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Sample records for necrosis factor inhibitors

  1. Tumor necrosis factor (TNF) inhibitor therapy for rheumatoid arthritis.

    PubMed

    Segal, Barbara; Rhodus, Nelson L; Patel, Ketan

    2008-12-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by inflammation involving large and small joints. Systemic manifestations as well as involvement of paraoral tissues contribute to morbidity. Tumor necrosis factor (TNF) plays a central role in RA by amplifying inflammation in multiple pathways that lead to joint destruction. Tumor necrosis factor inhibitors were first licensed for clinical use in 1998; 3 have been approved for the treatment of RA: Iinfliximab, etanercept, and adalimumab. The purpose of this paper is to review the pathogenesis of RA, the state of the art of therapy, and the most current information on the safety and efficacy of TNF inhibitors for treatment of RA.

  2. 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

  3. Therapeutic inhibitors of tumor necrosis factor in Crohn's disease.

    PubMed

    Ganesan, Srinivasan; Travis, Simon P L; Ahmad, Tariq; Jazrawi, Riadh

    2002-09-01

    Therapeutic options for patients with refractory ulcerative colitis or Crohn's disease have recently been augmented by the introduction of biological therapies. The pro-inflammatory cytokine, tumor necrosis factor (TNF)-alpha is present in elevated concentrations in patients with inflammatory bowel disease and inhibitors of TNF alpha have proved effective as treatment. Strategies aimed at reducing TNF in patients with Crohn's disease, include the mouse/human chimeric monoclonal antibody, infliximab (Centocor Inc), the humanized monoclonal antibody, CDP-571 (Celltech Group plc), the human recombinant TNF receptor fusion protein, etanercept (Immunex Corp), and thalidomide. New approaches, including the use of soluble TNF receptors, appear promising. This article reviews the evidence of therapeutic inhibition of TNF.

  4. 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

  5. Vasculitis Associated With Tumor Necrosis FactorInhibitors

    PubMed Central

    Sokumbi, Olayemi; Wetter, David A.; Makol, Ashima; Warrington, Kenneth J.

    2012-01-01

    Objective To describe the clinical characteristics, histopathologic features, and outcomes of patients in whom vasculitis developed in association with use of tumor necrosis factor-α (TNF-α) inhibitors. Patients and Methods This is a retrospective review of patients evaluated at Mayo Clinic, Rochester, Minnesota, from January 1, 1998, through March 31, 2011, with a diagnosis of vasculitis induced by anti–TNF-α therapy. Results Of 8 patients with vasculitis associated with anti–TNF-α therapy (mean age, 48.5 years), 6 (75%) were female. Four (50%) had rheumatoid arthritis, 1 (13%) had Crohn disease, and 3 (38%) had ulcerative colitis. Five (63%) were treated with infliximab, 2 (25%) with etanercept, and 1 (13%) with adalimumab. The mean duration of treatment before development of vasculitis was 34.5 months. The skin was the predominant organ affected (5 patients [63%]), with the most common cutaneous lesion being palpable purpura (4 of 5 [80%]). Two organs involved in systemic vasculitis were the peripheral nervous system (4 patients [50%]) and kidney (1 patient [13%]). All cases of vasculitis were histopathologically confirmed. Seven of 8 patients improved with discontinuation of therapy (mean time to resolution, 6.9 months) and adjuvant treatment (all 8 received prednisone; another agent was also used in 7); rechallenge with anti–TNF-α therapy was not attempted in any patient. At last follow-up, no patients had experienced a recurrence of vasculitis after therapy discontinuation. Conclusion Cutaneous small-vessel vasculitis was the most common finding, but systemic vasculitis, including peripheral nerve and renal vasculitis, was also frequently observed. PMID:22795634

  6. What factors determine patients' preference for tumour necrosis factor inhibitors in ankylosing spondylitis?

    PubMed

    Fajri, Dessy W; Brand, Caroline A; Dharmage, Shyamali C; Martin, Belinda J; Buchanan, Russell R C; Schachna, Lionel

    2009-05-01

    Tumour necrosis factor inhibitor (TNFi) therapy, either intravenous (IV) or subcutaneous (SQ), demonstrates similar efficacy in ankylosing spondylitis (AS). The objective of this study was to examine factors influencing patient preference of TNFi. Fifty-nine (79.7%) participants were male with mean age 43.9 years and disease duration of 22.0 years. Fifty-nine patients (79.7%) agreed with the statement 'My doctor gave me a choice and I made a decision based on my personal preference'. Patients commenced first on IV TNFi most commonly cited reduced frequency of injections (96.6%), administration by a trained professional (89.7%) and use of infusion time for leisure activities (86.2%). Patients commenced on SQ TNFi cited flexibility with timing of treatment (80%), shortened administration time (73.3%) and the convenience of home therapy (73.3%). Shared clinical decision-making between clinicians and patients may be desirable for AS patients commencing TNFi therapy.

  7. Concomitant disseminated histoplasmosis and disseminated tuberculosis after tumor necrosis factor inhibitor treatment: a case report.

    PubMed

    Muñoz-Oca, Juan E; Villarreal Morales, Martha L; Nieves-Rodriguez, Aracelis; Martínez-Bonilla, Lemuel

    2017-01-13

    Tumor necrosis factor antagonist inhibitors have transformed the approach to patients with severe autoimmune conditions, such as rheumatoid arthritis. Although the therapy can be highly effective, TNF-α inhibitors are associated with an increased risk of opportunistic infections. Here, we report a case of concomitant disseminated histoplasmosis and tuberculosis in a 65-year-old female with rheumatoid arthritis treated with TNF-α inhibitor. Both conditions can be found in disseminated form in immunosuppressed hosts, but co-infection is rare with only a few cases having been reported, to our knowledge, all in HIV patients. This case posed a considerable challenge for diagnosis and treatment due to the unusual disseminated co-infection, the overlapping symptoms, and the interactions between medications.

  8. Harms of Tumor Necrosis Factor Inhibitors in Rheumatic diseases: A focused Systematic Review of the Literature

    PubMed Central

    Jain, Archana; Singh, Jasvinder A.

    2013-01-01

    We performed a focused review of risk of harms of anti-tumor necrosis factor (TNF) inhibitors in adult rheumatic diseases. Increased risk of serious infections, tuberculosis and other opportunistic infections has been reported across various studies, with etanercept appearing to have modestly better safety profile in terms of tuberculosis and opportunistic infections and infliximab with higher risk of serious infections. Evidence suggests no increase in risk of cancer with anti-TNF biologics, but there is an increased risk of non-melanoma skin cancer. Elderly patients appear to be at increased risk of incident or worsening heart failure with anti-TNF biologic use. PMID:23444956

  9. Effect of tumor necrosis factorinhibitors on ambulatory 24-h blood pressure.

    PubMed

    Grossman, Chagai; Bornstein, Gil; Leibowitz, Avshalom; Ben-Zvi, Ilan; Grossman, Ehud

    2017-02-01

    Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly being used in inflammatory rheumatic diseases (IRD). The risk of cardiovascular disease is elevated in patients with IRD and TNF-α inhibitors reduce this risk. We assessed whether the beneficial effect of TNF-α inhibitors on cardiovascular risk is mediated by blood pressure reduction. We measured blood pressure levels with 24-h ambulatory blood pressure measurements device in patients with IRD before and 3 months after treatment with TNF-α inhibitors. The study population consisted of 15 subjects (6 men; mean age 45.9 ± 14.1 years). Most patients had either rheumatoid arthritis or psoriatic arthritis and adalimumab was the most common TNF-α inhibitor used. Mean 24-h systolic and diastolic blood pressure levels remained the same after treatment (121 ± 12/66 ± 7 before and 123 ± 11/67 ± 10 mm Hg after; p = 0.88 and 0.66, respectively). The study demonstrates that TNF-α inhibitors have no effect on blood pressure levels.

  10. Structures of adamalysin II with peptidic inhibitors. Implications for the design of tumor necrosis factor alpha convertase inhibitors.

    PubMed Central

    Gomis-Rüth, F. X.; Meyer, E. F.; Kress, L. F.; Politi, V.

    1998-01-01

    Crotalus adamanteus snake venom adamalysin II is the structural prototype of the adamalysin or ADAM family comprising proteolytic domains of snake venom metalloproteinases, multimodular mammalian reproductive tract proteins, and tumor necrosis factor alpha convertase, TACE, involved in the release of the inflammatory cytokine, TNFalpha. The structure of adamalysin II in noncovalent complex with two small-molecule right-hand side peptidomimetic inhibitors (Pol 647 and Pol 656) has been solved using X-ray diffraction data up to 2.6 and 2.8 A resolution. The inhibitors bind to the S'-side of the proteinase, inserting between two protein segments, establishing a mixed parallel-antiparallel three-stranded beta-sheet and coordinate the central zinc ion in a bidentate manner via their two C-terminal oxygen atoms. The proteinase-inhibitor complexes are described in detail and are compared with other known structures. An adamalysin-based model of the active site of TACE reveals that these small molecules would probably fit into the active site cleft of this latter metalloproteinase, providing a starting model for the rational design of TACE inhibitors. PMID:9521103

  11. Tumor necrosis factor-alpha inhibitors suppress CCL2 chemokine in monocytes via epigenetic modification.

    PubMed

    Lin, Yi-Ching; Lin, Yu-Chih; Huang, Ming-Yii; Kuo, Po-Lin; Wu, Cheng-Chin; Lee, Min-Sheng; Hsieh, Chong-Chao; Kuo, Hsuan-Fu; Kuo, Chang-Hung; Tsai, Wen-Chan; Hung, Chih-Hsing

    2017-03-01

    The treatment of rheumatoid arthritis (RA) with tumor necrosis factor-alpha (TNF-α) inhibitors could lead to adverse effects. Therefore, the identification of downstream therapeutic targets is important. Monocyte chemoattractant protein-1 (MCP-1, also called CCL2) is related to RA disease activity, and epigenetic modifications are hypothesized to regulate gene expression in RA pathogenesis. We studied the effects of two TNF-α inhibitors, etanercept and adalimumab, on CCL2 expression and the potentially associated intracellular mechanisms, including epigenetic regulation. Etanercept and adalimumab decreased CCL2 production in THP-1 cells and human primary monocytes, as detected using enzyme-linked immunosorbent assays, and these changes in the CCL2 levels were independent of the TNF-α levels. Etanercept and adalimumab suppressed mitogen-activated protein kinase (MAPK) phospho-p38, phospho-JNK, phospho-ERK and nuclear factor-κB (NF-κB) phospho-p65, as demonstrated using western blot analyses. The investigation of epigenetic modifications using chromatin immunoprecipitation revealed that etanercept and adalimumab down-regulated acetylation of histone (H)3 and H4 in the CCL2 promoter region by decreasing the recruitment of the NF-κB associated acetyltransferases p300, CBP and PCAF. Etanercept and adalimumab also down-regulated trimethylation of H3K4, H3K27, H3K36 and H3K79 in the CCL2 promoter region by decreasing the expression of the related methyltransferases WDR5 and Smyd2. We demonstrated that TNF-α inhibitors exert immunomodulatory effects on CCL2 expression in human monocytes via MAPKs, NF-κB and epigenetic modifications. These findings broaden the mechanistic knowledge related to TNF-α inhibitors and provide novel therapeutic targets for RA.

  12. Treatment with tumour necrosis factor inhibitor oxpentifylline does not improve corticosteroid dependent chronic active Crohn's disease.

    PubMed Central

    Bauditz, J; Haemling, J; Ortner, M; Lochs, H; Raedler, A; Schreiber, S

    1997-01-01

    BACKGROUND: In Crohn's disease, inflammation is presumably sustained by an increased production of proinflammatory cytokines, in particular tumour necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL 1 beta). TNF alpha can induce a host of cellular effector events resulting in perpetuation of the inflammatory process. In vivo studies with anti-TNF alpha antibody treatment have led to impressive clinical results. AIMS: To investigate whether treatment with the TNF alpha inhibitor oxpentifylline results in clinical improvement in corticosteroid dependent chronic active Crohn's disease. METHODS: Sixteen Crohn's disease patients received oxpentifylline 400 mg four times a day in a four week open label study. RESULTS: Blockade of TNF alpha production in 16 patients with corticosteroid dependent Crohn's disease did not improve the clinical disease activity (CDAI mean (SEM) 188.75 (5.65) versus 185.13 (10.87) or the endoscopic degree of inflammation (CDEIS 14.9 (2.87) versus 14.8 (2.27) or laboratory parameters. CONCLUSIONS: In this study, use of the TNF alpha inhibitor oxpentifylline does not improve inflammation in Crohn's disease. This finding suggests that there may be more key mediators than only TNF alpha in the inflammatory process in Crohn's disease. PMID:9176073

  13. Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Rheumatoid Arthritis

    PubMed Central

    Rodrigues, Ana Maria; Campanilho-Marques, Raquel; Ponte, Cristina; Canhão, Helena; Ainola, Mari

    2017-01-01

    Objective. Tumor necrosis factor (TNF) increases circulating osteoclast (OC) precursors numbers by promoting their proliferation and differentiation. The aim of this study was to assess the effect of TNF inhibitors (TNFi) on the differentiation and activity of OC in rheumatoid arthritis (RA) patients. Methods. Seventeen RA patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 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, in vitro OC differentiation assays, and qRT-PCR for OC specific genes was performed. Results. After TNFi therapy, patients had reduced RANKL surface expression in B-lymphocytes and the frequency of circulating classical CD14brightCD16− monocytes was decreased. Serum levels of sRANKL, sRANKL/OPG ratio, and CTX-I were reduced in RA patients after TNFi treatment. Moreover, after exposure to TNFi, osteoclast differentiation and activity were decreased, as well as the expression of TRAF6 and cathepsin K. Conclusion. We propose that TNFi arrests bone loss and erosion, through two pathways: direct reduction of osteoclast precursor numbers and inhibition of intracellular signaling pathways acting through TRAF6. PMID:28286757

  14. Monoclonal antibodies in rheumatoid arthritis: comparative effectiveness of tocilizumab with tumor necrosis factor inhibitors

    PubMed Central

    Tanaka, Toshio; Hishitani, Yoshihiro; Ogata, Atsushi

    2014-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation, systemic inflammation, and immunological abnormalities. Because cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 play a major role in the development of RA, their targeting could constitute a reasonable novel therapeutic strategy for treating RA. Indeed, worldwide clinical trials of TNF inhibiting biologic disease modifying antirheumatic drugs (bDMARDs) including infliximab, adalimumab, golimumab, certolizumab pegol, and etanercept as well as the humanized anti-human IL-6 receptor antibody, tocilizumab, have demonstrated outstanding clinical efficacy and tolerable safety profiles, resulting in worldwide approval for using these bDMARDs to treat moderate to severe active RA in patients with an inadequate response to synthetic disease modifying antirheumatic drugs (sDMARDs). Although bDMARDs have elicited to a paradigm shift in the treatment of RA due to the prominent efficacy that had not been previously achieved by sDMARDs, a substantial percentage of patients failed primary or secondary responses to bDMARD therapy. Because RA is a heterogeneous disease in which TNF-α and IL-6 play overlapping but distinct pathological roles, further studies are required to determine the best use of TNF inhibitors and tocilizumab in individual RA patients. PMID:24741293

  15. 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

  16. Parents' information needs in tumor necrosis factorinhibitor treatment decisions.

    PubMed

    Lipstein, Ellen A; Lovell, Daniel J; Denson, Lee A; Moser, David W; Saeed, Shehzad A; Dodds, Cassandra M; Britto, Maria T

    2013-03-01

    The aim of the study was to describe parents' experiences and the information used when making decisions about tumor necrosis factorinhibitor (TNFαi) treatment. We interviewed parents of children with Crohn disease (CD) or juvenile idiopathic arthritis who had experience deciding about TNFαi treatment. Interview questions focused on information used to make decisions and factors that influenced decision making. We used thematic analysis for all coding and analysis. Coding structure was developed by a multidisciplinary team review of the initial interviews. Two coders then coded the remaining interviews, compared coding, and resolved disagreements through discussion. Data were analyzed by thematic grouping and then compared between diseases. We interviewed 35 parents. For nearly all parents the decision about TNFαi treatment was the most challenging medical decision they had made; however, parents of children with CD experienced more stress and anxiety than did other parents. Both groups of parents sought information from multiple sources including health care providers, the Internet, and social contacts. They looked for information related to treatment effectiveness, adverse effects, and other individuals' treatment experiences. In CD, information was used to help make the decision, whereas in juvenile idiopathic arthritis it was used to confirm the decision. The decision-making experience, and associated information seeking, leaves some parents with long-lasting concerns and worry about TNFαi treatment. Providing parents with structured decision-making support may lead to more effective and efficient decision making, decreased psychosocial distress, and, ultimately, improved outcomes for their children.

  17. Soluble biomarkers associated with response to treatment with tumor necrosis factor inhibitors in psoriatic arthritis.

    PubMed

    Chandran, Vinod; Shen, Hua; Pollock, Remy A; Pellett, Fawnda J; Carty, Adele; Cook, Richard J; Gladman, Dafna D

    2013-06-01

    To identify soluble biomarkers associated with response to therapy with tumor necrosis factor inhibitors (TNFi) in patients with psoriatic arthritis (PsA). The study was conducted at a PsA clinic where patients are assessed every 6 months, and serum samples are collected and stored once a year at the time of clinical assessment. Forty patients with active PsA who gave serum samples prior to treatment with TNFi and after at least 3 months of therapy were identified. Patients were classified as TNFi responders if tender joint count was < 3, swollen joint count was 0, and Psoriasis Area and Severity Index score was < 4 at the time the second sample was collected. The following biomarkers were tested by ELISA: TNF superfamily 14, matrix metalloprotease-3 (MMP-3), receptor activator of nuclear factor kappa-B ligand, osteoprotegerin, cartilage oligomeric matrix protein (COMP), CPII, C2C and C1-2C, CS-846, and highly sensitive C-reactive protein. Paired t tests and logistic regression was used for statistical analyses. After a mean treatment duration of 11 months with TNFi (etanercept 28 patients, adalimumab 6, golimumab 4, infliximab 2), 29 patients were classified as TNFi responders. Baseline level of MMP-3 was independently associated with responder status (OR 1.067 for each 1-unit increase, p = 0.045). A reduction in MMP-3 levels with therapy increased the odds of achieving response (OR 1.213 for each 1-unit change, p = 0.030), whereas a reduction in COMP decreased the odds (OR 0.587, for each 100-unit increase, p = 0.039). None of the other biomarkers was associated with response. Baseline as well as reduction in serum MMP-3 and increase in serum COMP are independently associated with response to TNFi therapy in patients with PsA.

  18. 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

  19. Impact of Dose Tapering of Tumor Necrosis Factor Inhibitor on Radiographic Progression in Ankylosing Spondylitis

    PubMed Central

    Park, Jun Won; Kwon, Hyun Mi; Park, Jin Kyun; Choi, Ja-Young; Lee, Eun Bong; Song, Yeong Wook

    2016-01-01

    Objective To investigate the impact of dose reduction of tumor necrosis factor inhibitor (TNFi) on radiographic progression in ankylosing spondylitis (AS). Methods One hundred and sixty-five patients treated with etanercept or adalimumab were selected from a consecutive single-center observational cohort based on the availability of radiographs at baseline and after two- and/or four-years of follow up. Radiographs were assessed by two blinded readers using the modified Stokes AS Spinal Score (mSASSS). Radiographic progression in patients treated with standard-dose TNFi (standard-dose group, n = 49) was compared with patients whose dosage was tapered during the treatment (tapering group, n = 116) using linear mixed models. Results Baseline characteristics between two groups were comparable except for higher BASDAI (7.1 vs. 6.3, p = 0.003) in the standard-dose group. At two years after the treatment, mean dose quotient (S.D.) of the tapering group was 0.59 (0.17). During follow up, rate of radiographic progression in overall patients was 0.90 mSASSS units/year. Radiographic progression over time between the two groups was similar at the entire group level. However, in the subgroup of patients with baseline syndesmophytes, progression occurred significantly faster in the tapering group after the adjustment for baseline status (1.23 vs. 1.72 mSASSS units/year, p = 0.023). Results were consistent when radiographic progression was assessed by the number of newly developed syndesmophytes (0.52 vs. 0.73/year, p = 0.047). Sensitivity analysis after multiple imputation of missing radiographs also showed similar results. Conclusion A dose tapering strategy of TNFi is associated with more rapid radiographic progression in AS patients who have syndesmophytes at baseline. PMID:28033420

  20. Tumor Necrosis Factor Inhibitor Primary Failure Predicts Decreased Ustekinumab Efficacy in Psoriasis Patients.

    PubMed

    Sorensen, Eric P; Fanucci, Kristina A; Saraiya, Ami; Volf, Eva; Au, Shiu-chung; Argobi, Yahya; Mansfield, Ryan; Gottlieb, Alice B

    2015-08-01

    Additional studies are needed to examine the efficacy of ustekinumab in psoriasis patients who have previously been exposed to tumor necrosis factor inhibitors (TNFi). To examine the predictive effect of TNFi primary failure and the number of TNFi exposures on the efficacy of ustekinumab in psoriasis treatment. This retrospective study examined 44 psoriasis patients treated at the Tufts Medical Center Department of Dermatology between January 2008 and July 2014. Patients were selected if they were treated with ustekinumab and had ≥ 1 previous TNFi exposure. The following subgroups were compared: patients with vs without a previous TNFi primary failure, and patients with one vs multiple previous TNFi exposures. The efficacy measure used was the previously validated Simple Measure for Assessing Psoriasis Activity (S-MAPA), which is calculated by the product of the body surface area and physician global assessment. The primary outcome was the percentage improvement S-MAPA from course baseline at week 12 of ustekinumab treatment. Secondary outcomes were the psoriasis clearance, primary failure, and secondary failure rates with ustekinumab treatment. Patients with a previous TNFi primary failure had a significantly lower percentage improvement in S-MAPA score at week 12 of ustekinumab treatment compared with patients without TNFi primary failure (36.2% vs 61.1%, P=.027). Multivariate analysis demonstrated that this relationship was independent of patient demographics and medical comorbidities. Patients with multiple TNFi exposures had a non-statistically significant lower percentage S-MAPA improvement at week 12 (40.5% vs 52.9%, P=.294) of ustekinumab treatment compared with patients with a single TNFi exposure. Among psoriasis patients previously exposed to TNFi, a history of a previous TNFi primary failure predicts a decreased response to ustekinumab independent of patient demographics and medical comorbidities.

  1. 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

  2. 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.

  3. Effects of tumor necrosis factor α inhibitors extend beyond psoriasis: insulin sensitivity in psoriasis patients with type 2 diabetes mellitus.

    PubMed

    Al-Mutairi, Nawaf; Shabaan, Dalia

    2016-03-01

    Psoriasis is a chronic inflammatory disease that has been associated with an increased incidence of insulin resistance and diabetes mellitus (DM). Tumor necrosis factor (TNF) α inhibitors and IL-6 blockers, which are routinely used for the treatment of psoriasis, have been positively associated with insulin sensitivity. The aim of this study was to assess the effects of treatment with TNF-α inhibitors on insulin sensitivity in psoriatic patients with type 2 DM. This study confirms a beneficial effect of anti-TNF-α agents on insulin resistance and insulin sensitivity in psoriasis patients with type 2 DM.

