the tuberculin purified protein derivative (PPD) promoted an increased TNF-alpha production which was similar to that of untreated PBMC from tuberculosis patients. Thus, the increased TNF-alpha production in tuberculosis could be explained by the in vivo exposure of PBMC to mycobacterial antigens. In contrast, the concentration of PGE2 was weaker in the medium of untreated PBMC from tuberculosis patients than in the medium of PPD-treated control PBMC, suggesting that PGE2 synthesis by PBMC was limited in tuberculosis by unidentified factors. PMID:2387094

  19. Interleukin-8 down-regulates the oxidative burst induced by tumor necrosis factor alpha in neutrophils adherent to fibronectin.

    PubMed

    Ottonello, L; Lindley, I J; Pastorino, G; Dapino, P; Dallegri, F

    1994-01-01

    Human neutrophils (5 x 10(4) incubated on fibronectin precoated wells released 2.83 +/- .25 nmoles of superoxide (0(2)-) (x +/- 1 SEM, n = 15) in response to 5.9 nM (100 ng/ml) Tumor Necrosis Factor Alpha (TNF). On the contrary, the 0(2)- production induced by interleukin-8 (IL-8) (doses ranging from 0.1 nM to 1 microM) was comparable to that of "resting" cells (< .6 nmoles/5 x 10(4) cells). IL-8 (100 nM) did not affect the TNF-dependent 0(2)- production when added with TNF at the beginning of the assay, but reduced it by approximately 80% when added with TNF on neutrophils previously incubated for 1 hour on fibronectin. As compared with IL-8, N-formyl-methionyl-leucyl-phenylalanine (FMLP, 100 nM) failed to suppress the TNF-triggering o