  4. Inhibitor of Apoptosis Protein-1 Regulates Tumor Necrosis Factor-Mediated Destruction of Intestinal Epithelial Cells.

    PubMed

    Grabinger, Thomas; Bode, Konstantin J; Demgenski, Janine; Seitz, Carina; Delgado, M Eugenia; Kostadinova, Feodora; Reinhold, Cindy; Etemadi, Nima; Wilhelm, Sabine; Schweinlin, Matthias; Hänggi, Kay; Knop, Janin; Hauck, Christof; Walles, Heike; Silke, John; Wajant, Harald; Nachbur, Ueli; W Wei-Lynn, Wong; Brunner, Thomas

    2017-03-01

    Tumor necrosis factor (TNF) is a cytokine that promotes inflammation and contributes to pathogenesis of inflammatory bowel diseases. Unlike other cells and tissues, intestinal epithelial cells undergo rapid cell death upon exposure to TNF, by unclear mechanisms. We investigated the roles of inhibitor of apoptosis proteins (IAPs) in the regulation of TNF-induced cell death in the intestinal epithelium of mice and intestinal organoids. RNA from cell lines and tissues was analyzed by quantitative polymerase chain reaction, protein levels were analyzed by immunoblot assays. BIRC2 (also called cIAP1) was expressed upon induction from lentiviral vectors in young adult mouse colon (YAMC) cells. YAMC cells, the mouse colon carcinoma cell line MC38, the mouse macrophage cell line RAW 264.7, or mouse and human organoids were incubated with second mitochondrial activator of caspases (Smac)-mimetic compound LCL161 or recombinant TNF-like weak inducer of apoptosis (TNFSF12) along with TNF, and cell death was quantified. C57BL/6 mice with disruption of Xiap, Birc2 (encodes cIAP1), Birc3 (encodes cIAP2), Tnfrsf1a, or Tnfrsf1b (Tnfrsf1a and b encode TNF receptors) were injected with TNF or saline (control); liver and intestinal tissues were collected and analyzed for apoptosis induction by cleaved caspase 3 immunohistochemistry. We also measured levels of TNF and alanine aminotransferase in serum from mice. YAMC cells, and mouse and human intestinal organoids, died rapidly in response to TNF. YAMC and intestinal crypts expressed lower levels of XIAP, cIAP1, cIAP2, and cFLIP than liver tissue. Smac-mimetics reduced levels of cIAP1 and XIAP in MC38 and YAMC cells, and Smac-mimetics and TNF-related weak inducer of apoptosis increased TNF-induced cell death in YAMC cells and organoids-most likely by sequestering and degrading cIAP1. Injection of TNF greatly increased levels of cell death in intestinal tissue of cIAP1-null mice, compared with wild-type C57BL/6 mice, cIAP2-null mice, or

  5. 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

  6. Impact of obesity on the response to tumor necrosis factor inhibitors in axial spondyloarthritis.

    PubMed

    Micheroli, Raphael; Hebeisen, Monika; Wildi, Lukas M; Exer, Pascale; Tamborrini, Giorgio; Bernhard, Jürg; Möller, Burkhard; Zufferey, Pascal; Nissen, Michael J; Scherer, Almut; Ciurea, Adrian

    2017-07-19

    Few studies have investigated the impact of obesity on the response to tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). The aim of our study was to investigate the impact of different body mass index (BMI) categories on TNFi response in a large cohort of patients with axSpA. Patients with axSpA within the Swiss Clinical Quality Management (SCQM) program were included in the current study if they fulfilled the Assessment in Spondyloarthritis International Society (ASAS) criteria for axSpA, started a first TNFi after recruitment, and had available BMI data as well as a baseline and follow-up visit at 1 year (±6 months). Patients were categorized according to BMI: normal (BMI 18.5 to <25), overweight (BMI 25-30), and obese (BMI >30). We evaluated the proportion of patients achieving the 40% improvement in ASAS criteria (ASAS40), as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) improvement and status scores at 1 year. Patients having discontinued the TNFi were considered nonresponders. We controlled for age, sex, HLA-B27, axSpA type, BASDAI, BASMI, elevated C-reactive protein (CRP), current smoking, enthesitis, physical exercise, and co-medication with disease-modifying antirheumatic drugs, as well as with nonsteroidal anti-inflammatory drugs in multiple adjusted logistic regression analyses. A total of 624 axSpA patients starting a first TNFi were considered in the current study (332 patients of normal weight, 204 patients with overweight, and 88 obese patients). Obese individuals were older, had higher BASDAI levels, and had a more important impairment of physical function in comparison to patients of normal weight, while ASDAS and CRP levels were comparable between the three BMI groups. An ASAS40 response was reached by 44%, 34%, and 29% of patients of normal weight, overweight, and obesity, respectively (overall p = 0.02). Significantly lower odds ratios (ORs) for achieving ASAS40 response were found

  7. Cost of dose escalation in people with rheumatoid arthritis treated with tumour necrosis factor inhibitors across Europe.

    PubMed

    Holden, Sarah E; Currie, Craig J; Lennon, Martin; Reynolds, Alan V; Moots, Robert J

    2016-01-01

    The aim of this study was to calculate the marginal cost of dose escalation in people with rheumatoid arthritis treated with tumour necrosis factor (TNF) inhibitors across Europe. The proportion of people who escalate their dose of TNF inhibitor and the average percentage increase in TNF inhibitor cost associated with escalators versus non-escalators was calculated from previously published estimates, weighted by the sample size for each study. The number of people with rheumatoid arthritis treated with TNF inhibitors and the corresponding total drug sales were obtained for five European countries from Decision Resources' Pharmacor Market Forecast. Method 1 assumed that total sales of a TNF inhibitor represented the cost of an escalator multiplied by the number of escalators plus the cost of a non-escalator multiplied by the number of non-escalators. Method 2 assumed that the drug cost per day used to forecast total sales was calculated using the dose of TNF inhibitor used by non-escalators. The marginal cost of TNF inhibitor dose escalation was estimated by multiplying the difference in cost between escalators and non-escalators by the number of escalators. The estimated increase in TNF inhibitor costs associated with dose escalation in people with rheumatoid arthritis across five European countries (Germany, France, UK, Spain and Italy) was €51.5-54.4 million for adalimumab, €44.8-52.8 million for infliximab and €5.8-5.9 million for etanercept. Dose escalation of the TNF inhibitors adalimumab, etanercept and infliximab in people with rheumatoid arthritis has resulted in an increase in TNF inhibitor costs across five European countries.

  8. Immune response to influenza vaccination in children treated with methotrexate or/and tumor necrosis factor-alpha inhibitors.

    PubMed

    Woerner, Andreas; Sauvain, Marie-Josèphe; Aebi, Christoph; Otth, Margrit; Bolt, Isabel B

    2011-12-01

    In children treated with immunosuppressive medication such as methotrexate and tumor necrosis factor-alpha (TNF-α) inhibitors, additional immunizations are recommended because of increased susceptibility to infections. However, it is unclear if adequate antibody response to vaccinations can be established in children receiving methotrexate and/or TNF-α inhibitors. In a prospective open label study, we assessed seroprotection and seroconversion following influenza vaccination during 2 seasons (6 strains) in 36 children with autoimmune disease treated either with methotrexate (n=18), TNF-α inhibitors (n=10) or both (n=8) and a control group of 16 immunocompetent children. Influenza antibody titers were determined by hemagglutinin inhibition assay, before and 4-8 weeks after vaccination. Post-vaccination seroprotection (defined as a titer ≥1:40) did not significantly differ between immunosuppressed and immunocompetent subjects. Seroconversion, defined as the change from a nonprotective (< 1:40) to a protective titer (≥1:40) with at least a 4-fold titer increase, was less likely to occur in immunosuppressed patients, although no significant difference from the control group was established. Safety evaluation of vaccination showed no serious adverse events. Children receiving methotrexate and/or TNF-α inhibitors can be safely and effectively immunized against influenza, with a seroprotection after vaccination comparable to immunocompetent children.

  9. Abnormal production of tumor necrosis factor (TNF) -- alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected].

    PubMed

    Cortis, Elisabetta; De Benedetti, Fabrizio; Insalaco, Antonella; Cioschi, Stefania; Muratori, Flaminia; D'Urbano, Leila E; Ugazio, Alberto G

    2004-12-01

    We report a family with pyogenic sterile arthritis, pyoderna and acne syndrome (PAPA). The proband presented several episodes of sterile pyogenic arthritis and became unresponsive to glucocorticoids. After treatment with the tumor necrosis factor inhibitor etanercept, the disease underwent rapid and sustained clinical remission. Production of tumor necrosis factor-alpha by mononuclear cells of the proband and of the affected relatives was abnormally elevated.

  10. Tumor necrosis factorinhibitor-induced psoriasis: Systematic review of clinical features, histopathological findings, and management experience.

    PubMed

    Brown, Gabrielle; Wang, Eva; Leon, Argentina; Huynh, Monica; Wehner, Mackenzie; Matro, Rebecca; Linos, Eleni; Liao, Wilson; Haemel, Anna

    2017-02-01

    Tumor necrosis factor-α (TNF-α) inhibitors have been reported to induce new-onset psoriasis. To better define the demographic, clinical features, and treatment approach of TNF-α inhibitor-induced psoriasis. Systematic review of published cases of TNF-α inhibitor-induced psoriasis. We identified 88 articles with 216 cases of new-onset TNF-α inhibitor-induced psoriasis. The mean age at psoriasis onset was 38.5 years. The most common underlying diseases were Crohn disease (40.7%) and rheumatoid arthritis (37.0%). Patients underwent TNF-α therapy for an average of 14.0 months before psoriasis onset with 69.9% of patients experiencing onset within the first year. The majority of patients received skin-directed therapy, though patients who discontinued TNF therapy had the greatest resolution of symptoms (47.7%) compared with those who switched to a different TNF agent (36.7%) or continued therapy (32.9%). Retrospective review that relies on case reports and series. While TNF-α inhibitor cessation may result in resolution of induced psoriasis, lesions may persist. Decisions regarding treatment should be weighed against the treatability of TNF-α inhibitor-induced psoriasis, the severity of the background rheumatologic or gastrointestinal disease, and possible loss of efficacy with cessation followed by retreatment. Skin-directed therapy is a reasonable initial strategy except in severe cases. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  11. Effects of non-medical switching on outcomes among patients prescribed tumor necrosis factor inhibitors.

    PubMed

    Gibofsky, Allan; Skup, Martha; Mittal, Manish; Johnson, Scott J; Davis, Matthew; Chao, Jingdong; Rubin, David T

    2017-09-21

    To evaluate health care use and outcomes among patients who experienced a non-medical switch of their prescribed anti-tumor-necrosis-factor biological agent (anti-TNF) for cost containment reasons. Retrospective evaluation of Humedica electronic health records of patients ≥18 years old with anti-TNF treatment for immune conditions. Using natural language processing, stable patients who experienced a non-medical switch (for cost reasons) of their anti-TNF between 2007 and 2013 were identified (NMS cohort, n = 158) and matched to patients who did not (control cohort, n = 4804). Rates of office visits, emergency department visits, and hospitalizations at 30, 90, and 365 days following were evaluated. Medication-related adverse events, defined as subsequent medication change due to a side effect and/or efficacy-related reason were also compared. Adjusted rates of office visits were higher among the NMS cohort than the control cohort at 30 (46.4% vs. 31.7%, p < .001), 90 (71.0% vs. 57.0%, p < .001), and 365 days (87.8% vs. 76.8%, p < .001). Rates of emergency department use and hospitalization were comparable between cohorts. The NMS cohort had higher adjusted rates of medication-related adverse consequences (both increased side effects and diminished efficacy) than the control cohort at 30 (13.8% vs. 4.0%, p = .003), 90 (31.6% vs 9.6%, p < .001), and 365 days (54.7% vs. 20.3%, p < .001). Compared with controls, the NMS cohort had higher adjusted rates of subsequent medication change within 1 year (27.82% vs. 13.9%, p = .001). Non-medical switching among patients prescribed anti-TNFs was associated with increased health care use, medication-related side effects, and reports of diminished efficacy.

  12. Efficacy of switching between tumor necrosis factor-alfa inhibitors in psoriasis: results from the Italian Psocare registry.

    PubMed

    Piaserico, Stefano; Cazzaniga, Simone; Chimenti, Sergio; Giannetti, Alberto; Maccarone, Mara; Picardo, Mauro; Peserico, Andrea; Naldi, Luigi

    2014-02-01

    Some studies have shown that switching patients from one tumor necrosis factor (TNF)-alfa inhibitor to another may be beneficial when they have an inadequate response or an adverse event. We sought to assess the variables predicting the efficacy of the second TNF-alfa inhibitor in patients discontinuing the first TNF-alfa inhibitor. Data from all 5423 consecutive patients starting TNF-alfa inhibitor therapy for psoriasis between September 2005 and September 2010 who were included in the Italian Psocare registry were analyzed. In 105 patients who switched to a second TNF-alfa inhibitor who had complete follow-up data, 75% improvement in the Psoriasis Area Severity Index score (PASI 75) was reached by 29% after 16 weeks and by 45.6% after 24 weeks. Patients who switched because of secondary loss of efficacy (loss of initial PASI 75 response) or adverse events/intolerance were more likely to reach PASI 75 than those who switched as a result of primary inefficacy (PASI 75 never achieved) (hazard ratio 2.7, 95% confidence interval 1.3-5.5 vs hazard ratio 2.0, 95% confidence interval 1.0-3.9 and 1, respectively). There was a small number of patients with complete follow-up data. PASI 75 response in patients who switched from one anti-TNF-alfa agent to another was significantly reduced in patients who showed primary inefficacy of the first anti-TNF-alfa. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  13. Concurrent Intervention With Exercises and Stabilized Tumor Necrosis Factor Inhibitor Therapy Reduced the Disease Activity in Patients With Ankylosing Spondylitis

    PubMed Central

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

    2015-01-01

    Abstract 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

  14. Design of selective and soluble inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).

    PubMed

    Rabinowitz, M H; Andrews, R C; Becherer, J D; Bickett, D M; Bubacz, D G; Conway, J G; Cowan, D J; Gaul, M; Glennon, K; Lambert, M H; Leesnitzer, M A; McDougald, D L; Moss, M L; Musso, D L; Rizzolio, M C

    2001-11-22

    A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMP1 and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.

  15. 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.

  16. Stimulation of tumor necrosis factor alpha production in human monocytes by inhibitors of protein phosphatase 1 and 2A

    PubMed Central

    1992-01-01

    The protein phosphatase 1 and 2A inhibitor, okadaic acid, has been shown to stimulate many cellular functions by increasing the phosphorylation state of phosphoproteins. In human monocytes, okadaic acid by itself stimulates tumor necrosis factor alpha (TNF-alpha) mRNA accumulation and TNF-alpha synthesis. Calyculin A, a more potent inhibitor of phosphatase 1, has similar effects. TNF-alpha mRNA accumulation in okadaic acid-treated monocytes is due to increased TNF- alpha mRNA stability and transcription rate. The increase in TNF-alpha mRNA stability is more remarkable in okadaic acid-treated monocytes than the mRNA stability of other cytokines, such as interleukin 1 alpha (IL-1 alpha), IL-1 beta, and IL-6. Gel retardation studies show the stimulation of AP-1, AP-2, and NF-kappa B binding activities in okadaic acid-stimulated monocytes. This increase may correlate with the increase in TNF-alpha mRNA transcription rate. In addition to the stimulation of TNF-alpha secretion by monocytes, okadaic acid appears to modulate TNF-alpha precursor processing, as indicated by a marked increase in the cell-associated 26-kD precursor. These results suggest that active basal phosphorylation/dephosphorylation occurs in monocytes, and that protein phosphatase 1 or 2A is important in regulating TNF-alpha gene transcription, translation, and posttranslational modification. PMID:1324971

  17. Efficacy of incentive spirometer exercise on pulmonary functions of patients with ankylosing spondylitis stabilized by tumor necrosis factor inhibitor therapy.

    PubMed

    So, Min Wook; Heo, Hyun Mi; Koo, Bon San; Kim, Yong-Gil; Lee, Chang-Keun; Yoo, Bin

    2012-09-01

    To evaluate the effect of combining incentive spirometer exercise (ISE) with a conventional exercise (CE) on patients with ankylosing spondylitis (AS) stabilized by tumor necrosis factor (TNF) inhibitor therapy by comparing a combination group with a CE-alone group. Forty-six patients (44 men, 2 women) were randomized to the combination group (ISE plus CE; n=23) or the CE group (n=23). The CE regimen of both groups consisted of 20 exercises performed for 30 min once a day. The ISE was performed once a day for 30 min. The trial duration was 16 weeks. Patients were assessed before and at the end of treatment by measuring the Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index (BASFI), chest expansion, finger to floor distance, pulmonary function measures, and 6-min walk distance. Both groups improved significantly in terms of chest expansion (p<0.01), finger to floor distance (p<0.01), and BASFI (p<0.05) after completing the exercise program. However, only the combination group showed significant improvements in the forced vital capacity (p<0.05), total lung capacity (p<0.01), and vital capacity (p<0.05). Although this did not achieve statistical significance, the combination group was mildly superior to the CE-alone group in functional disability and pulmonary function measures. Combining ISE with a CE can provide positive results in patients whose AS has been clinically stabilized by TNF inhibitor therapy.

  18. 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.

    PubMed Central

    Gatanaga, T; Hwang, C D; Kohr, W; Cappuccini, F; Lucci, J A; Jeffes, E W; Lentz, R; Tomich, J; Yamamoto, R S; Granger, G A

    1990-01-01

    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 28 kDa 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 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. Images PMID:2174164

  19. 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.

  20. 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

  1. Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock.

    PubMed

    Du, Shi-lin; Yuan, Xue; Zhan, Sun; Tang, Luo-jia; Tong, Chao-yang

    2015-03-13

    Lipopolysaccharide (LPS), one of the most prominent pathogen-associated molecular patterns (PAMPs), activates macrophages, causing release of toxic cytokines (i.e. tumor necrosis factor (TNF)-α) that may provoke inflammation and endotoxin shock. Here, we tested the potential role of trametinib, a novel and highly potent MAPK/ERK kinase (MEK) inhibitor, against LPS-induced TNF-α response in monocytes, and analyzed the underlying mechanisms. We showed that trametinib, at nM concentrations, dramatically inhibited LPS-induced TNF-α mRNA expression and protein secretion in transformed (RAW 264.7 cells) and primary murine macrophages. In ex-vivo cultured human peripheral blood mononuclear cells (PBMCs), this MEK inhibitor similarly suppressed TNF-α production by LPS. For the mechanism study, we found that trametinib blocked LPS-induced MEK-ERK activation in above monocytes, which accounted for the defective TNF-α response. Macrophages or PBMCs treated with a traditional MEK inhibitor PD98059 or infected with MEK1/2-shRNA lentivirus exhibited a similar defect as trametinib, and nullified the activity of trametinib. On the other hand, introducing a constitutively-active (CA) ERK1 restored TNF-α production by LPS in the presence of trametinib. In vivo, mice administrated with trametinib produced low levels of TNF-α after LPS stimulation, and these mice were protected from LPS-induced endotoxin shock. Together, these results show that trametinib inhibits LPS-induced TNF-α expression and endotoxin shock probably through blocking MEK-ERK signaling.

  2. Tumour necrosis factor alpha inhibitor therapy and rehabilitation for the treatment of ankylosing spondylitis: a systematic review.

    PubMed

    Lubrano, Ennio; Spadaro, Antonio; Amato, Giorgio; Benucci, Maurizio; Cavazzana, Ilaria; Chimenti, Maria Sole; Ciancio, Giovanni; D Alessandro, Giuseppe; Angelis, Rossella De; Lupoli, Salvatore; Lurati, Alfredo Maria; Naclerio, Caterina; Russo, Romualdo; Semeraro, Angelo; Tomietto, Paola; Zuccaro, Carmelo; De Marco, Gabriele

    2015-04-01

    To systematically review the evidence for a synergistic effect of combining rehabilitation with biological anti-tumour necrosis factor (TNF) therapy in patients with ankylosing spondylitis (AS). Data were analysed to identify the most effective rehabilitation programmes, the best endpoints for effectiveness, and patient subgroups most likely to benefit from combination therapy. Systematic MEDLINE and Embase searches were performed to identify studies evaluating rehabilitation programmes and biological therapy in patients with AS. Evidence was categorised by study type, and efficacy, adverse effects and other outcomes were summarised. Of the 75 studies identified, 13 investigated the combination of a rehabilitation programme with TNF inhibitor therapy, while the remainder studied rehabilitation with standard therapy (often not specified). Data from these few studies suggest that combined rehabilitation plus anti-TNF therapy is more effective in terms of symptom severity, disease activity, disability and quality-of-life indices versus biologic alone or rehabilitation with standard medical therapy, or, in non-comparative studies, compared with baseline. The most effective rehabilitation appears to be supervised or in-patient programmes with an educational component. Available data do not provide guidance on most appropriate endpoints or identify patients most likely to benefit from combination therapy. Combined, TNF inhibitor and rehabilitation therapy appear to have a synergistic effect, possibly due to increased adherence to exercise. Exercise regimes are more effective if supervised and include an education component. Further randomized, controlled trials comparing endpoints and investigating longer-term benefits of combining TNF inhibitors with rehabilitation in different AS subgroups are needed. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. An update on the use of tumor necrosis factor alpha inhibitors in the treatment of ankylosing spondylitis.

    PubMed

    Osman, Mohammed S; Maksymowych, Walter P

    2017-02-01

    Ankylosing spondylitis is a chronic immune-mediated disease affecting the sacroiliac joints and the spine manifesting with new bone formation and osteopenia. Over the past decade, tumour necrosis factor alpha (TNF-α) inhibitors (TNFi) have become the cornerstone for therapy in improving functional outcomes, and decreasing disease activity in patients with a marginal benefit from non-steroidal anti-inflammatory (NSAID) therapy. At this time, it remains to be determined whether these agents decrease new bone formation, although some studies have recently suggested that. Areas covered: In this review we discuss the factors that favour a good response to these agents both initially and during maintenance, and some of the more recent studies outlining strategies for dose reduction. Expert commentary: Finally, we discuss the importance of using more objective tools for disease activity, such as magnetic resonance imaging, as a complementary tool for clinical assessments in both predicting responses to treatment but also in selecting patients most suited for targeted therapy.

  4. Recurrent Streptococcus agalactiae Toxic Shock Syndrome Triggered by a Tumor Necrosis FactorInhibitor

    PubMed Central

    Yoshida, Masataka; Takazono, Takahiro; Tashiro, Masato; Saijo, Tomomi; Morinaga, Yoshitomo; Yamamoto, Kazuko; Nakamura, Shigeki; Imamura, Yoshifumi; Miyazaki, Taiga; Sawai, Toyomitsu; Nishino, Tomoya; Izumikawa, Koichi; Yanagihara, Katsunori; Mukae, Hiroshi; Kohno, Shigeru

    2016-01-01

    Streptococcal toxic shock syndrome caused by group B streptococcus (GBS) is a rare, but lethal disease. We experienced a 45-year-old woman with pustular psoriasis who developed toxic shock-like syndrome during infliximab treatment. Surprisingly, similar episodes recurred three times in one year with restarting of infliximab treatments. In the third episode, GBS were detected in blood, urine, and vaginal secretion cultures. These episodes of shock syndrome were possibly due to GBS. To the best of our knowledge, this is the first case report of recurrent streptococcal toxic shock syndrome possibly caused by GBS which was induced by anti-TNF-α inhibitor therapy. The restarting of biological agents in patients with a history of toxic shock syndrome should therefore be avoided as much as possible. PMID:27803422

  5. Tumor necrosis factor.

    PubMed

    Chu, Wen-Ming

    2013-01-28

    Tumor necrosis factor (TNF) is a critical cytokine, which contributes to both physiological and pathological processes. This mini-review will briefly touch the history of TNF discovery, its family members and its biological and pathological functions. Then, it will focus on new findings on the molecular mechanisms of how TNF triggers activation of the NF-κB and AP-1 pathways, which are critical for expression of pro-inflammatory cytokines, as well as the MLKL cascade, which is critical for the generation of ROS in response to TNF. Finally, this review will briefly summarize recent advances in understanding TNF-induced cell survival, apoptosis and necrosis (also called necroptosis). Understanding new findings and emerging concepts will impact future research on the molecular mechanisms of TNF signaling in immune disorders and cancer-related inflammation.

  6. Neutrophil biomarkers predict response to therapy with tumor necrosis factor inhibitors in rheumatoid arthritis.

    PubMed

    Wright, Helen L; Cox, Trevor; Moots, Robert J; Edwards, Steven W

    2017-03-01

    Neutrophils are implicated in the pathology of rheumatoid arthritis (RA), but the mechanisms regulating their activation are largely unknown. RA is a heterogeneous disease, and whereas many patients show clinical improvement during TNF inhibitor (TNFi) therapy, a significant proportion fails to respond. In vitro activation of neutrophils with agents, including TNF, results in rapid and selective changes in gene expression, but how neutrophils contribute to TNF signaling in RA and whether TNFi sensitivity involves differential neutrophil responses are unknown. With the use of RNA sequencing (RNA-Seq), we analyzed blood neutrophils from 20 RA patients, pre-TNFi therapy, to identify biomarkers of response, measured by a decrease in disease activity score based on 28 joint count (DAS28), 12 wk post-therapy. Biomarkers were validated by quantitative PCR (qPCR) of blood neutrophils from 2 further independent cohorts of RA patients: 16 pre-TNFi and 16 predisease-modifying anti-rheumatic drugs (DMARDs). Twenty-three neutrophil transcripts predicted a 12-wk response to TNFi: 10 (IFN-regulated) genes predicting a European League against Rheumatism (EULAR) good response and 13 different genes [neutrophil granule protein (NGP) genes] predicting a nonresponse. Statistical analysis indicated a predictive sensitivity and specificity of each gene in the panel of >80%, with some 100% specific. A combination of 3 genes [cytidine monophosphate kinase 2 (CMPK2), IFN-induced protein with tetratricopeptide repeats 1B (IFIT1B), and RNASE3] had the greatest predictive power [area under the curve (AUC) 0.94]. No correlation was found for a response to DMARDs. We conclude that this panel of genes is selective for predicting a response to TNFi and is not a surrogate marker for disease improvement. We also show that in RA, there is great plasticity in neutrophil phenotype, with circulating cells expressing genes normally only expressed in more immature cells.

  7. Rehabilitation treatment in patients with ankylosing spondylitis stabilized with tumor necrosis factor inhibitor therapy: a randomized controlled trial.

    PubMed

    Masiero, Stefano; Bonaldo, Lara; Pigatto, Maurizia; Lo Nigro, Alessandro; Ramonda, Roberta; Punzi, Leonardo

    2011-07-01

    To assess the 2- (T1) and 6-month (T2) followup effects on pain, spine mobility, physical function, and disability outcome of a rehabilitation intervention in patients with ankylosing spondylitis (AS) stabilized with tumor necrosis factor (TNF) inhibitor therapy. Sixty-two outpatients (49 men, 13 women, mean age 47.5 ± 10.6 yrs) were randomized to rehabilitation plus an educational-behavioral (n = 20) program, to an educational-behavioral program only (n = 20), or to a control group (n = 22). The educational-behavioral program included 2 educational meetings and 12 rehabilitation exercise sessions (stretching, strengthening, chest and spine/hip joint flexibility exercises), which patients then performed at home. Outcome assessment at the end of rehabilitation training (T1) and at T2 was based on spinal pain intensity in the previous 4 weeks by self-report visual analog scale (VAS; 100 mm: 0 = no pain, 100 = maximum pain), BASMI, BASFI, BASDAI, and on chest expansion and the active range of motion of the cervical and lumbar spine measured by a pocket goniometer. The 3 groups were comparable at baseline. On intragroup comparison at T1, the rehabilitation group showed significant improvement in the BASMI and BASDAI, in chest expansion, and in most spinal active range of motion measurements. BASFI and cervical and lumbar VAS scores improved in both the rehabilitation and educational-behavioral groups. The positive results achieved in the rehabilitation group were maintained at the 6-month followup. Combining intensive group exercise with an educational-behavioral program can provide promising results in the management of patients with clinically stabilized AS on TNF inhibitor treatment.

  8. Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats.

    PubMed

    Altintas, Nejat; Erboga, Mustafa; Aktas, Cevat; Bilir, Bulent; Aydin, Murat; Sengul, Aysun; Ates, Zehra; Topcu, Birol; Gurel, Ahmet

    2016-02-01

    We aimed to investigate the preventive effect of Infliximab (IFX), a tumor necrosis factor (TNF)-α inhibitor, on bleomycin (BLC)-induced lung fibrosis in rats. Rats were assigned into four groups as follows: I-BLC group, a single intra-tracheal BLC (2.5 mg/kg) was installed; II-control group, a single intra-tracheal saline was installed; III-IFX + BLC group, a single-dose IFX (7 mg/kg) was administered intraperitoneally (i.p.), 72 h before the intra-tracheal BLC installation; IV-IFX group, IFX (7 mg/kg) was administered alone i.p. on the same day with IFX + BLC group. All animals were sacrificed on the 14th day of BLC installation. Levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, interleukin (IL)-6, periostin, YKL-40, nitric oxide (NO) in rat serum were measured, as well as, myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity, and reduced glutathione (GSH), hydroxyproline, malondialdehyde (MDA) content in lung homogenates. Lung tissues were stained with hematoxylin and eosin (H&E) for quantitative histological evaluation. The inducible nitric oxide synthase (iNOS) expression and cell apoptosis in the lung tissues were determined quantitatively by immunohistochemical staining (INOS) and by TUNNEL staining, respectively. BLC installation worsened antioxidant status (such as SOD, CAT, GPx, GSH, MPO), while it increased the serum TNF-α, TGF-β, IL-6, periostin, YKL-40, and lipid peroxidation, and collagen deposition, measured by MDA and hydroxyproline, respectively. IFX pretreatment improved antioxidant status as well as BLC-induced lung pathological changes, while it decreased the TNF-α, TGF-β, IL-6, periostin, YKL-40, lipid peroxidation and collagen deposition. Finally, histological, immunohistochemical, and TUNNEL evidence also supported the ability of IFX to prevent BLC-induced lung fibrosis. The results of the present study indicate that IFX pretreatment can attenuate

  9. 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

    Scott, David L; 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

    2015-03-13

    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. Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months. 24 rheumatology clinics in England. 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. 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. 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. quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data. 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 tumour necrosis factor inhibitor strategy and -0.45 with the alternative combined drug strategy. The difference between

  10. 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

  11. Tumor necrosis factor inhibitor therapy in ankylosing spondylitis: differential effects on pain and fatigue and brain correlates.

    PubMed

    Wu, Qi; Inman, Robert D; Davis, Karen D

    2015-02-01

    Ankylosing spondylitis is associated with back pain and fatigue and impacts mobility but can be treated with tumor necrosis factor inhibitors (TNFi). The differential effects of TNFi treatment on multiple symptoms and the brain is not well delineated. Thus, we conducted a 2-part study. In study 1, we conducted a retrospective chart review in 129 ankylosing spondylitis patients to assess TNFi effects on pain, fatigue, motor function, mobility, and quality of life (QoL). After at least 10 weeks of TNFi treatment, patients had clinically significant improvements (>30%) in pain (including neuropathic pain), most disease and QoL factors, and normalized sensory detection thresholds. However, residual fatigue (mean = 5.3) was prominent. Although 60% of patients had significant relief of pain, only 22% of patients had significant relief of both pain and fatigue. Therefore, the preferential TNFi treatment effect on pain compared with fatigue could contribute to suboptimal effects on QoL. Part 2 was a prospective study in 14 patients to identify TNFi treatment effects on pain, fatigue, sensory and psychological factors, and brain cortical thickness based on 3T magnetic resonance imaging. Centrally, TNFi was associated with statistically significant cortical thinning of motor, premotor, and posterior parietal regions. Pain intensity reduction was associated with cortical thinning of the secondary somatosensory cortex, and pain unpleasantness reduction was associated with the cortical thinning of motor areas. In contrast, fatigue reduction correlated with cortical thinning of the insula, primary sensory cortex/inferior parietal sulcus, and superior temporal polysensory areas. This indicates that TNFi treatment produces changes in brain areas implicated in sensory, motor, affective, and cognitive functions.

  12. Periodontal and serum protein profiles in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitor adalimumab.

    PubMed

    Kobayashi, Tetsuo; Yokoyama, Tomoko; Ito, Satoshi; Kobayashi, Daisuke; Yamagata, Akira; Okada, Moe; Oofusa, Ken; Narita, Ichiei; Murasawa, Akira; Nakazono, Kiyoshi; Yoshie, Hiromasa

    2014-11-01

    Tumor necrosis factor (TNF)-α inhibitor has been shown to affect the periodontal condition of patients with rheumatoid arthritis (RA). The aim of the present study is to assess the effect of a fully humanized anti-TNF-α monoclonal antibody, adalimumab (ADA), on the periodontal condition of patients with RA and to compare serum protein profiles before and after ADA therapy. The study participants consisted of 20 patients with RA treated with ADA. Clinical periodontal and rheumatologic parameters and serum cytokine levels were evaluated at baseline and 3 months later. Serum protein spot volume was examined with two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins with significant difference in abundance before and after ADA therapy were found and identified using mass spectrometry and protein databases. The patients showed a significant decrease in gingival index (P = 0.002), bleeding on probing (P = 0.003), probing depth (P = 0.002), disease activity score including 28 joints using C-reactive protein (P <0.001), and serum levels of TNF-α (P <0.001) and interleukin-6 (P <0.001) after ADA medication, although plaque levels were comparable. Among a total of 495 protein spots obtained, nine spots were significantly decreased in abundance at reassessment, corresponding to complement factor H, phospholipase D, serum amyloid A, complement component 4, and α-1-acid glycoprotein (P <0.01). These results suggest a beneficial effect of ADA therapy on the periodontal condition of patients with RA, which might be related to differences in serum protein profiles before and after ADA therapy.

  13. Continuous Improvement of Physical Functioning in Ankylosing Spondylitis Patients by Tumor Necrosis Factor Inhibitors: Three-Year Followup and Predictors.

    PubMed

    van Weely, Salima F E; Kneepkens, Eva L; Nurmohamed, Mike T; Dekker, Joost; van der Horst-Bruinsma, Irene E

    2016-10-01

    To establish the 3-year outcome and course of physical functioning and spinal mobility impairments in patients routinely treated with tumor necrosis factor inhibitors (TNFi) and to find predictors of physical functioning and spinal mobility impairments. Ankylosing spondylitis (AS) patients eligible for TNFi were followed in a 3-year prospective observational study. Prediction models were developed with linear mixed modeling. Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) were used as outcome measures for physical functioning and spinal mobility. A total of 257 patients were included and treated with etanercept (n = 174) or adalimumab (n = 83). Physical functioning improved significantly during the first 6 months after the start of TNFi. The BASFI score decreased from mean ± SD 5.4 ± 2.4 to 3.3 ± 2.6 at 6 months, and stabilized thereafter (BASFI third year score mean ± SD 3.6 ± 2.5). The BASMI showed no significant changes over time. Lower baseline BASFI and BASMI scores predicted a better level of physical functioning and spinal mobility after 3 years of TNFi therapy. Other predictors for a better 3-year outcome and course of physical functioning included absence of comorbidity, physical activity, younger age, and lower body mass index at baseline. Physical functioning in routinely TNFi-treated AS patients improved up to 6 months and stabilized thereafter. Therefore, it would be better to extend the period of evaluation of TNFi treatment to 6 months rather than the 3 months currently used. The risk factors of long-term physical functioning found in this study might help to identify patients at risk at an earlier stage and improve treatment strategy. © 2016, American College of Rheumatology.

  14. Persistence With Conventional Triple Therapy Versus a Tumor Necrosis Factor Inhibitor and Methotrexate in US Veterans With Rheumatoid Arthritis.

    PubMed

    Sauer, Brian C; Teng, Chia-Chen; Tang, Derek; Leng, Jianwei; Curtis, Jeffrey R; Mikuls, Ted R; Harrison, David J; Cannon, Grant W

    2017-03-01

    To compare persistence and adherence to triple therapy with the nonbiologic disease-modifying antirheumatic drugs (DMARDs) methotrexate (MTX), hydroxychloroquine, and sulfasalazine, versus a tumor necrosis factor inhibitor (TNFi) plus MTX in patients with rheumatoid arthritis (RA). Administrative and laboratory data were analyzed for US Veterans with RA initiating triple therapy or TNFi + MTX between January 2006 and December 2012. Treatment persistence 365 days postindex was calculated using 3 definitions. Definition 1 required no gap in therapy of ≥90 days for any drug in the original combination. Definition 2 required no added or switched DMARD, no decrease to nonbiologic DMARD monotherapy, and no termination of all DMARD therapies. Definition 3 was similar to definition 2 but allowed a switch to another drug within the same class. Adherence used a proportion of days covered of ≥80%. Propensity-weighted analysis with matched weights was used to balance covariates. The analysis included 4,364 RA patients (TNFi + MTX, n = 3,204; triple therapy, n = 1,160). In propensity-weighted analysis, patients in the TNFi + MTX group were significantly more likely than patients in the triple therapy group to satisfy all persistence criteria in definition 1 (risk difference [RD] 13.1% [95% confidence interval (95% CI) 9.2-17.0]), definition 2 (RD 6.4% [95% CI 2.3-10.5]), and definition 3 (RD 9.5% [95% CI 5.5-13.6]). Patients in the TNFi + MTX group also exhibited higher adherence during the first year (RD 7.2% [95% CI 3.8-10.5]). US Veterans with RA were significantly more likely to be persistent and adherent to combination therapy with TNFi + MTX than triple therapy with nonbiologic DMARDs. © 2016, American College of Rheumatology.

  15. Sarilumab improves patient-reported outcomes in rheumatoid arthritis patients with inadequate response/intolerance to tumour necrosis factor inhibitors

    PubMed Central

    Strand, Vibeke; Reaney, Matthew; Chen, Chieh-I; Proudfoot, Clare W J; Guillonneau, Sophie; Bauer, Deborah; Mangan, Erin; Graham, Neil M H; van Hoogstraten, Hubert; Lin, Yong; Pacheco-Tena, César; Fleischmann, Roy

    2017-01-01

    Objective To evaluate effects of the anti-interleukin-6 receptor monoclonal antibody sarilumab administered with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) on patient-reported outcomes (PROs) in the TARGET trial in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitors (TNF-IR). Methods 546 patients (81.9% female, mean age 52.9 years) were randomised to placebo, sarilumab 150 or 200 mg subcutaneously every 2 weeks + csDMARDs. PROs included patient global assessment (PtGA); pain and morning stiffness visual analogue scales; Health Assessment Questionnaire Disability Index (HAQ-DI); Short Form-36 Health Survey (SF-36); FACIT-Fatigue (FACIT-F); Work Productivity Survey-Rheumatoid Arthritis (WPS-RA) and Rheumatoid Arthritis Impact of Disease (RAID). Changes from baseline at weeks 12 and 24 were analysed using a mixed model for repeated measures; post hoc analyses included percentages of patients reporting improvements ≥ minimum clinically important differences (MCID) and scores ≥ normative values. Results Sarilumab + csDMARDs doses resulted in improvements from baseline at week 12 vs placebo + csDMARDs in PtGA, pain, HAQ-DI, SF-36 and FACIT-F that were maintained at week 24. Sarilumab improved morning stiffness and reduced the impact of RA on work, family, social/leisure activities participation (WPS-RA) and on patients' lives (RAID). Percentages of patients reporting improvements ≥MCID and ≥ normative scores were greater with sarilumab than placebo. Conclusions In patients with TNF-IR RA, 150 and 200 mg sarilumab + csDMARDs resulted in clinically meaningful patient-reported benefits on pain, fatigue, function, participation and health status at 12 and 24 weeks that exceeded placebo + csDMARDs, and were consistent with the clinical profile previously reported. Trial registration number NCT01709578; Results. PMID:28326189

  16. Treatment effectiveness and treatment patterns among rheumatoid arthritis patients after switching from a tumor necrosis factor inhibitor to another medication

    PubMed Central

    Bonafede, Machaon MK; Curtis, Jeffrey R; McMorrow, Donna; Mahajan, Puneet; Chen, Chieh-I

    2016-01-01

    Objectives After treatment failure with a tumor necrosis factor inhibitor (TNFi), patients with rheumatoid arthritis (RA) can switch to another TNFi (TNFi cyclers) or to a targeted disease-modifying antirheumatic drug (DMARD) with a non-TNFi mechanism of action (non-TNFi switchers). This study compared treatment patterns and treatment effectiveness between TNFi cyclers and non-TNFi switchers in patients with RA. Methods The analysis included a cohort of patients from the Truven Health Analytics MarketScan Commercial database with RA who switched from a TNFi (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) either to another TNFi or to a non-TNFi targeted DMARD (abatacept, tocilizumab, or tofacitinib) between January 1, 2010 and September 30, 2014. A claims-based algorithm was used to estimate treatment effectiveness based on six criteria (adherence, no dose increase, no new conventional therapy, no switch to another targeted DMARD, no new/increased oral glucocorticoid, and intra-articular injections on <2 days). Results The cohort included 5,020 TNFi cyclers and 1,925 non-TNFi switchers. Non-TNFi switchers were significantly less likely than TNFi cyclers to switch therapy again within 6 months (13.2% vs 19.5%; P<0.001) or within 12 months (29.7% vs 34.6%; P<0.001) and significantly more likely to be persistent on therapy at 12 months (61.8% vs 58.2%; P<0.001). Non-TNFi switchers were significantly more likely than TNFi cyclers to achieve all six of the claims-based effectiveness algorithm criteria for the 12 months after the initial switch (27% vs 24%; P=0.011). Conclusion Although the absolute differences were small, these results support switching to a non-TNFi targeted DMARD instead of TNFi cycling when patients with RA require another therapy after TNFi failure. PMID:27980429

  17. Psoriasis and palmoplantar pustulosis associated with tumor necrosis factorinhibitors: the Mayo Clinic experience, 1998 to 2010.

    PubMed

    Shmidt, Eugenia; Wetter, David A; Ferguson, Sara B; Pittelkow, Mark R

    2012-11-01

    Tumor necrosis factor (TNF)-α antagonists have been associated with the induction of de novo or worsening psoriasis. We sought to retrospectively examine the clinical characteristics and outcomes of patients with psoriasis associated with anti-TNF-α therapy. We performed a retrospective review of patients with new-onset or worsening psoriasis during TNF-α inhibitor therapy between 1998 and 2010. Of the 56 patients (mean age at psoriasis onset, 48.1 years), 41 (73%) were female. In all, 22 patients (39%) had Crohn's disease and 14 (25%) had rheumatoid arthritis. Thirty patients (54%) were treated with infliximab, 19 (34%) with adalimumab, and 7 (12%) with etanercept. New-onset or worsening psoriasis occurred after a mean treatment duration of 17.1 months. Plaque psoriasis (n = 27), palmoplantar pustulosis (n = 25), scalp psoriasis (n = 12), generalized pustular psoriasis (n = 7), erythrodermic psoriasis (n = 2), and inverse psoriasis (n = 2) were the cutaneous presentations. Among the 39 patients for whom full treatment response data were available, 33 (85%) had a complete or partial response; combined response rates (complete and partial) were slightly higher among those who discontinued anti-TNF-α therapy (16 of 17 patients [94%]) than among those who continued anti-TNF-α therapy (17 of 22 patients [77%]). Retrospective nature, possible referral bias, and lack of complete follow-up for some patients are limitations. Although some patients sufficiently controlled their psoriasis while continuing anti-TNF-α therapy, those who discontinued therapy achieved higher rates of complete response. Further studies should explore the efficacy and safety of switching to an alternative anti-TNF-α agent. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  18. Soluble tumor necrosis factor receptor 1 and tissue inhibitor of metalloproteinase-1 in hemolytic uremic syndrome with encephalopathy.

    PubMed

    Shiraishi, Masahiro; Ichiyama, Takashi; Matsushige, Takeshi; Iwaki, Takuma; Iyoda, Kuniaki; Fukuda, Ken; Makata, Haruyuki; Matsubara, Tomoyo; Furukawa, Susumu

    2008-05-30

    Enterohemorrhagic Escherichia coli (EHEC) induces hemorrhagic colitis and hemolytic uremic syndrome (HUS). Morbidity and mortality are increased in HUS patients with neurologic complications. To determine the pathogenesis of the central nervous system (CNS) involvement in HUS by EHEC, we determined the serum concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 (sTNFR1), IL-10, interferon-gamma (IFN-gamma), IL-2, IL-4, soluble E-selectin (sE-selectin), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) during the acute stage in children with HUS with or without CNS involvement. Serum concentrations of IL-6, IL-10, sTNFR1, sE-selectin, MMP-9, and TIMP-1, but not TNF-alpha, IFN-gamma, IL-2, or IL-4, were significantly higher in patients with HUS with encephalopathy compared with controls. Serum IL-6, sTNFR1 and TIMP-1 concentrations were significantly higher in patients with HUS with encephalopathy compared with those with HUS without encephalopathy (P=0.031, P=0.005, and P=0.007, respectively) and those with acute colitis without HUS (P=0.011, P<0.001, and P=0.005, respectively). There were no significant differences in hemoglobin, platelet counts, leukocyte counts, or serum concentrations of IL-10, sE-selectin, MMP-9, aspartate aminotransferase, lactate dehydrogenase, blood urea nitrogen, creatinine, or C-reactive protein between the HUS patients with and without encephalopathy. Our preliminary study suggests that serum IL-6, sTNFR1 and TIMP-1 levels, particularly sTNFR1 and TIMP-1, are important for predicting neurological complications in patients with HUS.

  19. 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.

  20. Reactive site mutations in tissue inhibitor of metalloproteinase-3 disrupt inhibition of matrix metalloproteinases but not tumor necrosis factor-alpha-converting enzyme.

    PubMed

    Wei, Shuo; Kashiwagi, Masahide; Kota, Smitha; Xie, Zhihong; Nagase, Hideaki; Brew, Keith

    2005-09-23

    Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a dual inhibitor of the matrix metalloproteinases (MMPs) and some adamalysins, two families of extracellular and cell surface metalloproteinases that function in extracellular matrix turnover and the shedding of cell surface proteins. The mechanism of inhibition of MMPs by TIMPs has been well characterized, and since the catalytic domains of MMPs and adamalysins are homologous, it was assumed that the interaction of TIMP-3 with adamalysins is closely similar. Here we report that the inhibition of the extracellular region of ADAM-17 (tumor necrosis factor alpha-converting enzyme (TACE)) by the inhibitory domain of TIMP-3 (N-TIMP-3) shows positive cooperativity. Also, mutations in the core of the MMP interaction surface of N-TIMP-3 dramatically reduce the binding affinity for MMPs but have little effect on the inhibitory activity for TACE. These results suggest that the mechanism of inhibition of ADAM-17 by TIMP-3 may be distinct from that for MMPs. The mutant proteins are also effective inhibitors of tumor necrosis factor alpha (TNF-alpha) release from phorbol ester-stimulated cells, indicating that they provide a lead for engineering TACE-specific inhibitors that may reduce side effects arising from MMP inhibition and are possibly useful for treatment of diseases associated with excessive TNF-alpha levels such as rheumatoid arthritis.

  1. Screening bicyclic peptide libraries for protein-protein interaction inhibitors: discovery of a tumor necrosis factor-α antagonist.

    PubMed

    Lian, Wenlong; Upadhyaya, Punit; Rhodes, Curran A; Liu, Yusen; Pei, Dehua

    2013-08-14

    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-α (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.

  2. 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

    2016-01-01

    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.

  3. The Rates of Serious Infections in HIV-infected Patients Who Received Tumor Necrosis Factor (TNF)-α Inhibitor Therapy for Concomitant Autoimmune Diseases

    PubMed Central

    Wangsiricharoen, Sintawat; Ligon, Colin; Gedmintas, Lydia; Dehrab, Admad; Tungsiripat, Marisa; Bingham, Clifton; Lozada, Carlos; Calabrese, Leonard

    2016-01-01

    Objectives To estimate the incidence of serious infections in patients with HIV infection and autoimmune disease who were treated with tumor necrosis factor (TNF) -α inhibitor therapy, and to compare these rates among stratified viral load levels. Methods Using a unified search strategy, four centers identified HIV-infected patients exposed to TNF-α inhibitors. Patient characteristics and infection data were assessed via chart review in all patients who were ≥18 years old and received TNF-α inhibitor therapy after HIV diagnosis between January 1999 and March 2015. Results Twenty-three patients with 26 uses of TNF-α inhibitor therapy provided 86.7 person-years of follow-up. Two (8.7%) experienced at least 1 serious infection episode, an overall incidence rate of 2.55 per 100 patient-years (95% CI 0.28–9.23). The incidence rate per 100 patient-years was 3.28 (95% CI 0.04–18.26) among patients with viral load > 500 copies/mL at therapy initiation and 2.09 (0.03–11.65) among patients with viral load ≤ 500 copies/mL. Conclusion This study suggests that TNF-α inhibitors may have a comparable rate of serious infections to the range of those observed in registry databases when used in patients with HIV infection under active care. PMID:27332039

  4. Comparison of tuberculosis incidence in ankylosing spondylitis and rheumatoid arthritis during tumor necrosis factor inhibitor treatment in an intermediate burden area.

    PubMed

    Kim, Hye Won; Park, Jin Kyun; Yang, Ji-Ae; Yoon, Young Im; Lee, Eun Young; Song, Yeong Wook; Kim, Hang Rae; Lee, Eun Bong

    2014-09-01

    Clinical characteristics of antitumor necrosis factor (TNF) agents-related tuberculosis (TB) in ankylosing spondylitis (AS) are not well described. The aim was to compare the incidences and the characteristics of TB in AS and rheumatoid arthritis (RA) during TNF inhibitor treatment. AS (n = 1,322) and RA (n = 3,154) patients who received medical care between January 2001 and August 2011 were enrolled. The incidence of TB in patients treated, or not, with TNF inhibitors and the clinical features associated with TB were explored. Seven patients with AS and seven with RA developed TB while receiving TNF inhibitor therapy, resulting in an incidence rate of 600.2/100,000 person-years (PYs) (95 % confidence interval (CI), 241.3-1236.3) for those with AS and 771.6/100,000 PYs (95 % CI, 310.2-1589.9) for those with RA. Incidence rate ratios for TNF inhibitor-treated vs. untreated patients were 4.87 for AS (95 % CI, 1.50-15.39; p < 0.001) and 3.61 for RA (95 % CI, 1.38-8.07; p < 0.001). Low body mass index was identified as a significant risk factor for TB in the AS group (odds ratio (OR), 13.0; p = 0.002). Extrapulmonary TB was predominant at 85.7 % during TNF inhibitor treatment. Three (42.8 %) of the AS patients, but none of the RA patients, developed TB with concomitant isoniazid. All AS patients recovered from TB whereas two of seven RA patients died. Treatment with TNF inhibitors significantly increases the risk of extrapulmonary TB in AS. Symptoms of infection should warrant clinicians to evaluate for TB during TNF inhibitor therapy in AS patients.

  5. Tumor Necrosis Factor Type α , a Potent Inhibitor of Endothelial Cell Growth in vitro, is Angiogenic in vivo

    NASA Astrophysics Data System (ADS)

    Frater-Schroder, Marijke; Risau, Werner; Hallmann, Rupert; Gautschi, Peter; Bohlen, Peter

    1987-08-01

    Tumor necrosis factor type α (TNF-α ) inhibits endothelial cell proliferation in vitro. Basal cell growth (in the absence of exogenously added growth factor) and fibroblast growth factor (FGF)-stimulated cell proliferation are inhibited in a dose-dependent manner from 0.1 to 10 ng/ml with half-maximal inhibition occurring at 0.5-1.0 ng of TNF-α per ml. Bovine aortic and brain capillary endothelial and smooth muscle cells are similarly affected. TNF-α is a noncompetitive antagonist of FGF-stimulated cell proliferation. Its action on endothelial cells is reversible and noncytotoxic. Surprisingly, TNF-α does not seem to inhibit endothelial cell proliferation in vivo. In the rabbit cornea, even a high dose of TNF-α (10 μ g) does not suppress angiogenesis induced by basic FGF. On the contrary, in this model system TNF-α stimulates neovascularization. The inflammatory response that is seen in the cornea after TNF-α implantation suggests that the angiogenic properties of this agent may be a consequence of leukocyte infiltration.

  6. Which factors influence radiographic progression during treatment with tumor necrosis factor inhibitors in clinical practice? Results from 930 patients with rheumatoid arthritis in the nationwide Danish DANBIO registry.

    PubMed

    Ørnbjerg, Lykke Midtbøll; Østergaard, Mikkel; Bøyesen, Pernille; Krogh, Niels Steen; Thormann, Anja; Tarp, Ulrik; Poulsen, Uta Engling; Espesen, Jakob; Schlemmer, Annette; Graudal, Niels; Kollerup, Gina; Jensen, Dorte Vendelbo; Madsen, Ole Rintek; Glintborg, Bente; Christensen, Torben; Lindegaard, Hanne; Bøhme, Wolfgang; Hansen, Annette; Andersen, Anne Rødgaard; Hetland, Merete Lund

    2014-12-01

    To investigate baseline characteristics associated with radiographic progression and the effect of disease activity, drug, switching, and withdrawal on radiographic progression in tumor necrosis factor (TNF) inhibitor-naive patients with rheumatoid arthritis (RA) followed for about 2 years after anti-TNF initiation in clinical practice. DANBIO-registered patients with RA who had available radiographs (anti-TNF initiation and ∼2 yrs followup) were included. Radiographs were scored, blinded to chronology with the Sharp/van der Heijde method and linked with DANBIO data. Baseline characteristics were investigated with univariate regression and significant variables included in a multivariable logistic regression analysis with ± radiographic progression [Δ total Sharp score (TSS) > 0] as dependent variable. Effect of time-averaged C-reactive protein (CRP), 28-joint Disease Activity Score with CRP (DAS28-CRP), and treatment status at followup were investigated with univariate regression analysis. The study included 930 patients. They were 75% women, 79% positive for IgM-rheumatoid factor (IgM-RF), median age was 57 yrs (range 19-88), disease duration 9 yrs (1-59), DAS28-CRP 5.0 (1.4-7.8), TSS median 15 [3-45 interquartile range (IQR)] and mean 31 (SD 40). Patients started treatment with infliximab (59%), etanercept (18%), or adalimumab (23%). At followup (median 526 days, IQR 392-735), 61% were treated with the initial anti-TNF, 29% had switched TNF inhibitor, and 10% had withdrawn. Twenty-seven percent of patients had progressed radiographically. ΔTSS was median 0.0 [0.0-0.5 IQR/mean 0.6 (SD 2.4)] units/year. Higher TSS, older age, positive IgM-RF, and concomitant prednisolone at baseline were associated with radiographic progression. Time-averaged DAS28-CRP and time-averaged CRP, but not type of TNF inhibitor, were associated with radiographic progression. Patients who stopped/switched during followup progressed more than patients who continued treatment. High TSS

  7. Safety of tumor necrosis factor inhibitors use for rheumatoid arthritis and ankylosing spondylitis in Africa, the Middle East, and Asia: focus on severe infections and tuberculosis.

    PubMed

    Hammoudeh, Mohammed; Alarfaj, Abdurhman; Chen, Der-Yuan; Djoudi, Hachemi; Youseif, Ehab; Zhu, Jian

    2013-03-01

    Multiple studies of patients in Western countries with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have indicated increased risk for active tuberculosis (TB) and other infections among these individuals. It has also been consistently reported that patients receiving tumor necrosis factor (TNF) inhibitors for these conditions have higher rates of active TB and other infections than RA or AS patients not receiving these medications. These issues have been studied less extensively in the Asia and Africa-Middle East regions, and information from these regions is important because of higher rates of TB in the general population. This paper reviews studies of RA and AS patients from Asia, Africa, and the Middle East who received TNF inhibitors. A literature search was conducted using http://www.ncbi.nlm.nih.gov/pubmed to collect and report these data. The years included in the PubMed literature search ranged from January 2000 to October 2011. Additionally, information from the China Hospital Knowledge Database was used to report data from Chinese patients with RA and AS treated with TNF inhibitors. Results from these studies indicate that the risk for active TB and other infections in AS and RA patients from Asia, Africa, and the Middle East are increased in patients receiving TNF inhibitors and that the risk is higher among those treated with monoclonal antibodies versus soluble TNF receptor.

  8. Periodontal therapy reduces the severity of active rheumatoid arthritis in patients treated with or without tumor necrosis factor inhibitors.

    PubMed

    Ortiz, P; Bissada, N F; Palomo, L; Han, Y W; Al-Zahrani, M S; Panneerselvam, A; Askari, A

    2009-04-01

    Rheumatoid arthritis (RA) and periodontitis are common chronic inflammatory conditions. Recent studies showed a beneficial effect of periodontal treatment on the severity of active RA. This study was undertaken to further examine the effect of non-surgical periodontal treatment on the signs and symptoms of RA in patients treated with or without anti-tumor necrosis factor-alpha (anti-TNF-alpha) medications. The effect of anti-TNF-alpha therapy on periodontitis also was assessed. Forty participants diagnosed with moderate/severe RA (under treatment for RA) and severe periodontitis were randomly assigned to receive initial non-surgical periodontal therapy with scaling/root planing and oral hygiene instructions (n = 20) or no periodontal therapy (n = 20). To control RA, all participants had been using disease-modifying anti-rheumatic drugs, and 20 had also been using anti-TNF-alpha before randomization. Probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), gingival index (GI), plaque index (PI), RA disease activity score 28 (DAS28), and erythrocyte sedimentation rate (ESR) were measured at baseline and 6 weeks later. Linear mixed models were used to identify significant differences between subjects who received periodontal treatment and those who did not. Patients receiving periodontal treatment showed a significant decrease in the mean DAS28, ESR (P <0.001), and serum TNF-alpha (P <0.05). There was no statistically significant decrease in these parameters in patients not receiving periodontal treatment. Anti-TNF-alpha therapy resulted in a significant improvement in CAL, PD, BOP, and GI. Non-surgical periodontal therapy had a beneficial effect on the signs and symptoms of RA, regardless of the medications used to treat this condition. Anti-TNF-alpha therapy without periodontal treatment had no significant effect on the periodontal condition.

  9. Periodontal Therapy Reduces the Severity of Active Rheumatoid Arthritis in Patients Treated With or Without Tumor Necrosis Factor Inhibitors

    PubMed Central

    Ortiz, P; Bissada, NF; Palomo, L; Han, YW; Al-Zahrani, MS; Panneerselvam, A; Askari, A

    2010-01-01

    Background Rheumatoid arthritis (RA) and periodontitis (PD) are common chronic inflammatory conditions. Recent studies have shown a beneficial effect of periodontal treatment on reducing the severity of active RA. This study was undertaken to further examine the effect of non-surgical periodontal treatment on signs and symptoms of RA in patients treated with or without anti-Tumor Necrosis Factor (TNF)-α medications. The effect of anti-TNF-α therapy on periodontitis also was assessed. Methods Forty participants diagnosed with moderate/severe RA (under treatment for RA) and severe periodontitis were randomly assigned to receive initial non-surgical periodontal therapy with scaling/root planing and oral hygiene instructions (n=20) or no periodontal therapy (n=20). To control RA, all participants had been using disease-modifying anti-rheumatic drugs (DMARDs), and 20 had been using anti-TNF-α in addition to DMARDs before randomization. Periodontal probing depth (PD), clinical attachment loss (CAL), bleeding on probing (BOP), gingival (GI) and plaque (PI) indices, RA disease activity score (DAS-28) and erythrocyte sedimentation rate (ESR) were measured at baseline and six weeks afterwards. Linear mixed models were used to identify significant differences between subjects receiving periodontal treatment and those who did not. Results Patients receiving periodontal treatment showed a significant decrease in the mean DAS28, ESR (p < 0.001) and serum TNF-α (p < 0.05). There was no statistically significant decrease in these parameters in those patients not receiving periodontal treatment. Anti- TNF-α therapy resulted in a significant improvement in CAL, PD, BOP and GI. Conclusions Non-surgical periodontal therapy had a beneficial effect on signs and symptoms of RA regardless of the medications used to treat this condition. Anti-TNF-α therapy without periodontal treatment has no significant effect on the periodontal condition. PMID:19335072

  10. Annual costs of tumor necrosis factor inhibitors using real-world data in a commercially insured population in the United States.

    PubMed

    Schabert, Vernon F; Watson, Crystal; Gandra, Shravanthi R; Goodman, Seth; Fox, Kathleen M; Harrison, David J

    2012-01-01

    To calculate annual cost per treated patient of tumor necrosis factor (TNF) inhibitors etanercept, adalimumab, and infliximab for common approved indications, based on actual TNF-inhibitor use in clinical practice. Adults with ≥1 claim for etanercept, adalimumab, or infliximab between January 2005 and March 2009 were identified from the IMS LifeLink™ Health Plan Claims Database. Patients new to therapy or continuing therapy (i.e., a prior claim for a TNF-inhibitor) were analyzed separately. Included patients had been enrolled from 180 days before the first TNF-inhibitor claim (index date) through 360 days after the index date and had a diagnosis during the pre-index period for rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis. Patients with Crohn's disease, ulcerative colitis, or juvenile idiopathic arthritis were excluded. Annual costs were calculated using wholesale acquisition costs for the TNF-inhibitor and Medicare Physician Fee Schedule for drug administration. Costs from restarting or switching TNF-inhibitor therapy during the first year were included. A total of 27,704 patients (11,528 new, 16,176 continuing) had claims for etanercept, adalimumab, or infliximab, most commonly (65%) for treatment of rheumatoid arthritis. The most commonly used agent was etanercept (14,777 patients; 53%), followed by adalimumab (6862 patients; 25%) and infliximab (6065 patients; 22%). Annual cost per treated patient was etanercept $14,873, adalimumab $17,766, and infliximab $21,256 across all indications. Annual cost per treated patient by disease was (etanercept/adalimumab/infliximab): rheumatoid arthritis ($14,314/$17,700/$20,390), psoriasis ($17,182/$17,682/$23,935), psoriatic arthritis ($15,030/$18,483/$24,974), and ankylosing spondylitis ($14,254/$16,925/$23,056). New and continuing patients showed similar results, with etanercept having the lowest costs. This analysis is limited to three TNF-inhibitors and a US managed-care population

  11. Evaluation of a novel subtilisin inhibitor gene and mutant derivatives for the expression and secretion of mouse tumor necrosis factor alpha by Streptomyces lividans.

    PubMed Central

    Lammertyn, E; Van Mellaert, L; Schacht, S; Dillen, C; Sablon, E; Van Broekhoven, A; Anné, J

    1997-01-01

    In order to evaluate the expression and secretion signals of the highly secreted subtilisin inhibitor of Streptomyces venezuelae CBS762.70 (VSI) for the production of heterologous proteins by Streptomyces lividans, mouse tumor necrosis factor alpha (mTNF) was chosen as a model protein. The mTNF cDNA was fused to the vsi signal sequence. The analysis of secretion by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and biological activity measurements revealed an efficient translocation of mTNF. Up to 300 mg of secreted biologically active mTNF per liter could be obtained in shaken-flask cultures. By analyzing the effects of mutations in the N region of the VSI signal peptide on secretion, we found that decreasing the +3 charge of the wild-type protein to +2 resulted in a 3- to 10-fold increase in secretion. PMID:9143114

  12. 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.

  13. 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

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

    2015-04-01

    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 (nonspecific 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.

  14. 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

  15. Home-based exercise therapy in ankylosing spondylitis: short-term prospective study in patients receiving tumor necrosis factor alpha inhibitors.

    PubMed

    Yigit, Semra; Sahin, Zerrin; Demir, Saliha Eroglu; Aytac, Deniz Hatun

    2013-01-01

    The importance of exercise and regular physiotherapy in patients with ankylosing spondylitis (AS) under treatment with tumor necrosis factor alpha inhibitors (TNFα inhibitors) was reported in some studies, but the literature on this topic is still scarce. The aim of this study was to assess the effects of home-based exercise therapy on functional capacity, disease activity, spinal mobility, quality of life, emotional state and fatigue in patients with AS receiving TNFα inhibitors. Forty-two AS patients were trained on the disease, and home-based exercise program was demonstrated to all the patients. At baseline and at the end of 10 week, we evaluated Bath AS Disease Activity Index, Bath AS Functional Index, Bath AS Metrology Index, Multidimensional Assessment of Fatigue Scale, Beck Depression Inventory and Short-Form 36. Patients following home-based exercise program five times a week at least 30 min per session (exercise group) were compared with those exercising less than five times a week (control group). At baseline, exercise and control group had similar demographic features. After 10 weeks, all outcome parameters showed statistically significant improvements in exercise group. There were significant differences in all the parameters except social functioning subscale of Short-Form 36 between groups in favor of exercise group at 10th week (P < 0.05). Home-based exercise program is an effective therapy in increasing functional capacity and joint mobility, decreasing disease activity, improving emotional state, fatigue and quality of life for AS patient receiving TNFα inhibitors. We need to find out new ways to provide continuity of AS patients with it.

  16. 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

  17. Non-length-dependent and length-dependent small-fiber neuropathies associated with tumor necrosis factor (TNF)-inhibitor therapy in patients with rheumatoid arthritis: expanding the spectrum of neurological disease associated with TNF-inhibitors.

    PubMed

    Birnbaum, Julius; Bingham, Clifton O

    2014-04-01

    Small-fiber neuropathy causes severe burning pain, requires diagnostic approaches such as skin biopsy, and encompasses two subtypes based on distribution of neuropathic pain. Such biopsy-proven subtypes of small-fiber neuropathies have not been previously described as complications of tumor necrosis factor (TNF)-inhibitor therapy. We therefore characterized clinical and skin biopsy findings in three rheumatoid arthritis (RA) patients who developed small-fiber neuropathies associated with TNF-inhibitors. We also conducted a systematic review of the literature to characterize subtypes of neuropathies previously reported in association with TNF-inhibitor therapy. Two patients presented with a "non-length-dependent" small-fiber neuropathy, experiencing unorthodox patterns of burning pain affecting the face, torso, and proximal extremities. Abnormal skin biopsy findings were limited to the proximal thigh, which is a marker of proximal-most dorsal root ganglia degeneration. In contrast, one patient presented with a "length-dependent" small-fiber neuropathy, experiencing burning pain only in the feet. Abnormal skin biopsy findings were limited to the distal feet, which is a marker of distal-most axonal degeneration. One patient developed a small-fiber neuropathy in the context of TNF-inhibitor-induced lupus. In all patients, neuropathies occurred during TNF-inhibitor-induced remission of RA disease activity and improved on withdrawal of TNF-inhibitors. We describe a spectrum of small-fiber neuropathies not previously reported in association with TNF-inhibitor therapy, with clinical and skin biopsy findings suggestive of dorsal root ganglia as well as axonal degeneration. The development of small-fiber neuropathies during inactive joint disease and improvement of neuropathic pain upon withdrawal of TNF-inhibitor suggest a causative role of TNF-inhibitors. © 2013 Published by Elsevier Inc.

  18. Non-length-dependent and length-dependent small-fiber neuropathies associated with tumor necrosis factor (TNF)-inhibitor therapy in patients with rheumatoid arthritis: Expanding the spectrum of neurological disease associated with TNF-inhibitors

    PubMed Central

    Birnbaum, Julius; Bingham, Clifton O.

    2015-01-01

    Objective Small-fiber neuropathy causes severe burning pain, requires diagnostic approaches such as skin biopsy, and encompasses two subtypes based on distribution of neuropathic pain. Such biopsy-proven subtypes of small-fiber neuropathies have not been previously described as complications of tumor necrosis factor (TNF)-inhibitor therapy. Methods We therefore characterized clinical and skin biopsy findings in three rheumatoid arthritis (RA) patients who developed small-fiber neuropathies associated with TNF-inhibitors. We also conducted a systematic review of the literature to characterize subtypes of neuropathies previously reported in association with TNF-inhibitor therapy. Results Two patients presented with a “non-length-dependent” small-fiber neuropathy, experiencing unorthodox patterns of burning pain affecting the face, torso, and proximal extremities. Abnormal skin biopsy findings were limited to the proximal thigh, which is a marker of proximal-most dorsal root ganglia degeneration. In contrast, one patient presented with a “length-dependent” small-fiber neuropathy, experiencing burning pain only in the feet. Abnormal skin biopsy findings were limited to the distal feet, which is a marker of distal-most axonal degeneration. One patient developed a small-fiber neuropathy in the context of TNF-inhibitor-induced lupus. In all patients, neuropathies occurred during TNF-inhibitor-induced remission of RA disease activity and improved on withdrawal of TNF-inhibitors. Conclusions We describe a spectrum of small-fiber neuropathies not previously reported in association with TNF-inhibitor therapy, with clinical and skin biopsy findings suggestive of dorsal root ganglia as well as axonal degeneration. The development of small-fiber neuropathies during inactive joint disease and improvement of neuropathic pain upon withdrawal of TNF-inhibitor suggest a causative role of TNF-inhibitors. PMID:24439654

  19. Immunomodulatory therapy with tumour necrosis factor α inhibitors in children with antinuclear antibody-associated chronic anterior uveitis: long-term results.

    PubMed

    Doycheva, Deshka; Zierhut, Manfred; Blumenstock, Gunnar; Stuebiger, Nicole; Januschowski, Kai; Voykov, Bogomil; Deuter, Christoph

    2014-04-01

    The aim of the study was to assess the long-term efficacy and tolerability of tumour necrosis factor α (TNFα) inhibitors in the therapy of children with refractory antinuclear antibody (ANA)-associated chronic anterior uveitis. Retrospective analysis of 31 children with ANA-associated uveitis, treated with TNFα inhibitors with a follow-up period of at least 2 years. The outcome measures included: control of inflammation, corticosteroid-sparing potential and side effects. Twenty-three children (74%) were treated with adalimumab, five children (16%) with infliximab and three children (10%) with etanercept. Control of uveitis, defined as 0 anterior chamber cells while on ≤2 drops/day topical corticosteroids, was achieved in 22 of 31 patients (71%) after 1 year (95% CI 52% to 86%), and in 21 of 29 patients (72%) after 2 years of treatment (95% CI 53% to 87%). Control of uveitis was observed in 18 of 23 children (78%) treated with adalimumab, and in two of five children (40%) treated with infliximab. In all children treated with etanercept, no sufficient inflammatory control was found. Systemic corticosteroids could be discontinued in 71% (12/17 children) and topical corticosteroids in 55% (17/31) of the patients. Treatment-related side effects were found in nine children (29%, rate: 0.10/patient-year). Our data show that adalimumab and infliximab have beneficial effects in the therapy of severe ANA-associated anterior uveitis in children.

  20. 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

  1. Bcl-2 inhibitors sensitize tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by uncoupling of mitochondrial respiration in human leukemic CEM cells.

    PubMed

    Hao, Ji-Hui; Yu, Ming; Liu, Feng-Ting; Newland, Adrian C; Jia, Li

    2004-05-15

    Previous studies have shown that the lymphoblastic leukemia CEM cell line is resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis because of a low expression of caspase-8. Bcl-2 inhibitors, BH3I-2' and HA14-1, are small cell-permeable nonpeptide compounds, are able to induce apoptosis by mediating cytochrome c release, and also lead to dissipation of the mitochondrial membrane potential (DeltaPsim). This study aimed to use the Bcl-2 inhibitors to sensitize CEM cells to TRAIL-induced apoptosis by switching on the mitochondrial apoptotic pathway. We found that a low dose of BH3I-2' or HA14-1, which did not induce cytochrome c release, greatly sensitized CEM cells to TRAIL-induced apoptosis. In a similar manner to the classical uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), both BH3I-2' and HA14-1 induced a reduction in DeltaPsim, a generation of reactive oxygen species (ROS), an increased mitochondrial respiration, and a decreased ATP synthesis. This uncoupling function of the Bcl-2 inhibitors was responsible for the synergy with TRAIL-induced apoptosis. CCCP per se did not induce apoptosis but again sensitized CEM cells to TRAIL-induced apoptosis by uncoupling mitochondrial respiration. The uncoupling effect facilitated TRAIL-induced Bax conformational change and cytochrome c release from mitochondria. Inhibition of caspases failed to block TRAIL-mediated cell death when mitochondrial respiration was uncoupled. We observed that BH3I-2', HA14-1, or CCCP can overcome resistance to TRAIL-induced apoptosis in TRAIL-resistant cell lines, such as CEM, HL-60, and U937. Our results suggest that the uncoupling of mitochondrial respiration can sensitize leukemic cells to TRAIL-induced apoptosis. However, caspase activation per se does not represent an irreversible point of commitment to TRAIL-induced cell death when mitochondrial respiration is uncoupled.

  2. 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.

  3. Effects of tumor necrosis factorinhibitors in mothers and daughters concordant for HLA-B27-positive ankylosing spondylitis.

    PubMed

    Caso, Francesco; Costa, Luisa; Del Puente, Antonio; Rigante, Donato; Selmi, Carlo; Fabbroni, Marta; Scarpa, Raffaele; Galeazzi, Mauro; Frediani, Bruno; Cantarini, Luca

    2015-01-01

    Pharmacogenomics is considered as the new frontier to predict the response to treatments and it can also be based on the comparison of family members being treated for the same condition. No data are available on the impact of anti-tumour necrosis factor (TNF)-α therapies in members of the same family with ankylosing spondylitis (AS). We describe three mother-daughter couples concordant for AS and HLA-B27, both treated with TNF-α inhibitors, for whom the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP were evaluated during a follow-up of 24 months. All patients manifested improvements of all scores, but the daughters had a more prominent effect achieving faster complete disease remission. We hypothesise that longer standing chronic inflammation and older age may cause a less prompt and effective response to treatment in SA when compared with their genetically related controls.

  4. Peripheral administration of the selective inhibitor of soluble Tumor Necrosis Factor (TNF) XPro®1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats

    PubMed Central

    Barnum, Christopher J.; Chen, Xi; Chung, Jaegwon; Chang, Jianjun; Williams, Martha; Grigoryan, Nelly; Tesi, Raymond J.; Tansey, Malú G.

    2014-01-01

    BACKGROUND Parkinson's disease (PD) is a complex multi-system age-related neurodegenerative disorder. Targeting the ongoing neuroinflammation in PD patients is one strategy postulated to slow down or halt disease progression. Proof-of-concept studies from our group demonstrated that selective inhibition of soluble Tumor Necrosis Factor (solTNF) by intranigral delivery of dominant negative TNF (DN-TNF) inhibitors reduced neuroinflammation and nigral dopamine (DA) neuron loss in endotoxin and neurotoxin rat models of nigral degeneration. OBJECTIVE As a next step toward human clinical trials, we aimed to determine the extent to which peripherally administered DN-TNF inhibitor XPro®1595 could: i) cross the blood-brain-barrier in therapeutically relevant concentrations, ii) attenuate neuroinflammation (microglia and astrocyte), and iii) mitigate loss of nigral DA neurons in rats receiving a unilateral 6-hydroxydopamine (6-OHDA) striatal lesion. METHODS Rats received unilateral 6-OHDA (20 μg into the right striatum). Three or 14 days after lesion, rats were dosed with XPro®1595 (10 mg/kg in saline, subcutaneous) every third day for 35 days. Forelimb asymmetry was used to assess motor deficits after the lesion; brains were harvested 35 days after the lesion for analysis of XPro®1595 levels, glial activation, and nigral DA neuron number. RESULTS Peripheral subcutaneous dosing of XPro®1595 achieved plasma levels of 1–8 μg/mL and CSF levels of 1–6 ng/mL depending on the time the rats were killed after final XPro®1595 injection. Irrespective of start date, XPro®1595 significantly reduced microglia and astrocyte number in SNpc whereas loss of nigral DA neurons was attenuated when drug was started 3, but not 14 days after the 6-OHDA lesion. CONCLUSIONS Our data suggest that systemically administered XPro®1595 may have disease-modifying potential in PD patients where inflammation is part of their pathology. PMID:25061061

  5. Comparison of the clinical effectiveness of tumour necrosis factor inhibitors and abatacept after insufficient response to tocilizumab in patients with rheumatoid arthritis.

    PubMed

    Akiyama, Mitsuhiro; Kaneko, Yuko; Kondo, Harumi; Takeuchi, Tsutomu

    2016-11-01

    The aim of this study is to compare the clinical effectiveness of tumour necrosis factor inhibitors (TNFi) and abatacept (ABT) after insufficient response to tocilizumab (TCZ) in patients with rheumatoid arthritis (RA). Among 527 RA patients treated with TCZ, 63 patients were enrolled who switched TCZ to alternative biologic agents because of moderate or high disease activity assessed by the Clinical Disease Activity Index (CDAI). They were divided into two groups, TNF inhibitors (TNFi) or abatacept (ABT), and compared for clinical effectiveness and adverse events at week 24. Forty-two were switched to TNFi, and 21 to ABT. TNFi included 19 infliximab, 3 adalimumab, 8 etanercept, 9 golimumab, and 3 certolizumab-pegol. Baseline characteristics at the switch were comparable except for the concomitant methotrexate use (TNFi 71.4 vs ABT 28.6 %, P = 0.003). The proportion of patients achieving CDAI ≤ 10 (remission or low disease activity) at week 24 was significantly higher in TNFi than ABT (64.3 vs 23.8 %, P = 0.003), and the values of the CDAI at week 24 was significantly better in TNFi than ABT (mean, 11.8 vs 16.4, P = 0.021) although the drug retention rate was not different between the two groups (73.8 vs 71.4 %, P = 0.803). No serious adverse event was observed in both groups. TNFi may be more effective than ABT to achieve clinical remission or low disease activity after insufficient response to TCZ in patients with RA, although drug retention rate and safety are comparable.

  6. Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis-a proof of principle and exploratory trial: is dose tapering practical in good responders?

    PubMed

    Ibrahim, Fowzia; Lorente-Cánovas, Beatriz; Doré, Caroline J; Bosworth, Ailsa; Ma, Margaret H; Galloway, James B; Cope, Andrew P; Pande, Ira; Walker, David; Scott, David L

    2017-08-17

    RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response. We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0-6) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6-12) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares (DAS28 increasing ⩾0.6 with at least one additional swollen joint) were the primary outcome. Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0-6 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls (adjusted hazard ratio 2.81, 95% CI: 0.99, 7.94; P = 0.051). Analysing all tapered patients after controls were re-randomized (months 6-12) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare (adjusted hazard ratio 3.47, 95% CI: 1.26, 9.58; P = 0.016). Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states. EudraCT, https://www.clinicaltrialsregister.eu , 2010-020738-24; ISRCTN registry, https://www.isrctn.com , 28955701.

  7. Characteristics Predicting Tuberculosis Risk under Tumor Necrosis FactorInhibitors: Report from a Large Multicenter Cohort with High Background Prevalence.

    PubMed

    Kisacik, Bunyamin; Pamuk, Omer Nuri; Onat, Ahmet Mesut; Erer, Sait Burak; Hatemi, Gulen; Ozguler, Yesim; Pehlivan, Yavuz; Kilic, Levent; Ertenli, Ihsan; Can, Meryem; Direskeneli, Haner; Keser, Gökhan; Oksel, Fahrettin; Dalkilic, Ediz; Yilmaz, Sedat; Pay, Salih; Balkarli, Ayse; Cobankara, Veli; Cetin, Gözde Yildirim; Sayarlioglu, Mehmet; Cefle, Ayse; Yazici, Ayten; Avci, Ali Berkant; Terzioglu, Ender; Ozbek, Suleyman; Akar, Servet; Gul, Ahmet

    2016-03-01

    Screening strategies for latent tuberculosis (TB) before starting tumor necrosis factor (TNF)-α inhibitors have decreased the prevalence of TB among patients who are treated with these agents. However, despite vigilant screening, TB continues to be an important problem, especially in parts of the world with a high background TB prevalence. The aim of this study was to determine the factors related to TB among a large multicenter cohort of patients who were treated with anti-TNF. Fifteen rheumatology centers participated in this study. Among the 10,434 patients who were treated with anti-TNF between September 2002 and September 2012, 73 (0.69%) had developed TB. We described the demographic features and disease characteristics of these 73 patients and compared them to 7695 patients who were treated with anti-TNF, did not develop TB, and had complete data available. Among the 73 patients diagnosed with TB (39 men, 34 women, mean age 43.6 ± 13 yrs), the most frequent diagnoses were ankylosing spondylitis (n = 38) and rheumatoid arthritis (n = 25). More than half of the patients had extrapulmonary TB (39/73, 53%). Six patients died (8.2%). In the logistic regression model, types of anti-TNF drugs [infliximab (IFX), OR 3.4, 95% CI 1.88-6.10, p = 0.001] and insufficient and irregular isoniazid use (< 9 mos; OR 3.15, 95% CI 1.43-6.9, p = 0.004) were independent predictors of TB development. Our results suggest that TB is an important complication of anti-TNF therapies in Turkey. TB chemoprophylaxis less than 9 months and the use of IFX therapy were independent risk factors for TB development.

  8. Management of perioperative tumour necrosis factor α inhibitors in rheumatoid arthritis patients undergoing arthroplasty: a systematic review and meta-analysis

    PubMed Central

    Menon, Indu; Christos, Paul J.; Smethurst, Rie; Bykerk, Vivian P.

    2016-01-01

    Objective. Tumour necrosis factor α inhibitors (TNFis) are widely used in RA patients who undergo surgery, and optimal perioperative management must balance the risk of infection with the risk of post-operative flare. The purpose of this study is to examine the impact of TNFi exposure on surgical site infections (SSIs) in RA patients undergoing elective orthopaedic surgery by systematic review and meta-analysis. Methods. A systematic review of the literature and meta-analysis were performed using PUBMED, EMBASE and the Cochrane Central Register of Controlled Trials, through May 2014. Two independent reviewers screened titles and abstracts, and analysed selected papers in detail. Included studies assessed RA patients with or without TNFi exposure prior to orthopaedic surgery, and described post-operative infections. Study quality was assessed using the Oxford Centre for Evidence-based Medicine Levels of Evidence. Meta-analyses of the individual study odds ratios (ORs) were conducted, and each pooled OR was calculated using a random effects model. Results. Eight observational studies and three case control studies met inclusion criteria; risk of bias was low in eight studies and moderate in three. Publication bias was not apparent. These studies represent 3681 patients with recent exposure to TNFis (TNFi+) and 4310 with no recent exposure to TNFis (TNFi−) at the time of surgery. The TNFi+ group had higher risk of developing SSI compared with patients in the TNFi− group (random effects model: OR 2.47 (95% CI 1.66, 3.68); P < 0.0001). Conclusion. Data from the available literature suggest that there is an increased risk of SSIs in RA patients who use or have recently used TNFis at the time of elective orthopaedic surgery. Prospective studies to confirm these findings and establish the optimal withhold and restart time of TNFis, in the context of other risk factors for infection in RA patients such as higher disease activity, corticosteroid use, smoking and

  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. Tip-Loaded Dissolvable Microneedle Arrays Effectively Deliver Polymer-Conjugated Antibody Inhibitors of Tumor-Necrosis-Factor-Alpha Into Human Skin.

    PubMed

    Korkmaz, Emrullah; Friedrich, Emily E; Ramadan, Mohamed H; Erdos, Geza; Mathers, Alicia R; Ozdoganlar, O Burak; Washburn, Newell R; Falo, Louis D

    2016-11-01

    Autoinflammatory skin diseases are characterized by a disequilibrium of cytokines in the local skin microenvironment, suggesting that local delivery of therapeutics, including anticytokine antibodies, may provide benefit without the unwanted off-target effects of systemically delivered therapies. Rapid diffusion of therapeutics away from the target site has been a challenge to the development of local therapies. Conjugation of high molecular weight hydrophilic polymers to cytokine neutralizing mAbs has been shown to be an effective strategy for local control of inflammation in healing burn wounds. However, the burn application is unique because the skin barrier is already breached. For the treatment of autoinflammatory skin diseases, the major challenge for local delivery lies in penetrating the stratum corneum. Here, we investigate a new therapeutic approach combining the use of tip-loaded dissolvable microneedle arrays (TL-dMNAs) for local application of polymer-conjugated antibody inhibitors of tumor-necrosis-factor-alpha (TNF-α). Specifically, intradermal delivery and pharmacokinetics of (anti-TNF-α-Ab)-(high molecular weight hyaluronic acid [HA]) conjugates from tip-loaded, obelisk-shaped dissolvable microneedle arrays were investigated in living human skin. The results indicate (1) TL-dMNAs can be successfully fabricated to integrate (anti-TNF-α-Ab)-HA at the tip portion of the microneedles while preserving the biological activity necessary for antibody ligand binding; (2) (anti-TNF-α-Ab)-HA can be effectively delivered into human skin using obelisk-shaped TL-dMNAs; and (3) polymer conjugation effectively inhibits antibody diffusion from the delivery site. Taken together, these results support the evaluation of microneedle array-based delivery of varying polymer-antibody conjugates for the treatment of inflammatory skin diseases.

  11. Top-down Versus Step-up Prescribing Strategies for Tumor Necrosis Factor Alpha Inhibitors in Children and Young Adults with Inflammatory Bowel Disease.

    PubMed

    Lee, Wan-Ju; Briars, Leslie; Lee, Todd A; Calip, Gregory S; Suda, Katie J; Schumock, Glen T

    2016-10-01

    Early initiation of tumor necrosis factor-alpha inhibitor (TNFI) therapy for children and young adults with inflammatory bowel disease (IBD) is not well described. We conducted a retrospective cohort study of children and young adults (≤24 yr) newly diagnosed with IBD using health insurance claims from 2009 to 2013. The conventional "step-up" approach was defined as TNFI initiation >30 days after first IBD medication prescription, whereas the "top-down" approach was defined as new TNFI prescription within 30 days of first IBD medication prescription. Switching rates, time to initiation, discontinuation, and adherence to TNFIs were compared between the 2 strategies. A total of 11,962 IBD patients were identified. Among 3300 TNFI users, 1298 (39.3%) were treated with the top-down approach, whereas 2002 (60.7%) were treated with the step-up approach. Top-down approach use increased from 31.4% to 49.8% during the 5-year period, and under this approach, most patients were treated with TNFIs alone. Time to TNFI initiation was shorter for patients diagnosed in more recent years. Patients treated with the top-down strategy had lower rates of corticosteroid use (32.5% versus 94.2%) compared with step-up treatment but presented a higher rate of TNFI discontinuation. The 2 strategies both exhibited high adherence (mean proportion of days covered: 83.7%-95.4%). Early TNFI initiation increased over time for children and young adults with IBD and was related to lower rates of corticosteroid use compared with the conventional approach. However, the higher rate of TNFI discontinuation under the top-down approach requires further examination.

  12. Tumor necrosis factorinhibitor treatment and the risk of incident cardiovascular events in patients with early rheumatoid arthritis: a nested case-control study.

    PubMed

    Desai, Rishi J; Rao, Jaya K; Hansen, Richard A; Fang, Gang; Maciejewski, Matthew; Farley, Joel

    2014-11-01

    To compare the risk of cardiovascular (CV) events between use of tumor necrosis factorinhibitors (TNFi) and nonbiologic disease-modifying antirheumatic drugs (DMARD) in patients with early rheumatoid arthritis (RA). A nested case-control study was conducted using data from Truven's MarketScan commercial and Medicare claims database for patients with early RA who started treatment with either a TNFi or a nonbiologic DMARD between January 1, 2008, and December 31, 2010. Date of CV event diagnosis for cases was defined as the event date, and 12 age-matched and sex-matched controls were sampled using incidence density sampling. Drug exposure was defined into the following mutually exclusive categories hierarchically: (1) current use of TNFi (with or without nonbiologics), (2) past use of TNFi (with or without nonbiologics), (3) current use of nonbiologics only, and (4) past use of nonbiologics only. Current use was defined as any use in the period 90 days prior to the event date. Conditional logistic regression models were used to derive incidence rate ratios (IRR). From the cohort of patients with early RA, 279 cases of incident CV events and 3348 matched controls were identified. The adjusted risk of CV events was not significantly different between current TNFi users and current nonbiologic users (IRR 0.92, 95% CI 0.59-1.44). However, past users of nonbiologics showed significantly higher risk compared to current nonbiologic users (IRR 1.47, 95% CI 1.04-2.08). No differences in the CV risk were found between current TNFi and current nonbiologic DMARD treatment in patients with early RA.

  13. Twelve-Year Retention Rate of First-Line Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis: Real-Life Data From a Local Registry.

    PubMed

    Favalli, Ennio Giulio; Pregnolato, Francesca; Biggioggero, Martina; Becciolini, Andrea; Penatti, Alessandra Emiliana; Marchesoni, Antonio; Meroni, Pier Luigi

    2016-04-01

    To evaluate the 12-year survival of the first tumor necrosis factor inhibitor (TNFi) treatment in a cohort of rheumatoid arthritis (RA) patients, comparing the between-groups discontinuation rates for infliximab, etanercept, and adalimumab. RA patients treated with their first TNFi were investigated from a local registry. Before and after adjusting for propensity scores, overall and by individual TNFi 12-year drug retention was evaluated. Drug survival rates were calculated using the Kaplan-Meier method and compared by the Cox extended model. Subanalyses were performed according to concomitant methotrexate (MTX) and discontinuation reasons. Of 583 patients, 222 were treated with infliximab, 179 with etanercept, and 182 with adalimumab; 33.7% and 26% discontinued the first TNFi because of inefficacy or adverse events, respectively. The overall 12-year drug survival rate for the unmatched population was 23.4%. In the propensity score-adjusted population, the hazard ratio (HR) for treatment discontinuation was significantly greater for adalimumab and infliximab versus etanercept (HR 2.89 [95% confidence interval (95% CI) 2.2-3.78] and HR 2.56 [95% CI 1.92-3.4], respectively), and no difference was found between and for adalimumab versus infliximab (HR 1.16 [95% CI 0.91-1.47]). The incidence of withdrawal due to secondary inefficacy was stable from 3 to 12 years for etanercept, but progressively increased for the monoclonal antibodies. Concomitant MTX significantly increased the survival of both adalimumab and etanercept (HR 1.48 [95% CI 1.18-1.86]). The overall 12-year drug survival rate was 23.4%, being significantly higher for etanercept than adalimumab and infliximab. Etanercept discontinuations for inefficacy did not increase from 3 to 12 years. Concomitant MTX increased adalimumab and etanercept drug survival. © 2016, American College of Rheumatology.

  14. 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

  15. 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

    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; Kim, Yong-Gil

    2016-01-01

    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. 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. 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). Instances of tuberculosis were treated successfully in our AS patients, even when given concomitantly with TNF inhibitors. We suggest that early resumption of TNF inhibitors in AS patients

  16. Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis.

    PubMed

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

    2017-04-01

    Patients with rheumatoid arthritis (RA) are at increased risk of myocardial infarction (MI) compared with subjects without RA, with the increased risk driven potentially by inflammation. Tumour necrosis factor inhibitors (TNFi) may modulate the risk and severity of MI. We compared the risk and severity of MI in patients treated with TNFi with that in those receiving synthetic disease-modifying antirheumatic drugs (sDMARDs). This analysis included patients with RA recruited from 2001 to 2009 to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis starting TNFi (etanercept/infliximab/adalimumab) and a biologic-naïve comparator cohort receiving sDMARD. All patients were followed via physician and patient questionnaires and national death register linkage. Additionally, all patients were linked to the Myocardial Ischaemia National Audit Project, a national registry of hospitalisations for MI. Patients were censored at first verified MI, death, 90 days following TNFi discontinuation, last physician follow-up or 20 April 2010, whichever came first. The risk of first MI was compared between cohorts using COX regression, adjusted with propensity score deciles (PD). MI phenotype and severity were compared using descriptive statistics. 6-month mortality post MI was compared using logistic regression. 252 verified first MIs were analysed: 58 in 3058 patients receiving sDMARD and 194 in 11 200 patients receiving TNFi (median follow-up per person 3.5 years and 5.3 years, respectively). The PD-adjusted HR of MI in TNFi referent to sDMARD was 0.61 (95% CI 0.41 to 0.89). No statistically significant differences in MI severity or mortality were observed between treatment groups. Patients with RA receiving TNFi had a decreased risk of MI compared with patients with RA receiving sDMARD therapy over the medium term. This might be attributed to a direct action of TNFi on the atherosclerotic process or better overall disease control. Published by the

  17. A Phase IIb Study of ABT‐494, a Selective JAK‐1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–Tumor Necrosis Factor Therapy

    PubMed Central

    Emery, Paul; Camp, Heidi S.; Friedman, Alan; Wang, Li; Othman, Ahmed A.; Khan, Nasser; Pangan, Aileen L.; Jungerwirth, Steven; Keystone, Edward C.

    2016-01-01

    Objective To compare the efficacy and safety of ABT‐494, a novel selective JAK‐1 inhibitor, with placebo in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti–tumor necrosis factor (anti‐TNF) agent. Methods In this 12‐week, double‐blind, placebo‐controlled, dose‐ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti‐TNF agent were randomized equally to receive immediate‐release ABT‐494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12. Results At week 12, significantly more patients receiving ABT‐494 (53–71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose‐response relationship among all ABT‐494 doses (P < 0.001). ACR50 and ACR70 response rates were significantly higher in those receiving ABT‐494 (36–42% and 22–26%, respectively) than in those receiving placebo (16% and 4%, respectively). Changes from baseline in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) were significantly greater for all doses of ABT‐494 than for placebo (P ≤ 0.01). Onset of action of ABT‐494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28‐CRP (P < 0.001 for 6–18 mg). The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection. Infection rates were higher at higher doses of ABT‐494, but no infections were serious. No deaths were reported among those receiving ABT‐494. Conclusion In patients with an inadequate response or

  18. From the Medical Board of the National Psoriasis Foundation: Recommendations for screening for hepatitis B infection prior to initiating anti-tumor necrosis factor-alfa inhibitors or other immunosuppressive agents in patients with psoriasis.

    PubMed

    Motaparthi, Kiran; Stanisic, Vladimir; Van Voorhees, Abby S; Lebwohl, Mark G; Hsu, Sylvia

    2014-01-01

    No consensus exists regarding the optimal laboratory screening for hepatitis B infection that should be performed before initiating therapy with tumor necrosis factor-alfa inhibitors or other immunosuppressive agents. We sought to give guidelines on which tests to order for hepatitis B screening. We review the pathophysiology and serology of hepatitis B infection and provide recommendations for screening for hepatitis B infection in patients with psoriasis before beginning anti-tumor necrosis factor-alfa therapy or other immunosuppressive agents. We propose the standardized use of triple serology testing: hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody in combination with liver function tests as screening. Conclusions based on review of available literature is a limitation. All patients with psoriasis who are candidates for tumor necrosis factor-alfa inhibitor should undergo screening for hepatitis B virus infection using the triple serology: hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody. It is advisable that patients, who are candidates for ustekinumab, cyclosporine, or methotrexate undergo the same screening. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  19. 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

  20. Safe re-administration of tumor necrosis factor-alpha (TNFα) inhibitors in patients with rheumatoid arthritis or ankylosing spondylitis who developed active tuberculosis on previous anti-TNFα therapy.

    PubMed

    Suh, Young Sun; Kwok, Seung-Ki; Ju, Ji Hyeon; Park, Kyung-Su; Park, Sung-Hwan; Yoon, Chong-Hyeon

    2014-01-01

    There is no consensus on whether it is safe to re-administer tumor necrosis factor-alpha (TNFα) inhibitors in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) flared after withdrawal of TNFα inhibitors due to active tuberculosis (TB). We evaluated the safety of restarting anti-TNFα therapy in patients with TNFα-associated TB. We used data of 1,012 patients with RA or AS treated with TNFα inhibitors at Seoul St. Mary's Hospital between January 2003 and July 2013 to identify patients who developed active TB. Demographic and clinical data including the results of tuberculin skin tests (TST) and interferon-γ releasing assays (IGRA) were collected. Fifteen patients developed active TB. Five cases were occurred in RA and 10 cases in AS. Nine of 15 patients had a negative TST or IGRA and 6 TST-positive patients had received prophylaxis prior to initiating anti-TNFα therapy. All patients discontinued TNFα inhibitors with starting the treatment of TB. Eight patients were re-administered TNFα inhibitors due to disease flares and promptly improved without recurrence of TB. TNFα inhibitors could be safely resumed after starting anti-TB regimen in patients with RA or AS.

  1. Raf Kinase Inhibitor Protein (RKIP) Inhibits Tumor Necrosis Factor-α (TNF-α) Induced Adhesion Molecules Expression in Vascular Smooth Muscle Bells by Suppressing (Nuclear Transcription Factor-κB (NF-kappaB) Pathway.

    PubMed

    Jing, Shen-Hong; Gao, Xuan; Yu, Bo; Qiao, Hong

    2017-10-06

    BACKGROUND Raf kinase inhibitor protein (RKIP) regulates growth and differentiation and plays a role in key signal transduction cascades in mammalian cells. Nevertheless, the underlying mechanism for which RKIP regulates cell-cell adhesion remains unknown. Our study investigated the function of the RKIP overexpression on adhesion molecules expression induced by tumor necrosis factor (TNF)-α in cultured mouse vascular smooth muscle cells (MOVACs). MATERIAL AND METHODS The expression levels of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were detected by ELISA kit, reverse transcription-PCR, and western blot assays. The protein expression of RKIP, p65, and inhibitor of nuclear factor (NF)-κBα (IκBα) were detected by western blot analysis. The activity of NF-kappaB was determined using a Dual-Luciferase Reporter assay. RESULTS The results showed that MOVACs transfected with pCMV5-HA-RKIP significantly inhibited TNF-α induced mRNA and protein expression of ICAM-1 and VCAM-1. The adhesion of THP-1 cells was also detected and inhibited by pCMV5-HA-RKIP in TNF-α-treated MOVACs. RKIP also suppressed the TNF-α-induced activation of NF-kappaB and the protein expression of phosphorylated IκB-α, and promoted the protein expression of IkB-α and nuclear translocation of p65 NF-kappaB. Furthermore, RKIP and the inhibitor of NF-kappaB (BAY11-7082) reduced the upregulation of ICAM-1 and VACM-1 induced by TNF-α. CONCLUSIONS Taken together, these results suggested that RKIP may inhibit the TNF-α-induced expression of adhesion molecules in MOVACs through inactivation of the NF-kappaB pathway.

  2. Tumor necrosis factor-alpha inhibitor-induced lupus-like syndrome presenting as fever of unknown origin in a liver transplant recipient: case report and concise review of the literature.

    PubMed

    Page, A V; Liles, W C

    2008-06-01

    A 44-year-old man was admitted to the hospital with fever and myalgias 11 years after deceased donor liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis. During hospitalization, he developed anemia, thrombocytopenia, and serositis. An extensive series of investigations eliminated infectious, malignant, thrombotic, and metabolic causes of fever. Because the patient had received tumor necrosis factor (TNF)-alpha inhibitor therapy for refractory pouchitis, a diagnosis of TNF-alpha inhibitor-induced lupus-like syndrome was considered. Further evaluation revealed an elevated antinuclear antibody titer of 1:640. Following discontinuation of the TNF-alpha inhibitor and a brief course of systemic corticosteroid therapy, the patient's symptoms resolved. TNF-alpha inhibitor therapy is increasingly used for posttransplantation management of inflammatory bowel disease, and drug-induced lupus is an increasingly recognized complication of such therapy. Because TNF-alpha inhibitor-induced lupus may not be recognized due to its nonspecific symptoms and the potential coexisting illnesses present in transplant recipients, a high index of suspicion is required.

  3. Hepatosplenic T-cell lymphoma arising in patients with immunodysregulatory disorders: a study of 7 patients who did not receive tumor necrosis factorinhibitor therapy and literature review.

    PubMed

    Yabe, Mariko; Medeiros, L Jeffrey; Daneshbod, Yahya; Davanlou, Masoud; Bueso-Ramos, Carlos E; Moran, Elisa J; Young, Ken H; Miranda, Roberto N

    2017-02-01

    Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive extranodal T-cell lymphoma that can arise in patients with underlying immune disorders. Others have suggested that tumor necrosis factor (TNF)-α inhibitor therapy for immune disorders increases the risk of HSTCL. To assess for a potential relationship between HSTCL and the use of TNF-α inhibitors, we searched for patients with HSTCL and underlying immune disorders at our institution. We identified 7 patients with a median age of 38 years. Five patients had Crohn disease, 1 ulcerative colitis, and 1 rheumatoid arthritis. In 6 patients, medication history for the immune disorder was available: 6 patients received 6-mercaptopurine or azathioprine, and 2 patients received steroids; no patients received TNF-α inhibitors. In all 7 patients, the histologic, immunophenotypic, and cytogenetic findings were similar to cases of HSTCL that arise in immunocompetent patients. We reviewed the literature and identified 60 patients with immune disorders who subsequently developed HSTCL. These patients were treated with immunosuppressive drugs in 89%, TNF-α inhibitors in 56%, and both therapies in 54%, and 1 (2%) patient was treated with TNF-α inhibitors only. Our cohort and literature review indicates that TNF-α inhibitor therapy is not essential for the development of HSTCL in patients with immunodysregulatory disorders, and implies that immunosuppressive drugs or other factors (eg, genetic predisposition, chronic antigenic stimulation) may be more critical in the pathogenesis in this context. Although these data are observational, they have implications for the use of TNF-α inhibitors in patients with inflammatory bowel disease and other immunodysregulatory disorders.

  4. Tumour necrosis factorinhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation.

    PubMed Central

    Corbett, Mark; Soares, Marta; Jhuti, Gurleen; Rice, Stephen; Spackman, Eldon; Sideris, Eleftherios; Moe-Byrne, Thirimon; Fox, Dave; Marzo-Ortega, Helena; Kay, Lesley; Woolacott, Nerys; Palmer, Stephen

    2016-01-01

    BACKGROUND Tumour necrosis factor (TNF)-α inhibitors (anti-TNFs) are typically used when the inflammatory rheumatologic diseases ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-AxSpA) have not responded adequately to conventional therapy. Current National Institute for Health and Care Excellence (NICE) guidance recommends treatment with adalimumab, etanercept and golimumab in adults with active (severe) AS only if certain criteria are fulfilled but it does not recommend infliximab for AS. Anti-TNFs for patients with nr-AxSpA have not previously been appraised by NICE. OBJECTIVE To determine the clinical effectiveness, safety and cost-effectiveness within the NHS of adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, within their licensed indications, for the treatment of severe active AS or severe nr-AxSpA (but with objective signs of inflammation). DESIGN Systematic review and economic model. DATA SOURCES Fifteen databases were searched for relevant studies in July 2014. REVIEW METHODS Clinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis methods. Results from other studies were summarised narratively. Only full economic evaluations that compared two or more options and considered both costs and consequences were included in the systematic review of cost-effectiveness studies. The differences in the approaches and assumptions used across the studies, and also those in the manufacturer's submissions, were examined in order to explain any discrepancies in the findings and to identify key areas of uncertainty. A de novo decision model was developed with a generalised framework for evidence synthesis that pooled change in disease activity (BASDAI and BASDAI 50) and simultaneously synthesised information on function (BASFI) to determine the long-term quality-adjusted life-year and cost burden of the disease in the economic model. The decision model was

  5. A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-α) inhibitors, adalimumab and infliximab, for Crohn's disease.

    PubMed

    Dretzke, J; Edlin, R; Round, J; Connock, M; Hulme, C; Czeczot, J; Fry-Smith, A; McCabe, C; Meads, C

    2011-02-01

    Crohn's disease (CD) is a severe, lifelong disease characterised by inflammation of the gastrointestinal mucosa. The impact on patients and society is high as ill health can be lifelong and can negatively affect patients' quality of life. Costs to the NHS are high, particularly for patients needing hospitalisation. Conventional treatment pathways are complex. More recently, a group of drugs called tumour necrosis factor (TNF) inhibitors (anti-TNF-α agents) have been evaluated for their effectiveness in CD. One of these, infliximab, is currently recommended by the National Institute for Health and Clinical Excellence (NICE; 2002) for patients with severe, active CD where patients are refractory to or intolerant of conventional treatment. To investigate whether there is evidence for greater clinical effectiveness or cost-effectiveness for either adalimumab or infliximab. Cochrane Library (Cochrane Central Register of Controlled Trials) 2007 Issue 2; MEDLINE (Ovid) 2000 to May/June 2007; MEDLINE In-Process & Other Non-Indexed Citations (Ovid) 4 June and 26 June 2007; EMBASE (Ovid) 2000 to May/June 2007. The European Medicines Agency, the US Food and Drug Administration and other relevant websites. Standard systematic review methods were used for study identification and selection, data extraction and quality assessment. Only randomised controlled trials (RCTs) comparing adalimumab or infliximab with standard treatment (placebo), RCTs comparing adalimumab with infliximab, or RCTs comparing different dosing regimens of either adalimumab or infliximab in adults and children with moderate-to-severe active CD intolerant or resistant to conventional treatment were eligible for inclusion. A systematic review of published studies on the cost and cost-effectiveness of adalimumab and infliximab was undertaken. The economic models of cost-effectiveness submitted by the manufacturers of both drugs were critically appraised and, where appropriate, rerun using parameter inputs

  6. Tumour necrosis factorinhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation.

    PubMed

    Corbett, Mark; Soares, Marta; Jhuti, Gurleen; Rice, Stephen; Spackman, Eldon; Sideris, Eleftherios; Moe-Byrne, Thirimon; Fox, Dave; Marzo-Ortega, Helena; Kay, Lesley; Woolacott, Nerys; Palmer, Stephen

    2016-02-01

    Tumour necrosis factor (TNF)-α inhibitors (anti-TNFs) are typically used when the inflammatory rheumatologic diseases ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-AxSpA) have not responded adequately to conventional therapy. Current National Institute for Health and Care Excellence (NICE) guidance recommends treatment with adalimumab, etanercept and golimumab in adults with active (severe) AS only if certain criteria are fulfilled but it does not recommend infliximab for AS. Anti-TNFs for patients with nr-AxSpA have not previously been appraised by NICE. To determine the clinical effectiveness, safety and cost-effectiveness within the NHS of adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, within their licensed indications, for the treatment of severe active AS or severe nr-AxSpA (but with objective signs of inflammation). Systematic review and economic model. Fifteen databases were searched for relevant studies in July 2014. Clinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis methods. Results from other studies were summarised narratively. Only full economic evaluations that compared two or more options and considered both costs and consequences were included in the systematic review of cost-effectiveness studies. The differences in the approaches and assumptions used across the studies, and also those in the manufacturer's submissions, were examined in order to explain any discrepancies in the findings and to identify key areas of uncertainty. A de novo decision model was developed with a generalised framework for evidence synthesis that pooled change in disease activity (BASDAI and BASDAI 50) and simultaneously synthesised information on function (BASFI) to determine the long-term quality-adjusted life-year and cost burden of the disease in the economic model. The decision model was developed in accordance with the NICE reference case. The

  7. Longterm safety and efficacy of abatacept through 5 years of treatment in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor inhibitor therapy.

    PubMed

    Genovese, Mark C; Schiff, Michael; Luggen, Michael; Le Bars, Manuela; Aranda, Richard; Elegbe, Ayanbola; Dougados, Maxime

    2012-08-01

    To evaluate abatacept safety and efficacy over 5 years in patients with rheumatoid arthritis (RA) who had inadequate response to anti-tumor necrosis factor (TNF) therapy in the ATTAIN trial. Patients completing the 6-month, double-blind (DB) placebo-controlled period were eligible to enter the longterm extension (LTE), where all patients received abatacept every 4 weeks (∼10 mg/kg, according to weight range). Safety, efficacy, physical function, and health-related quality of life were monitored throughout. In total, 317 patients (218 DB abatacept, 99 DB placebo) entered the LTE; 150 (47.3%) completed it. Overall incidences of serious adverse events, infections, serious infections, malignant neoplasms, and autoimmune events did not increase during the LTE versus the DB period. American College of Rheumatology responses with abatacept at Month 6 were maintained over 5 years. At Year 5, among patients who received abatacept for 5 years and had available data, 38/103 (36.9%) achieved low disease activity as defined by the 28-joint Disease Activity Score (DAS28)/C-reactive protein (CRP); 23/103 (22.3%) achieved DAS28/CRP-defined remission. Health Assessment Questionnaire response was achieved by 62.5% of patients remaining on treatment at Year 5; mean improvements from baseline in physical component summary and mental component summary scores were 7.34 and 6.42, respectively. High proportions of patients maintained efficacy and physical function benefits or improved their disease state at each timepoint throughout the LTE, if remaining on abatacept treatment. Safety remained consistent, and abatacept efficacy was maintained from 6 months to 5 years, demonstrating the benefits of switching to abatacept in this difficult-to-treat population of patients with RA previously failing anti-TNF therapy.

  8. [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.

  9. 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.

  10. 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.

  11. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report.

    PubMed

    Gómez-Reino, Juan J; Carmona, Loreto; Valverde, Vicente Rodríguez; Mola, Emilio Martín; Montero, Maria Dolores

    2003-08-01

    The long-term safety of therapeutic agents that neutralize tumor necrosis factor (TNF) is uncertain. Recent evidence based on spontaneous reporting shows an association with active tuberculosis (TB). We undertook this study to determine and describe the long-term safety of 2 of these agents, infliximab and etanercept, in rheumatic diseases based on a national active-surveillance system following the commercialization of the drugs. We analyzed the safety data actively collected in the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) database, which was launched in February 2000 by the Spanish Society of Rheumatology. For the estimation of TB risk, the annual incidence rate in patients treated with these agents was compared with the background rate and with the rate in a cohort of patients with rheumatoid arthritis (RA) assembled before the era of anti-TNF treatment. Seventy-one participating centers sent data on 1,578 treatments with infliximab (86%) or etanercept (14%) in 1,540 patients. Drug survival rates (reported as the cumulative percentage of patients still receiving medication) for infliximab and etanercept pooled together were 85% and 81% at 1 year and 2 years, respectively. Instances of discontinuation were essentially due to adverse events. Seventeen cases of TB were found in patients treated with infliximab. The estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001. These findings represent a significant increased risk compared with background rates. In the first 5 months of 2002, after official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case was registered (in January). Therapy with infliximab is associated with an increased risk of active TB. Proper measures are needed to prevent and manage this adverse event.

  12. Endotoxin Tolerance Inhibits Degradation of Tumor Necrosis Factor Receptor-Associated Factor 3 by Suppressing Pellino 1 Expression and the K48 Ubiquitin Ligase Activity of Cellular Inhibitor of Apoptosis Protein 2.

    PubMed

    Li, Peizhi; Liu, Hongxiang; Zhang, Yiyin; Liao, Rui; He, Kun; Ruan, Xiongzhong; Gong, Jianping

    2016-09-15

    Pellino 1 positively regulates Toll-like receptor 4 signaling by regulating tumor necrosis factor receptor-associated factor 3 (TRAF3) degradation and is suppressed with the induction of endotoxin tolerance. However, the role of TRAF3 in endotoxin tolerance is largely unknown. In this study, we found that lipopolysaccharide (LPS) stimulation decreased TARF3 protein expression in mouse Kupffer cells (KCs) and liver tissues, whereas endotoxin tolerization abrogated this effect. Degradative TRAF3 K48-linked ubiquitination and the cytoplasmic translocation of the MYD88-associated multiprotein complex were significantly inhibited in tolerized KCs, which led to markedly impaired activation of MYD88-dependent JNK and p38 and downregulation of inflammatory cytokines. TRAF3 ablation failed to induce a fully endotoxin-tolerant state in RAW264.7 cells. Pellino 1 knockdown in Raw264.7 cells did not impair induction of cIAP2 in response to LPS but inhibited the K63-linked ubiquitination of cellular inhibitor of apoptosis protein 2 (cIAP2) and K48-linked ubiquitination of TRAF3 protein. We also found upregulation of Pellino 1 and downregulation of TRAF3 in liver tissues of patients with cholangitis. Our findings reveal a novel mechanism that endotoxin tolerance reprograms mitogen-activated protein kinase signaling by suppressing Pellino 1-mediated K63-linked ubiquitination of cIAP2, K48-linked ubiquitination, and degradation of TRAF3. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  13. Acquired Factor V Inhibitor

    PubMed Central

    Hirai, Daisuke; Yamashita, Yugo; Masunaga, Nobutoyo; Katsura, Toshiaki; Akao, Masaharu; Okuno, Yoshiaki; Koyama, Hiroshi

    2016-01-01

    Inhibitors directed against factor V rarely occur, and the clinical symptoms vary. We herein report the case of a patient who presented with a decreased factor V activity that had decreased to <3 %. We administered vitamin K and 6 units of fresh frozen plasma, but she thereafter developed an intracerebral hemorrhage. It is unclear whether surgery >10 years earlier might have caused the development of a factor V inhibitor. The treatment of acquired factor V inhibitors is mainly the transfusion of platelet concentrates and corticosteroids. Both early detection and the early initiation of the treatment of factor V inhibitor are thus considered to be important. PMID:27746446

  14. Development of predictive pharmacophore model for in silico screening, and 3D QSAR CoMFA and CoMSIA studies for lead optimization, for designing of potent tumor necrosis factor alpha converting enzyme inhibitors

    NASA Astrophysics Data System (ADS)

    Murumkar, Prashant Revan; Zambre, Vishal Prakash; Yadav, Mange Ram

    2010-02-01

    A chemical feature-based pharmacophore model was developed for Tumor Necrosis Factor-α converting enzyme (TACE) inhibitors. A five point pharmacophore model having two hydrogen bond acceptors (A), one hydrogen bond donor (D) and two aromatic rings (R) with discrete geometries as pharmacophoric features was developed. The pharmacophore model so generated was then utilized for in silico screening of a database. The pharmacophore model so developed was validated by using four compounds having proven TACE inhibitory activity which were grafted into the database. These compounds mapped well onto the five listed pharmacophoric features. This validated pharmacophore model was also used for alignment of molecules in CoMFA and CoMSIA analysis. The contour maps of the CoMFA/CoMSIA models were utilized to provide structural insight for activity improvement of potential novel TACE inhibitors. The pharmacophore model so developed could be used for in silico screening of any commercial/in house database for identification of TACE inhibiting lead compounds, and the leads so identified could be optimized using the developed CoMSIA model. The present work highlights the tremendous potential of the two mutually complementary ligand-based drug designing techniques (i.e. pharmacophore mapping and 3D-QSAR analysis) using TACE inhibitors as prototype biologically active molecules.

  15. Age-related trends in injection site reaction incidence induced by the tumor necrosis factor-α (TNF-α) inhibitors etanercept and adalimumab: the Food and Drug Administration adverse event reporting system, 2004-2015

    PubMed Central

    Matsui, Toshinobu; Umetsu, Ryogo; Kato, Yamato; Hane, Yuuki; Sasaoka, Sayaka; Motooka, Yumi; Hatahira, Haruna; Abe, Junko; Fukuda, Akiho; Naganuma, Misa; Kinosada, Yasutomi; Nakamura, Mitsuhiro

    2017-01-01

    Tumor necrosis factor-α (TNF-α) inhibitors are increasingly being used as treatment for rheumatoid arthritis (RA). However, the administration of these drugs carries the risk of inducing injection site reaction (ISR). ISR gives rise to patient stress, nervousness, and a decrease in quality of life (QoL). In order to alleviate pain and other symptoms, early countermeasures must be taken against this adverse event. In order to improve understanding of the risk factors contributing to the induction of ISR, we evaluated the association between TNF-α inhibitors and ISR by applying a logistic regression model to age-stratified data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The FAERS database contains 7,561,254 reports from January 2004 to December 2015. Adjusted reporting odds ratios (RORs) (95% Confidence Intervals) were obtained for interaction terms for age-stratified groups treated with etanercept (ETN) and adalimumab (ADA). The adjusted RORs for ETN* ≥ 70 and ADA* ≥ 70 groups were the lowest among the age-stratified groups undergoing the respective monotherapies. Furthermore, we found that crude RORs for ETN + methotrexate (MTX) combination therapy and ADA + MTX combination therapy were lower than those for the respective monotherapies. This study was the first to evaluate the relationship between aging and ISR using the FAERS database. PMID:28260984

  16. Risks for opportunistic tuberculosis infection in a cohort of 873 patients with inflammatory bowel disease receiving a tumor necrosis factorinhibitor.

    PubMed

    Byun, Ja Min; Lee, Chang Kyun; Rhee, Sang Youl; Kim, Hyo-Jong; Im, Jong Pil; Park, Dong Il; Eun, Chang Soo; Jung, Sung-Ae; Shin, Jeong Eun; Lee, Kang-Moon; Cheon, Jae Hee

    2015-03-01

    Real-world epidemiological data on tuberculosis (TB) infection in patients with inflammatory bowel disease (IBD) receiving TNF-α inhibitors are scarce. We investigated the risks for and case characteristics of TB in a large cohort of IBD patients treated with TNF-α inhibitors in Korea, where TB is endemic. We performed an observational study on all TB cases identified in a cohort of 873 IBD subjects treated with TNF-α inhibitors from January 2001 to December 2013. The standardized incidence ratio (SIR) of TB was calculated using data from the matched general population. A total of 25 newly developed TB cases were identified in the cohort (pulmonary TB, 84% [21/25]; extrapulmonary TB, 16% [4/25]). The adjusted SIR of TB was 41.7 (95% confidence interval, 25.3-58.0), compared with that of the matched general population. Nineteen of the 25 patients (76%) developed TB within 2-62 months of initiation of TNF-α inhibitor treatment despite screening negative for latent TB infection (LTBI), whereas three patients with LTBI (12%, 3/25) developed TB 3 months after completion of chemoprophylaxis. The outcomes of TB treatment were mostly favorable, although one death from peritoneal TB was noted. The type of TNF-α inhibitor prescribed (infliximab) was a significant predictor of TB (p = 0.033). TNF-α inhibitor treatment strikingly increases the risk of TB infection in an IBD population from a TB endemic area. Continuous evaluation of the development of de novo TB infection in IBD patients subjected to long-term TNF inhibitor therapy is mandatory.

  17. Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders.

    PubMed

    Bahia, Malkeet S; Silakari, Om

    2010-05-01

    Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy.

  18. Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study.

    PubMed

    Ohtori, Seiji; Miyagi, Masayuki; Eguchi, Yawara; Inoue, Gen; Orita, Sumihisa; Ochiai, Nobuyasu; Kishida, Shunji; Kuniyoshi, Kazuki; Nakamura, Junichi; Aoki, Yasuchika; Ishikawa, Tetsuhiro; Arai, Gen; Kamoda, Hiroto; Suzuki, Miyako; Takaso, Masashi; Furuya, Takeo; Toyone, Tomoaki; Takahashi, Kazuhisa

    2012-03-15

    Prospective randomized trial. To examine the effect of the tumor necrosis factor alpha (TNF-α) inhibitor, etanercept, on radicular pain by its epidural administration onto spinal nerves in patients with lumbar spinal stenosis. TNF-α is thought to play a crucial role in the radicular pain caused by lumbar disc herniation and spinal stenosis. Intravenous infusion of infliximab for sciatica has been examined in 2 studies; however, the results were equivocal. Eighty patients with low back and radicular leg pain were investigated. We diagnosed the patients by physical examination, and X-ray and magnetic resonance imaging. In 40 patients, we epidurally administered 2.0 mL of lidocaine and 10 mg of etanercept onto the affected spinal nerve, and 2.0 mL of lidocaine and 3.3 mg of dexamethasone was used in 40 patients. Low back pain, leg pain, and leg numbness were evaluated using a visual analogue scale (VAS) and Oswestry Disability Index (ODI) score before and for 1 month after epidural administration. Low back pain, leg pain, and leg numbness in the 2 groups were not significantly different before epidural administration. Epidural administration of etanercept was more effective than dexamethasone for leg pain (3 days, and 1, 2, and 4 weeks: P < 0.05), low back pain (3 days, and 1 and 2 weeks: P < 0.05), and leg numbness (3 days, and 1 and 2 weeks: P < 0.05). No adverse event was observed in either group. Our results indicate that epidural administration of a TNF-α inhibitor onto the spinal nerve produced pain relief, but no adverse event. TNF-α inhibitors may be useful tools for the treatment of radicular pain caused by spinal stenosis.

  19. Cost–utility of different treatment strategies after the failure of tumour necrosis factor inhibitor in rheumatoid arthritis in the Finnish setting

    PubMed Central

    Soini, Erkki J. O.; Eklund, Kari; Puolakka, Kari

    2010-01-01

    Objective. To evaluate the cost–utility of different treatment strategies in severe RA after TNF-inhibitor failure. Methods. The cost-effectiveness of treatment strategies was compared in a group of hypothetical Finnish RA patients. Initially, the patients received either best supportive care (BSC) or one of the following treatments before BSC: adalimumab (ADAL), abatacept (ABAT), etanercept (ETAN), infliximab (INFL) or rituximab (RTX). Further treatments were added to the most cost-effective strategy in a stepwise manner. The analysis was performed on an Excel-based Markov state transition model using the probabilistic approach. The clinical outcomes related to treatments were estimated from published clinical trials. The gained quality-adjusted life-years (QALYs) were estimated based on Health Utilities Index (HUI-3) and disease severity scores (HAQ). The resource use and costs were obtained from the Finnish treatment practice, one published study, the Finnish Unit Cost list and Finnish Medicine Tariffs. Results. Treatment with RTX was more effective and less costly than treatment with ADAL, ABAT or ETAN after TNF-inhibitor failure. An additional QALY gained with RTX costs 30 248 euros compared with BSC. The incremental cost-effectiveness ratios (ICERs) are 50 941, 50 372, 36 121 and 67 003 euros per QALY gained for adding ADAL, ETAN, INFL and ABAT to the RTX strategy, respectively. According to the cost-effectiveness acceptability frontier (CEAF), only BSC or treatments with RTX or RTX followed by INFL should be considered after TNF-inhibitor failure, if willingness to pay is between 0 and 50 000 euros per QALY gained. Conclusions. Treatment with RTX is a cost-effective treatment strategy in RA patients in Finland. PMID:20100793

  20. Rebound in Measures of Disease Activity and Symptoms in Corrona Registry Patients with Psoriatic Arthritis Who Discontinue Tumor Necrosis Factor Inhibitor Therapy after Achieving Low Disease Activity.

    PubMed

    Harrold, Leslie R; Stolshek, Bradley S; Rebello, Sabrina; Collier, David H; Mutebi, Alex; Wade, Sally W; Malley, Wendi; Greenberg, Jeffrey D; Etzel, Carol J

    2017-10-01

    Rebound may occur in patients with psoriatic arthritis (PsA) who discontinue TNF inhibitor (TNFi) therapy in low disease activity (LDA). Using physician and patient reports, we quantified rebound following TNFi discontinuation [defined as Clinical Disease Activity Index (CDAI) score > 10 or TNFi restart] and time to rebound in adults with PsA in LDA (CDAI score ≤ 10) at TNFi discontinuation. Rebound occurred in 73% (69/94) of patients soon after discontinuation (median time to rebound 8.0 mos, 95% CI 6.0-12.0). Rebound occurred frequently in patients with PsA after TNFi discontinuation. TNFi discontinuation after achieving LDA should be carefully considered.

  1. CD6 and Syntaxin Binding Protein 6 Variants and Response to Tumor Necrosis Factor Alpha Inhibitors in Danish Patients with Rheumatoid Arthritis

    PubMed Central

    Krintel, Sophine B.; Essioux, Laurent; Wool, Assaf; Johansen, Julia S.; Schreiber, Ehud; Zekharya, Tomer; Akiva, Pinchas; Østergaard, Mikkel; Hetland, Merete L.

    2012-01-01

    Background TNFα inhibitor therapy has greatly improved the treatment of patients with rheumatoid arthritis, however at least 30% do not respond. We aimed to investigate insertions and deletions (INDELS) associated with response to TNFα inhibitors in patients with rheumatoid arthritis (RA). Methodology and Principal Findings In the DANBIO Registry we identified 237 TNFα inhibitor naïve patients with RA (81% women; median age 56 years; disease duration 6 years) who initiated treatment with infliximab (n = 160), adalimumab (n = 56) or etanercept (n = 21) between 1999 and 2008 according to national treatment guidelines. Clinical response was assessed at week 26 using EULAR response criteria. Based on literature, we selected 213 INDELS potentially related to RA and treatment response using the GeneVa® (Compugen) in silico database of 350,000 genetic variations in the human genome. Genomic segments were amplified by polymerase chain reaction (PCR), and genotyped by Sanger sequencing or fragment analysis. We tested the association between genotypes and EULAR good response versus no response, and EULAR good response versus moderate/no response using Fisher’s exact test. At baseline the median DAS28 was 5.1. At week 26, 68 (29%) patients were EULAR good responders, while 81 (34%) and 88 (37%) patients were moderate and non-responders, respectively. A 19 base pair insertion within the CD6 gene was associated with EULAR good response vs. no response (OR = 4.43, 95% CI: 1.99–10.09, p = 7.211×10−5) and with EULAR good response vs. moderate/no response (OR = 4.54, 95% CI: 2.29–8.99, p = 3.336×10−6). A microsatellite within the syntaxin binding protein 6 (STXBP6) was associated with EULAR good response vs. no response (OR = 4.01, 95% CI: 1.92–8.49, p = 5.067×10−5). Conclusion Genetic variations within CD6 and STXBP6 may influence response to TNFα inhibitors in patients with RA. PMID:22685579

  2. [Acquired coagulant factor inhibitors].

    PubMed

    Nogami, Keiji

    2015-02-01

    Acquired coagulation factor inhibitors are an autoimmune disease causing bleeding symptoms due to decreases in the corresponding factor (s) which result from the appearance of autoantibodies against coagulation factors (inhibitor). This disease is quite different from congenital coagulation factor deficiencies based on genetic abnormalities. In recent years, cases with this disease have been increasing, and most have anti-factor VIII autoantibodies. The breakdown of the immune control mechanism is speculated to cause this disease since it is common in the elderly, but the pathology and pathogenesis are presently unclear. We herein describe the pathology and pathogenesis of factor VIII and factor V inhibitors. Characterization of these inhibitors leads to further analysis of the coagulation process and the activation mechanisms of clotting factors. In the future, with the development of new clotting examination method (s), we anticipate that further novel findings will be obtained in this field through inhibitor analysis. In addition, detailed elucidation of the coagulation inhibitory mechanism possibly leading to hemostatic treatment strategies for acquired coagulation factor disorders will be developed.

  3. 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

  4. Inhibitor of apoptosis proteins (IAPs) and their antagonists regulate spontaneous and tumor necrosis factor (TNF)-induced proinflammatory cytokine and chemokine production.

    PubMed

    Kearney, Conor J; Sheridan, Clare; Cullen, Sean P; Tynan, Graham A; Logue, Susan E; Afonina, Inna S; Vucic, Domagoj; Lavelle, Ed C; Martin, Seamus J

    2013-02-15

    Inhibitor of apoptosis proteins (IAPs) play a major role in determining whether cells undergo apoptosis in response to TNF as well as other stimuli. However, TNF is also highly proinflammatory through its ability to trigger the secretion of multiple inflammatory cytokines and chemokines, which is arguably the most important role of TNF in vivo. Indeed, deregulated production of TNF-induced cytokines is a major driver of inflammation in several autoimmune conditions such as rheumatoid arthritis. Here, we show that IAPs are required for the production of multiple TNF-induced proinflammatory mediators. Ablation or antagonism of IAPs potently suppressed TNF- or RIPK1-induced proinflammatory cytokine and chemokine production. Surprisingly, IAP antagonism also led to spontaneous production of chemokines, particularly RANTES, in vitro and in vivo. Thus, IAPs play a major role in influencing the production of multiple inflammatory mediators, arguing that these proteins are important regulators of inflammation in addition to apoptosis. Furthermore, small molecule IAP antagonists can modulate spontaneous as well as TNF-induced inflammatory responses, which may have implications for use of these agents in therapeutic settings.

  5. The Deubiquitinase Inhibitor PR-619 Sensitizes Normal Human Fibroblasts to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-mediated Cell Death*

    PubMed Central

    Crowder, Roslyn N.; Dicker, David T.; El-Deiry, Wafik S.

    2016-01-01

    TNF-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapy that selectively targets cancer cell death while non-malignant cells remain viable. Using a panel of normal human fibroblasts, we characterized molecular differences in human foreskin fibroblasts and WI-38 TRAIL-resistant cells and marginally sensitive MRC-5 cells compared with TRAIL-sensitive human lung and colon cancer cells. We identified decreased caspase-8 protein expression and protein stability in normal fibroblasts compared with cancer cells. Additionally, normal fibroblasts had incomplete TRAIL-induced caspase-8 activation compared with cancer cells. We found that normal fibroblasts lack the ubiquitin modification of caspase-8 required for complete caspase-8 activation. Treatment with the deubiquitinase inhibitor PR-619 increased caspase-8 ubiquitination and caspase-8 enzymatic activity and sensitized normal fibroblasts to TRAIL-mediated apoptosis. Therefore, posttranslational regulation of caspase-8 confers resistance to TRAIL-induced cell death in normal cells through blockade of initiation of the extrinsic cell death pathway. PMID:26757822

  6. A microcosting study of immunogenicity and tumour necrosis factor alpha inhibitor drug level tests for therapeutic drug monitoring in clinical practice.

    PubMed

    Jani, Meghna; Gavan, Sean; Chinoy, Hector; Dixon, William G; Harrison, Beverley; Moran, Andrew; Barton, Anne; Payne, Katherine

    2016-12-01

    To identify and quantify resource required and associated costs for implementing TNF-α inhibitor (TNFi) drug level and anti-drug antibody (ADAb) tests in UK rheumatology practice. A microcosting study, assuming the UK National Health Service perspective, identified the direct medical costs associated with providing TNFi drug level and ADAb testing in clinical practice. Resource use and costs per patient were identified via four stages: identification of a patient pathway with resource implications; estimation of the resources required; identification of the cost per unit of resource (2015 prices); and calculation of the total costs per patient. Univariate and multiway sensitivity analyses were performed using the variation in resource use and unit costs. Total costs for TNFi drug level and concurrent ADAb testing, assessed using ELISAs on trough serum levels, were £152.52/patient (range: £147.68-159.24) if 40 patient samples were tested simultaneously. For the base-case analysis, the pre-testing phase incurred the highest costs, which included booking an additional appointment to acquire trough blood samples. The additional appointment was the key driver of costs per patient (67% of the total cost), and labour accounted for 10% and consumables 23% of the total costs. Performing ELISAs once per patient (rather than in duplicate) reduced the total costs to £133.78/patient. This microcosting study is the first assessing the cost of TNFi drug level and ADAb testing. The results could be used in subsequent cost-effectiveness analyses of TNFi pharmacological tests to target treatments and inform future policy recommendations. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology.

  7. Xanthohumol from hop (Humulus lupulus L.) is an efficient inhibitor of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha release in LPS-stimulated RAW 264.7 mouse macrophages and U937 human monocytes.

    PubMed

    Lupinacci, Elvira; Meijerink, Jocelijn; Vincken, Jean-Paul; Gabriele, Bartolo; Gruppen, Harry; Witkamp, Renger F

    2009-08-26

    Activated macrophages in adipose tissue play a major role in the chronic inflammatory process that has been linked to the complications of overweight and obesity. The hop plant (Humulus lupulus L.) has been described to possess both anti-inflammatory and antidiabetic effects. In the present study, the chemical composition of a hop crude extract (HCE) was investigated by ultrahigh-performance liquid chromatography (UHPLC). Next, HCE and various fractions obtained by preparative HPLC were tested for their ability to inhibit production of two pro-inflammatory cytokines, monocyte chemoattractant protein-1 (MCP-1, CCL2) and tumor necrosis factor-alpha (TNF-alpha), which play crucial roles in the complications of obesity. The hop chalcone xanthohumol was found to be the most potent inhibitor of both cytokines in LPS-activated RAW 264.7 mouse macrophages and U937 human monocytes. Moreover, other constituents, namely, iso-alpha-acids, in combination with the beta-acid hulupone, showed a moderate but selective inhibitory activity only on MCP-1 release. These findings underscore the potential health effects of hop and support further optimization, selection, and use of this plant.

  8. Comparative efficacy and safety of tocilizumab, rituximab, abatacept and tofacitinib in patients with active rheumatoid arthritis that inadequately responds to tumor necrosis factor inhibitors: a Bayesian network meta-analysis of randomized controlled trials.

    PubMed

    Lee, Young Ho; Bae, Sang-Cheol

    2016-11-01

    This study aimed to assess the relative efficacy and safety of biologics and tofacitinib in patients with rheumatoid arthritis (RA) showing an inadequate response to tumor necrosis factor (TNF) inhibitors. We performed a Bayesian network meta-analysis to combine the direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of tocilizumab, rituximab, abatacept and tofacitinib in patients with RA that inadequately responds to TNF inhibitors. Four RCTs including 1796 patients met the inclusion criteria. The tocilizumab 8 mg group showed a significantly higher American College of Rheumatology 20% (ACR20) response rate than the abatacept and tofacitinib groups. Ranking probability based on surface under the cumulative ranking curve (SUCRA) indicated that tocilizumab 8 mg had the highest probability of being the best treatment for achieving the ACR20 response rate (SUCRA = 0.9863), followed by rituximab (SUCRA = 0.6623), abatacept (SUCRA = 0.5428), tocilizumab 4 mg (SUCRA = 0.4956), tofacitinib 10 mg (SUCRA = 0.4715), tofacitinib 5 mg (SUCRA = 0.3415) and placebo (SUCRA = 0). In contrast, the safety based on the number of withdrawals due to adverse events did not differ significantly among the treatment options. Tocilizumab 8 mg was the second-line non-TNF biologic with the highest performance regarding an early good response based on ACR20 response rate and acceptable safety profile, followed by rituximab, abatacept and tofacitinib in patients with RA and an inadequate response to anti-TNF therapy, and none of these treatments were associated with a significant risk of withdrawal due to adverse events. © 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  9. [The effect of tumor necrosis factor alpha on hepatic necrosis in viral hepatitis].

    PubMed

    Yu, Y; Si, C; Lang, Z

    1996-01-01

    In order to investigate the effect of tumor necrosis factor alpha (TNF alpha) on hepatocyte necrosis in viral hepatitis, TNF alpha with or without D-galactosamine (D-Gal) was injected into the abdominal cavity of rats. No effect was observed after injection of TNF alpha alone. After injection of TNF alpha with D-Gal, the total bilirubin level in rat blood increased and hepatocyte necrosis appeared (P < 0.05). Moreover, anti-TNF alpha McAb blocked the effect of hepatocyte necrosis produced by D-Gal and lipopolysaccharide (LPS). 130 samples of hepatic tissue were stained with anti-TNF alpha McAb by using ABC immunohistochemistry method. It was found that more severe the hepatocyte necrosis, more the positive cells expressing TNF alpha. There were more TNF alpha positive cells in the tissue of severe hepatitis. These results suggested that TNF alpha is a mediator in hepatocyte necrosis.

  10. Necrosis

    MedlinePlus

    ... this page, please enable JavaScript. Necrosis is the death of body tissue. It occurs when too little blood flows to the tissue. This can be from injury, radiation, or chemicals. Necrosis cannot be reversed. When large ...

  11. 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 Central

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

    2016-01-01

    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

  12. 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.

  13. Stimulation of neutrophils by tumor necrosis factor

    SciTech Connect

    Klebanoff, S.J.; Vadas, M.A.; Harlan, J.M.; Sparks, L.H.; Gamble, J.R.; Agosti, J.M.; Waltersdorph, A.M.

    1986-06-01

    Human recombinant tumor necrosis factor (TNF) was shown to be a weak direct stimulus of the neutrophil respiratory burst and degranulation. The stimulation, as measured by iodination, H/sub 2/O/sub 2/ production, and lysozyme release, was considerably increased by the presence of unopsonized zymosan in the reaction mixture, an effect which was associated with the increased ingestion of the zymosan. TNF does not act as an opsonin but, rather, reacts with the neutrophil to increase its phagocytic activity. TNF-dependent phagocytosis, as measured indirectly by iodination, is inhibited by monoclonal antibodies (Mab) 60.1 and 60.3, which recognize different epitopes on the C3bi receptor/adherence-promoting surface glycoprotein of neutrophils. Other neutrophil stimulants, namely N-formyl-methionyl-leucyl-phenylalanine, the Ca2+ ionophore A23187, and phorbol myristic acetate, also increase iodination in the presence of zymosan; as with TNF, the effect of these stimulants is inhibited by Mab 60.1 and 60.3, whereas, in contrast to that of TNF, their stimulation of iodination is unaffected by an Mab directed against TNF. TNF may be a natural stimulant of neutrophils which promotes adherence to endothelial cells and to particles, leading to increased phagocytosis, respiratory burst activity, and degranulation.

  14. Tumor necrosis factor alpha inhibitors have no effect on a human T-lymphotropic virus type-I (HTLV-I)-infected cell line from patients with HTLV-I-associated myelopathy.

    PubMed

    Fukui, Shoichi; Nakamura, Hideki; Takahashi, Yoshiko; Iwamoto, Naoki; Hasegawa, Hiroo; Yanagihara, Katsunori; Nakamura, Tatsufumi; Okayama, Akihiko; Kawakami, Atsushi

    2017-02-03

    While tumor necrosis factor alpha (TNF-α) inhibitors (TNFi) and other biologics are very effective against autoimmune diseases, they can also cause infectious diseases. Therefore, it is important to clarify whether the TNFi sometimes used to treat patients with rheumatoid arthritis (RA) complicated with human T-lymphotropic virus type-I (HTLV-I) infection have the unintended side effect of promoting HTLV-I proliferation. We used the HTLV-I-infected cell line HCT-5, derived from spinal fluid cells of a patient with HTLV-I associated myelopathy, to evaluate the production of cytokines and chemokines, TNF-α receptor (TNFR), the expression of HTLV-I associated genes, the HTLV-I proviral load (PVL), the expression of HTLV-I structural protein, and apoptosis. We used Jurkat cells as a control. Supernatants of HCT-5 showed time-dependent elevations of IL-6, RANTES and ICAM-1. HCT-5 supernatants treated with infliximab, adalimumab, etanercept (ETN), golimumab and certolizumab pegol showed no significant differences in the levels of these molecules compared to the control. Neither TNFR1 nor TNFR2 expression was altered by any TNFi treatment, relative to phosphate-buffered saline (PBS) treatment, with the exception that TNFR2 was significantly decreased and internalized in HCT-5 cells by ETN treatment. The HTLV-I associated genes Tax and HBZ and the PVL levels were not significantly changed. Immunofluorescence staining of HCT-5 for an HTLV-I-associated protein, GAG, was also not significantly different between any of the TNFi treatments and the PBS treatment. DNA ladders as an index of apoptosis were not detected. Apoptotic cells were not increased by the addition of any TNFi. In vitro, TNFi did not affect the cytokine profiles, expression of associated genes and proteins, proviral load or apoptosis of HCT-5 cells. The results suggested that TNFi treatment of RA patients complicated with HTLV-I might have no effect on HTLV-I infection.

  15. Tocilizumab in patients with active rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs or tumor necrosis factor inhibitors: subanalysis of Spanish results of an open-label study close to clinical practice.

    PubMed

    Álvaro-Gracia, José M; Fernández-Nebro, Antonio; García-López, Alicia; Guzmán, Manuel; Blanco, Francisco J; Navarro, Francisco J; Bustabad, Sagrario; Armendáriz, Yolanda; Román-Ivorra, José A

    2014-01-01

    To analyze the Spanish experience in an international study which evaluated tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor inhibitors (TNFis) in a clinical practice setting. Subanalysis of 170 patients with RA from Spain who participated in a phase IIIb, open-label, international clinical trial. Patients presented inadequate response to DMARDs or TNFis. They received 8mg/kg of tocilizumab every 4 weeks in combination with a DMARD or as monotherapy during 20 weeks. Safety and efficacy of tocilizumab were analyzed. Special emphasis was placed on differences between failure to a DMARD or to a TNFi and the need to switch to tocilizumab with or without a washout period in patients who had previously received TNFi. The most common adverse events were infections (25%), increased total cholesterol (38%) and transaminases (15%). Five patients discontinued the study due to an adverse event. After six months of tocilizumab treatment, 71/50/30% of patients had ACR 20/50/70 responses, respectively. A higher proportion of TNFi-naive patients presented an ACR20 response: 76% compared to 64% in the TNFi group with previous washout and 66% in the TNFi group without previous washout. Safety results were consistent with previous results in patients with RA and an inadequate response to DMARDs or TNFis. Tocilizumab is more effective in patients who did not respond to conventional DMARDs than in patients who did not respond to TNFis. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  16. Angiotensin-converting enzyme inhibitors improve hepatic steatosis by modulating expression of tumour necrosis factor-alpha, interleukin-6 and adiponectin receptor-2 in rats with type 2 diabetes.

    PubMed

    Zhang, Xia; Li, Zhong-Zhuan; Liu, Dong-Fang; Xu, Xin; Mei, Zhe-Chuan; Shen, Wei

    2009-07-01

    1. Angiotensin-converting enzyme inhibitors (ACEI) are hypotensive drugs that have been shown to prevent Type 2 diabetes mellitus (T2DM) in high-risk individuals. However, in T2DM, the effects of ACEI on hepatic steatosis are not known. The aim of the present study was to examine the effects of ACEI on changes in liver histology and hepatic mRNA expression of adipokines in rats with T2DM. 2. Thirty-six rats were divided into a normal control group, a T2DM group and a fosinopril-treated group. After six weeks of treatment with 5 mg/kg per day fosinopril, an ACEI, changes in liver histology, serum fasting glucose (FG), insulin, triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, adiponectin were evaluated, as was hepatic TNF-alpha, IL-6 and adiponectin receptor-2 (adipoR2) mRNA expression. 3. The degree of hepatic steatosis and inflammation, serum FG, insulin, TG, TC, ALT, TNF-alpha and IL-6 concentrations and hepatic TNF-alpha and IL-6 mRNA expression were significantly higher in rats with T2DM than in normal controls. Serum adiponectin concentrations and hepatic adipoR2 mRNA expression in rats with T2DM were significantly lower than in normal controls. Fosinopril significantly reduced the degree of hepatic steatosis, serum FG, insulin, ALT, TNF-alpha and IL-6 concentrations and hepatic TNF-alpha and IL-6 mRNA expression. Fosinopril significantly increased serum adiponectin concentrations and hepatic adipoR2 mRNA expression. 4. In conclusion, the ACEI improved insulin sensitivity and hepatic steatosis in rats with T2DM by increasing circulating adiponectin and hepatic adipoR2 levels, in addition to reducing pro-inflammatory cytokine levels in the circulation and liver.

  17. Concurrent treatment with a tumor necrosis factor-alpha inhibitor and veno-venous extracorporeal membrane oxygenation in a post-hematopoietic stem cell transplant patient with idiopathic pneumonia syndrome: a case report.

    PubMed

    Koinuma, Toshitaka; Nunomiya, Shin; Wada, Masahiko; Koyama, Kansuke; Suzuki, Takahiro

    2014-01-01

    Idiopathic pneumonia syndrome (IPS) is a fatal non-infectious respiratory complication that develops after hematopoietic stem cell transplantation (HSCT). Because of the poor prognosis of post-HSCT patients with IPS requiring mechanical ventilatory support, performing extracorporeal membrane oxygenation (ECMO) has been regarded as relatively contraindicated in these patients. A tumor necrosis factor-alpha inhibitor, etanercept, has been reported to be a promising treatment option for post-HSCT patients with IPS; however, the phase III clinical trial of etanercept has recently been terminated without definitive conclusion. If post-HSCT patients with IPS really benefit from etanercept, mechanical ventilation (MV)-dependent IPS patients might be worth receiving ECMO treatment in line with the protective lung strategy. We therefore performed veno-venous ECMO (VV-ECMO), which substantially acted as an extracorporeal carbon dioxide removal, on a 56-year-old post-HSCT male with severe MV-dependent IPS due to graft-versus-host disease. Although a serious bleeding complication due to post-HSCT thrombocytopenia occurred, the VV-ECMO was continued for 11 days. The patient successfully entered remission of the IPS and was finally extubated on the 12th MV day. However, the patient soon complained of dyspnea, probably due to cytomegalovirus infection and/or exacerbation of the IPS, and was reintubated after 3 days of extubation. The patient then rapidly developed irreversible type II respiratory failure despite the administration of etanercept and an anti-cytomegalovirus agent and died on the eighth re-MV day. The autopsy findings of the patient revealed diffuse alveolar damage and alveolar hemorrhage, accompanied with bronchitis obliterans in his lungs, as well as whole body cytomegalovirus infection, which were compatible with the clinical diagnosis of the patient. We think that the legitimacy of this treatment strategy is dependent on the overall prognosis of IPS, which is

  18. 4G/5G plasminogen activator inhibitor-1 and -308 A/G tumor necrosis factor-α promoter gene polymorphisms in Argentinean lupus patients: focus on lupus nephritis.

    PubMed

    Muñoz, Sebastián Andrés; Aranda, Federico; Allievi, Alberto; Orden, Alberto Omar; Perés Wingeyer, Silvia; Trobo, Rosana; Alvarez, Analía; Eimon, Alicia; Barreira, Juan Carlos; Schneeberger, Emilce; Dal Pra, Fernando; Sarano, Judith; Hofman, Julio; Chamorro, Julián; de Larrañaga, Gabriela

    2014-02-01

    We investigated the relationship between the 4G/5G plasminogen activator inhibitor (PAI-1) and -308 A/G tumor necrosis factor-α (TNF-α) polymorphisms and the clinical and biochemical features of systemic lupus erythematosus (SLE) in an Argentinean patient cohort. A total of 402 patients were studied, including 179 SLE patients and 223 healthy individuals. PCR-RLFP was used to determine the genotypes of the 4G/5G PAI-1 and -308 A/G TNF-α polymorphisms. SLE patients with lupus nephritis (LN) (n = 86) were compared with patients without LN (n = 93). Additionally, LN patients were divided into proliferative LN and non-proliferative LN groups according to the results of the renal biopsies. No significant differences were noted in the genotype distributions or allele frequencies of these TNF-α and PAI-1 polymorphisms between SLE patients and controls. There were higher numbers of criteria for SLE, more lupus flares and higher damage scores in LN patients, but there were similar frequencies of anti-phospholipid antibody (APA) positivity and anti-phospholipid syndrome. No significant difference was noted for any studied variable between the proliferative LN and non-proliferative LN groups except for the presence of APA. We found no significant differences in the TNF-α and PAI-1 genotype distributions or allele frequencies between groups. We found that the -308 A/G TNF-α and 4G/5G PAI-1 polymorphisms are not associated with susceptibility to SLE in an Argentinean population. We also did not find any association between the presence of any specific allele or genotype and the development of LN in SLE patients. Finally, no association was noted between either of the two polymorphisms and the severity of renal disease.

  19. Golimumab in patients with active rheumatoid arthritis who have previous experience with tumour necrosis factor inhibitors: results of a long-term extension of the randomised, double-blind, placebo-controlled GO-AFTER study through week 160

    PubMed Central

    Smolen, Josef S; Kay, Jonathan; Landewé, Robert B M; Matteson, Eric L; Gaylis, Norman; Wollenhaupt, Jurgen; Murphy, Frederick T; Zhou, Yiying; Hsia, Elizabeth C; Doyle, Mittie K

    2012-01-01

    Objective The aim of this study was to assess long-term golimumab therapy in patients with rheumatoid arthritis (RA) who discontinued previous tumour necrosis factor alpha (TNFα) inhibitor(s) for any reason. Methods Results through week 24 of this multicentre, randomised, double-blind, placebo-controlled study of active RA (≥4 tender, ≥4 swollen joints) were previously reported. Patients received placebo (Group 1), 50 mg golimumab (Group 2) or 100 mg golimumab (Group 3) subcutaneous injections every 4 weeks. Patients from Groups 1 and 2 with <20% improvement in tender/swollen joints at week 16 early escaped to golimumab 50 mg and 100 mg, respectively. At week 24, Group 1 patients crossed over to golimumab 50 mg, Group 2 continued golimumab 50/100 mg per escape status and Group 3 maintained dosing. Data through week 160 are reported. Results 459 of the 461 randomised patients were treated; 236/459 (51%) continued treatment through week 160. From week 24 to week 100, ACR20 (≥20% improvement in American College of Rheumatology criteria) response and ≥0.25 unit HAQ (Health Assessment Questionnaire) improvement were sustained in 70–73% and 75–81% of responding patients, respectively. Overall at week 160, 63%, 67% and 57% of patients achieved ACR20 response and 59%, 65% and 64% had HAQ improvement ≥0.25 unit in Groups 1, 2 and 3, respectively. Adjusted for follow-up duration, adverse event incidences (95% CI) per 100 patient-years among patients treated with golimumab 50 mg and 100 mg were 4.70 (2.63 to 7.75) and 8.07 (6.02 to 10.58) for serious infection, 0.95 (0.20 to 2.77) and 2.04 (1.09 to 3.49) for malignancy and 0.00 (0.00 to 0.94) and 0.62 (0.17 to 1.59) for death, respectively. Conclusion In patients with active RA who discontinued previous TNF-antagonist treatment, golimumab 50 and 100 mg injections every 4 weeks yielded sustained improvements in signs/symptoms and physical function in ∼57–67% of patients who continued treatment. Golimumab

  20. Tumor necrosis factor interaction with gold nanoparticles

    NASA Astrophysics Data System (ADS)

    Tsai, De-Hao; Elzey, Sherrie; Delrio, Frank W.; Keene, Athena M.; Tyner, Katherine M.; Clogston, Jeffrey D.; Maccuspie, Robert I.; Guha, Suvajyoti; Zachariah, Michael R.; Hackley, Vincent A.

    2012-05-01

    We report on a systematic investigation of molecular conjugation of tumor necrosis factor-α (TNF) protein onto gold nanoparticles (AuNPs) and the subsequent binding behavior to its antibody (anti-TNF). We employ a combination of physical and spectroscopic characterization methods, including electrospray-differential mobility analysis, dynamic light scattering, polyacrylamide gel electrophoresis, attenuated total reflectance-Fourier transform infrared spectroscopy, fluorescence assay, and enzyme-linked immunosorbent assay. The native TNF used in this study exists in the active homotrimer configuration prior to conjugation. After binding to AuNPs, the maximum surface density of TNF is (0.09 +/- 0.02) nm-2 with a binding constant of 3 × 106 (mol L-1)-1. Dodecyl sulfate ions induce desorption of monomeric TNF from the AuNP surface, indicating a relatively weak intermolecular binding within the AuNP-bound TNF trimers. Anti-TNF binds to both TNF-conjugated and citrate-stabilized AuNPs, showing that non-specific binding is significant. Based on the number of anti-TNF molecules adsorbed, a substantially higher binding affinity was observed for the TNF-conjugated surface. The inclusion of thiolated polyethylene glycol (SH-PEG) on the AuNPs inhibits the binding of anti-TNF, and the amount of inhibition is related to the number ratio of surface bound SH-PEG to TNF and the way in which the ligands are introduced. This study highlights the challenges in quantitatively characterizing complex hybrid nanoscale conjugates, and provides insight on TNF-AuNP formation and activity.We report on a systematic investigation of molecular conjugation of tumor necrosis factor-α (TNF) protein onto gold nanoparticles (AuNPs) and the subsequent binding behavior to its antibody (anti-TNF). We employ a combination of physical and spectroscopic characterization methods, including electrospray-differential mobility analysis, dynamic light scattering, polyacrylamide gel electrophoresis

  1. Modulation of topoisomerase activities by tumor necrosis factor.

    PubMed

    Baloch, Z; Cohen, S; Fresa, K; Coffman, F D

    1995-01-01

    A number of chemotherapeutic agents which inhibit the DNA topoisomerases markedly potentiate cell death mediated by tumor necrosis factor, suggesting a role for these enzymes in the TNF cytotoxic mechanism. To investigate this possibility, topoisomerase I and II activities were assayed following TNF addition to murine L929 cells. Topoisomerase I and II activities increased within 15 min of TNF addition and returned to baseline levels within 1 and 2 hr, respectively. The increases in both topoisomerase activities were blocked by H-7 (but not H-8) and similar increases were seen following PMA addition. However, concentrations of H-7 which blocked the increased topoisomerase activities had no effect on TNF cytotoxicity nor on the enhancement of TNF cytotoxicity by topoisomerase inhibitors. Thus, in these cells topoisomerase activities are directly modified by TNF during the initial phases of a cytotoxic response. However, neither TNF cytotoxicity nor the enhancement of TNF cytotoxicity by topoisomerase inhibitors appears to require the TNF-mediated increases in topoisomerase activities.

  2. One-Year Tuberculosis Risk in Rheumatoid Arthritis Patients Starting Their First Tumor Necrosis Factor Inhibitor Therapy from 2008 to 2012 in Taiwan: A Nationwide Population-Based Cohort Study

    PubMed Central

    Chen, Der-Yuan; Chen, Yi-Ming; Chao, Wen-Cheng; Liao, Tsai-Ling

    2016-01-01

    Objective To investigate the risk of tuberculosis (TB) among rheumatoid arthritis (RA) patients within 1 year after initiation of tumor necrosis factor inhibitor (TNFi) therapy from 2008 to 2012. Methods We used the 2003–2013 Taiwanese National Health Insurance Research Database to identify RA patients who started any RA-related medical therapy from 2008 to 2012. Those who initiated etanercept or adalimumab therapy during 2008–2012 were selected as the TNFi group and those who never received biologic disease-modifying anti-rheumatic drug therapy were identified as the comparison group after excluding the patients who had a history of TB or human immunodeficiency virus infection/acquired immune deficiency syndrome. We used propensity score matching (1:6) for age, sex, and the year of the drug index date to re-select the TNFi group and the non-TNFi controls. After adjusting for potential confounders, hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to examine the 1-year TB risk in the TNFi group compared with the non-TNFi controls. Subgroup analyses according to the year of treatment initiation and specific TNFi therapy were conducted to assess the trend of 1-year TB risk in TNFi users from 2008 to 2012. Results This study identified 5,349 TNFi-treated RA patients and 32,064 matched non-TNFi-treated controls. The 1-year incidence rates of TB were 1,513 per 105 years among the TNFi group and 235 per 105 years among the non-TNFi controls (incidence rate ratio, 6.44; 95% CI, 4.69–8.33). After adjusting for age, gender, disease duration, comoridities, history of TB, and concomitant medications, TNFi users had an increased 1-year TB risk (HR, 7.19; 95% CI, 4.18–12.34) compared with the non-TNFi-treated controls. The 1-year TB risk in TNFi users increased from 2008 to 2011 and deceased in 2012 when the Food and Drug Administration in Taiwan announced the Risk Management Plan for patients scheduled to receive TNFi therapy. Conclusion This

  3. One-Year Tuberculosis Risk in Rheumatoid Arthritis Patients Starting Their First Tumor Necrosis Factor Inhibitor Therapy from 2008 to 2012 in Taiwan: A Nationwide Population-Based Cohort Study.

    PubMed

    Lim, Chong-Hong; Lin, Ching-Heng; Chen, Der-Yuan; Chen, Yi-Ming; Chao, Wen-Cheng; Liao, Tsai-Ling; Chen, Hsin-Hua

    2016-01-01

    To investigate the risk of tuberculosis (TB) among rheumatoid arthritis (RA) patients within 1 year after initiation of tumor necrosis factor inhibitor (TNFi) therapy from 2008 to 2012. We used the 2003-2013 Taiwanese National Health Insurance Research Database to identify RA patients who started any RA-related medical therapy from 2008 to 2012. Those who initiated etanercept or adalimumab therapy during 2008-2012 were selected as the TNFi group and those who never received biologic disease-modifying anti-rheumatic drug therapy were identified as the comparison group after excluding the patients who had a history of TB or human immunodeficiency virus infection/acquired immune deficiency syndrome. We used propensity score matching (1:6) for age, sex, and the year of the drug index date to re-select the TNFi group and the non-TNFi controls. After adjusting for potential confounders, hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to examine the 1-year TB risk in the TNFi group compared with the non-TNFi controls. Subgroup analyses according to the year of treatment initiation and specific TNFi therapy were conducted to assess the trend of 1-year TB risk in TNFi users from 2008 to 2012. This study identified 5,349 TNFi-treated RA patients and 32,064 matched non-TNFi-treated controls. The 1-year incidence rates of TB were 1,513 per 105 years among the TNFi group and 235 per 105 years among the non-TNFi controls (incidence rate ratio, 6.44; 95% CI, 4.69-8.33). After adjusting for age, gender, disease duration, comoridities, history of TB, and concomitant medications, TNFi users had an increased 1-year TB risk (HR, 7.19; 95% CI, 4.18-12.34) compared with the non-TNFi-treated controls. The 1-year TB risk in TNFi users increased from 2008 to 2011 and deceased in 2012 when the Food and Drug Administration in Taiwan announced the Risk Management Plan for patients scheduled to receive TNFi therapy. This study showed that the 1-year TB risk in RA

  4. (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), a selective and orally active inhibitor of tumor necrosis factor-alpha convertase.

    PubMed

    Beck, G; Bottomley, G; Bradshaw, D; Brewster, M; Broadhurst, M; Devos, R; Hill, C; Johnson, W; Kim, H-J; Kirtland, S; Kneer, J; Lad, N; Mackenzie, R; Martin, R; Nixon, J; Price, G; Rodwell, A; Rose, F; Tang, J-P; Walter, D S; Wilson, K; Worth, E

    2002-07-01

    Tumor necrosis factor-alpha (TNF-alpha), a cytokine secreted by inflammatory cells, has been implicated in several inflammatory disease states. (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), is a potent, orally active inhibitor of the TNF-alpha convertase (TACE), an enzyme responsible for proteolytic cleavage of the membrane bound precursor, pro-TNF-alpha. Ro 32-7315 inhibited a recombinant form of TACE (IC(50) = 5.2 nM) with selectivity over related matrix metalloproteinases. In a cellular assay system, THP-1 cell line, and in human and rat whole blood, Ro 32-7315 significantly reduced lipopolysaccharide (LPS)-induced TNF-alpha release with IC(50) values of 350 +/- 14 nM (n = 5), 2.4 +/- 0.5 microM (n = 5), and 110 +/- 18 nM (n = 5), respectively. Oral administration of Ro 32-7315 to Wistar rats caused a dose-dependent inhibition of LPS-induced release of systemic TNF-alpha with an ED(50) of 25 mg/kg. Treatment (days 0-14) of Allen and Hamburys hooded rats with Ro 32-7315 (2.5, 5, 10, and 20 mg/kg, i.p., twice daily) significantly reduced adjuvant-induced secondary paw swelling (42, 71, 83, and 93%, respectively) as compared with the vehicle group. In the Ro 32-7315-treated group, the reduced paw swelling was associated with improved lesion score and joint mobility. Furthermore, in a placebo-controlled, single-dose study, Ro 32-7315 given orally (450 mg) significantly suppressed ex vivo, LPS-induced TNF-alpha release in the whole-blood samples taken from healthy male and female volunteers (mean inhibition of 42% over a 4-h duration, n = 6). These data collectively support the potential use of such a compound for the oral treatment of inflammatory disorders.

  5. 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.

  6. Newest clinical trial results with antitumor necrosis factor and nonantitumor necrosis factor biologics for rheumatoid arthritis.

    PubMed

    Navarro-Millán, Iris; Curtis, Jeffrey R

    2013-05-01

    To highlight recent evidence from the clinical trials of anti-tumor necrosis factor (TNF) and non anti-TNF biologics for rheumatoid arthritis (RA) focused on comparative clinical efficacy including safety outcomes and medication discontinuation. Patients with RA are sometimes able to attain low disease activity or remission since the introduction of biologic therapy for RA. Biologics like anti-TNF, anti-interleukin-6 (IL-6), anti-CD20 and those that modulate T-cell co-stimulation have consistently shown good efficacy in patients with RA. Preliminary data from comparative efficacy studies to evaluate the potential differences between anti-TNF and non anti-TNF biologics have shown little differences among these. There is ongoing work in comparative efficacy to answer this question further. Biologic therapy in RA has significantly changed the course of RA in the last decade. Recently published clinical trials have been focused on comparative efficacy, cardiovascular safety of biologics and potential anti-TNF therapy discontinuation in patients with RA.

  7. [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.

  8. 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.

  9. Evidence for ovarian tumor necrosis factor

    SciTech Connect

    Roby, K.F.

    1989-01-01

    Ovarian folliculogenesis and luteal formation occur concomitantly with the development of new blood vessels that function in nutritional support of the developing follicles. As follicles undergo atresia and the corpus luteum regresses, blood vessels supplying these tissues degenerate. The first study determined if the ovary contained factors that might regulate ovarian angiogenesis. The bovine ovary was subjected to ammonium sulfate (AS) precipitation and the precipitates (ppt.) were assayed in vitro for effects on endothelial cell (CPAE) and fibroblast (3T3 and L929) incorporation of {sup 3}H-thymidine. Heparin sepharose (HS) chromatography of the 80% AS ppt. revealed the inhibitory activity on CPAE and L929 cells did not bind to HS but was found in the HS column breakthrough (80% BT). Sizing chromatography of the 80% BT indicated thymidine incorporation inhibitory activity exhibited a molecular weight of 30,000-50,000 Daltons. TNF was immunohistochemically localized in the human, bovine and rat ovary. Frozen sections were incubated with polyclonal antibody to human recombinant TNF. Antigen-antibody binding was visualized using a Biotin-StreptAvidin peroxidase technique. Immunoreactive TNF (I-TNF) was localized in corpora lutea and the more antral layers of granulosa cells in antral follicles. Incubation of sections with anti-TNF in the presence of excess TNF resulted in lose of immunostaining. Cell blotting and ELISA further indicated I-TNF was present in granulosa cells. In order to determine whether TNF had an effect on follicular steroidogenesis, preovulatory follicles from cyclic proestrus rats were incubated in vitro for up to 24 hours with various doses of human recombinant TNF. Stepwise increases in progesterone (P) accumulation in the incubation media were observed with 30-300 pM TNF.

  10. Effect of tetrandrine on calcium-dependent tumour necrosis factor-alpha production in glia-neurone mixed cultures.

    PubMed

    Wang, Bin; Yang, Li; Yan, Hong-Li; Wang, Meng; Xiao, Ji-Gao

    2005-10-01

    Tumour necrosis factor-alpha is believed to have a deleterious role in the pathophysiology of brain injury. Tetrandrine has protective effect on neuronal cells, however, the mechanisms involved in its action have not been clearly established. The aim of this study was to investigate the role of tetrandrine on calcium-dependent tumour necrosis factor-alpha production in glia-neurone mixed cultures. Glia-neurone mixed cultures were treated by addition of Ca2+ regulating agents for a period of 6 hr. Tetrandrine or/and TMB-8 were added 30 min. before the stimulation. The supernatant tumour necrosis factor-alpha levels were quantified by enzyme-linked immunosorbent assay. Exposure of lipopolysaccharide 10 and 100 ng/ml caused significant increase in tumour necrosis factor-alpha production respectively, with no alteration in cultures treated with 1 ng/ml lipopolysaccharide. Glia-neurone mixed cultures exhibited a marked elevation in tumour necrosis factor-alpha production after exposure to CaCl2, KCl, thapsigargin, BHQ and norepinephrine in the presence of lipopolysaccharide at 1 ng/ml respectively. Tetrandrine 0.3, 1, and 3 microM concentration-dependently reduced tumour necrosis factor-alpha production evoked by CaCl2 or KCl. Tetrandrine preincubation had no significant effect on the response to Ca2+-ATPase inhibitor thapsigargin or BHQ. Norepinephrine-induced tumour necrosis factor-alpha production was significantly reduced by tetrandrine and almost abolished by combination of tetrandrine and intracellular Ca2+ release inhibitor TMB-8. These results suggested that tetrandrine at a concentration of 0.3, 1, or 3 microM inhibited tumour necrosis factor-alpha production induced by Ca2+ entry in glia-neurone mixed cultures.

  11. Polymorphism in the tumour necrosis factor receptor II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis

    PubMed Central

    Glossop, John R; Dawes, Peter T; Nixon, Nicola B; Mattey, Derek L

    2005-01-01

    Levels of soluble tumour necrosis factor receptors (sTNFRs) are elevated in the circulation of patients with rheumatoid arthritis (RA). Although these receptors can act as natural inhibitors of tumour necrosis factor-α, levels of sTNFRs in RA appear to be insufficient to prevent tumour necrosis factor-α induced inflammation. The factors that regulate circulating levels of sTNFRs are unclear, but polymorphisms in the tumour necrosis factor receptor genes may play a role. We investigated the relationship between polymorphisms in the tumour necrosis factor receptor I (TNF-RI) and II (TNF-RII) genes and levels of sTNFRs in two groups of Caucasian RA patients: one with early (disease duration ≤2 years; n = 103) and one with established disease (disease duration ≥5 years; n = 151). PCR restriction fragment length polymorphism analysis was used to genotype patients for the A36G polymorphism in the TNF-RI gene and the T676G polymorphism in TNF-RII. Levels of sTNFRs were measured using ELISA. We also isolated T cells from peripheral blood of 58 patients with established RA with known TNF-R genotypes, and release of sTNFRs into the culture medium was measured in cells incubated with or without phytohaemagglutinin. Serum levels of the two sTNFRs (sTNF-RI and sTNF-RII) were positively correlated in both populations, and the level of each sTNFR was significantly higher in the patients with established disease (P < 0.0001). Multiple regression analyses corrected for age, sex and disease duration revealed a significant trend toward decreasing sTNF-RI and sTNF-RII levels across the TNF-RII genotypes (TT > TG > GG) of patients with established disease (P for trend = 0.01 and P for trend = 0.03, respectively). A similar nonsignificant trend was seen for early disease. No relationship with the TNF-RI A36G polymorphism was observed. sTNFRs released by isolated T cells exhibited a similar trend toward decreasing levels according to TNF-RII genotype, although only the association

  12. Shedding of tumor necrosis factor receptors by activated human neutrophils

    PubMed Central

    1990-01-01

    The capacity of human neutrophils (PMN) to bind tumor necrosis factor (TNF) was rapidly lost when the cells were incubated in suspension with agents that can stimulate their migratory and secretory responses. Both physiological (poly)peptides (FMLP, C5a, CSF-GM) and pharmacologic agonists (PMN, calcium ionophore A23187) induced the loss of TNF receptors (TNF-R) from the cell surface. Half-maximal loss in TNF-R ensued after only approximately 2 min with 10(-7) M FMLP at 37 degrees C, and required only 10(-9) M FMLP during a 30-min exposure. However, there were no such changes even with prolonged exposure of PMN to FMLP at 4 degrees or 16 degrees C. Scatchard analysis revealed loss of TNF- binding sites without change in their affinity (Kd approximately 0.4 nM) as measured at incompletely modulating concentrations of FMLP, C5a, PMA, or A23187. The binding of anti-TNF-R mAbs to PMN decreased in parallel, providing independent evidence for the loss of TNF-R from the cell surface. At the same time, soluble TNF-R appeared in the medium of stimulated PMN. This inference was based on the PMN- and FMLP-dependent generation of a nonsedimentable activity that could inhibit the binding of TNF to fresh human PMN or to mouse macrophages, and the ability of mAbs specific for human TNF-R to abolish inhibition by PMN-conditioned medium of binding of TNF to mouse macrophages. Soluble TNF-R activity was associated with a protein of Mr approximately 28,000 by ligand blot analysis of cell-free supernatants of FMLP-treated PMN. Thus, some portion of the FMLP-induced loss of TNF-R from human PMN is due to shedding of TNF-R. Shedding was unaffected by inhibitors of serine and thiol proteases and could not be induced with phosphatidylinositol- specific phospholipase C. Loss of TNF-R from PMN first stimulated by other agents may decrease their responsiveness to TNF. TNF-R shed by PMN may be one source of the TNF-binding proteins found in body fluids, and may blunt the actions of the

  13. Tumor necrosis factor-alpha antagonism by the murine tumor necrosis factor-alpha receptor 2-Fc fusion protein exacerbates histoplasmosis in mice.

    PubMed

    Deepe, George S

    2007-06-01

    Treatment of some inflammatory conditions with tumor necrosis factor-alpha (TNF-alpha) antagonists is efficacious, but such treatments are associated with infections with intracellular pathogens, including Histoplasma capsulatum. We explored protective immunity to H. capsulatum in mice given a fusion protein consisting of TNF-alpha receptor 2 (TNFR2) bound to the Fc portion of mouse IgG1. Intraperitoneal administration of this inhibitor exacerbated primary or secondary pulmonary infection at dosages ranging from 1 to 5 mg/kg. All mice with primary infection given the inhibitor succumbed to infection within 10-21 days of treatment. In secondary histoplasmosis, mice receiving 1, but not 5, mg/kg survived treatment. Fungal burden was increased even if treatment with the inhibitor was initiated after the onset of infection. The inflammatory response of the lungs of mice given the inhibitor did not differ from that of mice given control vehicle. Susceptibility was not associated with major alterations in cytokines known to protect or exacerbate infection. However, expression of nitric oxide synthase 2 (NOS2) was depressed early in primary infection. These results demonstrate that antagonism of endogenous TNF-alpha by this fusion protein modulates susceptibility. Impaired immunity is not a result of altered cytokine responses or changes in the inflammation and may not be demonstrable in other murine strains.

  14. Structure/Function analysis of p55 tumor necrosis factor receptor and fas-associated death domain. Effect on necrosis in L929sA cells.

    PubMed

    Boone, E; Vanden Berghe, T; Van Loo, G; De Wilde, G; De Wael, N; Vercammen, D; Fiers, W; Haegeman, G; Vandenabeele, P

    2000-12-01

    Tumor necrosis factor (TNF) induces a typical apoptotic cell death program in various cell lines by interacting with the p55 tumor necrosis factor receptor (TNF-R55). In contrast, triggering of the fibrosarcoma cell line L929sA gives rise to characteristic cellular changes resulting in necrosis. The intracellular domain of TNF-R55 can be subdivided into two parts: a membrane-proximal domain (amino acids 202-325) and a C-terminal death domain (DD) (amino acids 326-413), which has been shown to be necessary and sufficient for apoptosis. Structure/function analysis of TNF-R55-mediated necrosis in L929sA cells demonstrated that initiation of necrotic cell death, as defined by swelling of the cells, rapid membrane permeabilization, absence of nuclear condensation, absence of DNA hypoploidy, and generation of mitochondrial reactive oxygen intermediates, is also confined to the DD. The striking synergistic effect of the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone on TNF-induced necrosis was also observed with receptors solely containing the DD. TNF-R55-mediated necrosis is not affected by the dominant negative deletion mutant of the Fas-associated death domain (FADD-(80-205)) that lacks the N-terminal death effector domain. Moreover, overexpression of FADD-(80-205) in L929sA is cytotoxic and insensitive to CrmA, while the cytotoxicity due to overexpression of the deletion mutant FADD-(1-111) lacking the DD is prevented by CrmA. These results demonstrate that the death domain of FADD can elicit an active necrotic cell death pathway.

  15. The role of tumor necrosis factor-α in the pathogenesis of vitiligo.

    PubMed

    Camara-Lemarroy, Carlos R; Salas-Alanis, Julio C

    2013-10-01

    Vitiligo is an acquired immune disorder of the skin characterized by the presence of white depigmented macules. Its immunopathogenesis is not completely understood, but inflammatory alterations in the skin microenvironment, and particularly increased expression of the cytokine tumor necrosis factor-α (TNFα), are thought to be essential regulators of melanocyte dysfunction and death. In this article we review the evidence that implicates TNFα in the pathogenesis of vitiligo, including studies on serum and tissue levels of TNFα, TNFα gene polymorphisms, in vitro studies, and therapeutic trials using TNFα inhibitors. TNFα emerges as a complex mediator with apparently conflicting roles in vitiligo.

  16. Tumour necrosis factor alpha and use of infliximab

    PubMed Central

    Shrim, Alan; Koren, Gideon

    2005-01-01

    QUESTION A 27-year-old patient of mine with rheumatoid arthritis has been treated with infliximab for the last 5 years. She is planning her first pregnancy. How should I advise her regarding use of infliximab during pregnancy, bearing in mind that infliximab substantially improved her medical condition? ANSWER Infliximab (Remicade) has not been tested in pregnant animals because it does not interact with non–human tumour necrosis factor (TNF) alpha. Several case reports describing women who used infliximab during pregnancy do not suggest a strong association with adverse pregnancy outcomes. More studies are required to determine infliximab’s safety during pregnancy. PMID:15934268

  17. Anti-tumor necrosis factor therapy inhibits lung metastasis in an osteosarcoma cell line.

    PubMed

    Kato, Hiroaki; Wakabayashi, Hiroki; Naito, Yohei; Kato, Sho; Nakagawa, Taro; Matsumine, Akihiko; Sudo, Akihiro

    2015-01-01

    Osteosarcoma is the most common primary malignancy of bone, and patients often develop pulmonary metastases. In a previous study, tumor necrosis factor (TNF)-α treatment of human osteosarcoma cells increases their metastatic ability in an animal model. TNF-α can act as a tumor necrosis factor and also as a tumor-promoting factor. In the present study, the effect of a TNF-α inhibitor on osteosarcoma aggressiveness and pulmonary metastases was investigated in vitro and in vivo. The effect of infliximab, a TNF-α inhibitor, on a metastatic osteosarcoma 143B cell growth and motility was investigated in vitro. An orthotopic xenograft model of 143B cell growth and spontaneous metastasis in SCID mice was used to assess the in vivo effect of infliximab. Infliximab greatly reduced cell motility and pulmonary metastases in 143B cells. The mechanism of pulmonary metastasis inhibition involved decreased expression of CXC chemokine receptor 4 (CXCR4), Rho (small GTPase protein), and its effector. These results suggest a novel role for TNF-α inhibition in the reduction or prevention of pulmonary metastases of osteosarcoma in this animal model. TNF-α inhibition may become a preventive therapeutic option for the pulmonary metastases of osteosarcoma. © 2014 S. Karger AG, Basel.

  18. 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.

  19. Tumor Necrosis Factor Receptor/Tumor Necrosis Factor Family Members in Antiviral CD8 T-Cell Immunity

    PubMed Central

    2010-01-01

    CD8 memory T cells can play a critical role in protection against repeated exposure to infectious agents such as viruses, yet can also contribute to the immunopathology associated with these pathogens. Understanding the mechanisms that control effective memory responses has important ramifications for vaccine design and in the management of adverse immune reactions. Recent studies have implicated several members of the tumor necrosis factor receptor (TNFR) family as key stimulatory and inhibitory molecules involved in the regulation of CD8 T cells. In this review, we discuss their control of the generation, persistence, and reactivation of CD8 T cells during virus infection. PMID:20377415

  20. Mediation of mouse natural cytotoxic activity by tumour necrosis factor

    NASA Astrophysics Data System (ADS)

    Ortaldo, John R.; Mason, Llewellyn H.; Mathieson, Bonnie J.; Liang, Shu-Mei; Flick, David A.; Herberman, Ronald B.

    1986-06-01

    Natural cell-mediated cytotoxic activity in the mouse has been associated with two types of effector cells, the natural killer (NK) cell and the natural cytotoxic (NC) cell, which seem to differ with regard to their patterns of target selectivity, cell surface characteristics and susceptibility to regulatory factors1. During studies on the mechanism of action of cytotoxic molecules, it became evident that WEHI-164, the prototype NC target cell, was highly susceptible to direct lysis by both human and mouse recombinant tumour necrosis factor (TNF). Here we show that NC, but not NK activity mediated by normal splenocytes, is abrogated by rabbit antibodies to recombinant and natural TNF, respectively. Thus, the cell-mediated activity defined as NC is due to release of TNF by normal spleen cells and does not represent a unique natural effector mechanism.

  1. Tumor necrosis factor alpha-induced angiogenesis depends on in situ platelet-activating factor biosynthesis

    PubMed Central

    1994-01-01

    Tumor necrosis factor (TNF) alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Therefore, it was suggested that the angiogenic properties of this agent might be consequent to the production of secondary mediators. Since TNF-alpha stimulates the synthesis of platelet-activating factor (PAF) by monocytes and endothelial cells, we investigated the possible involvement of PAF in the angiogenic effect of TNF-alpha. Angiogenesis was studied in a murine model in which Matrigel was used as a vehicle for the delivery of mediators. In this model the angiogenesis induced by TNF-alpha was shown to be inhibited by WEB 2170, a specific PAF receptor antagonist. Moreover, in mice injected with TNF-alpha, PAF was detected within the Matrigel, 6 and 24 h after TNF-alpha injection. The synthesis of PAF within the Matrigel was concomitant with the early migration of endothelial cells and infiltration of monocytes. No infiltration of lymphocytes or polymorphonuclear leukocytes was observed. Synthetic PAF as well as PAF extracted and purified from mice challenged with TNF-alpha induced a rapid angiogenic response, inhibited by WEB 2170. These results suggest that the angiogenic effect of TNF-alpha is, at least in part, mediated by PAF synthesized from monocytes and/or endothelial cells infiltrating the Matrigel plug. PMID:7516414

  2. 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.

  3. Acute tubular necrosis associated with mTOR inhibitor therapy: a real entity biopsy-proven.

    PubMed

    Izzedine, H; Escudier, B; Rouvier, P; Gueutin, V; Varga, A; Bahleda, R; Soria, J C

    2013-09-01

    The protein kinase mTOR (mammalian target of rapamycin) is a critical regulator of cellular metabolism, growth, and proliferation. Inhibitors of mTOR have immunosuppressive and anti-cancer effects, but their effects on the progression of kidney disease are not fully understood. Their most common side-effects include stomatitis, rash, dyslipidemia, hyperglycemia, fatigue, and pneumonitis. However, to the best of our knowledge these agents have not been previously reported to cause severe acute kidney injury (AKI). We describe four cases of patients with cancer who developed AKI after starting mTOR inhibitor therapy. A kidney biopsy showed acute tubular necrosis (ATN) with prominent tubular dysfunction. Withdrawal of the drug leads to a rapid recovery in two cases. However, a fixed renal dysfunction was noted in the other two cases, one of which will remain dialysis-dependent. Such patients lead to a broad differential diagnosis of AKI including prerenal AKI, ATN, cancer-related GN, and drug-induced acute interstitial nephritis. Accurate history, physical examination, laboratory data, and kidney biopsy are highlighted in establishing the correct diagnosis in such patients. ATN have not been reported with mTOR inhibitor use. These cases demonstrated a potentially new and serious adverse consequence occurring with the use of an mTOR inhibitor, of which physicians need to be aware.

  4. Aloe emodin inhibits the cytotoxic action of tumor necrosis factor.

    PubMed

    Harhaji, Ljubica; Mijatovic, Sanja; Maksimovic-Ivanic, Danijela; Popadic, Dusan; Isakovic, Aleksandra; Todorovic-Markovic, Biljana; Trajkovic, Vladimir

    2007-07-30

    We demonstrate the capacity of an herbal anthraquinone aloe emodin to reduce the cytotoxicity of the proinflammatory cytokine tumor necrosis factor (TNF) towards L929 mouse fibrosarcoma and U251 human glioma cell lines. Aloe emodin inhibited both TNF-induced cell necrosis and apoptosis, but it did not reduce cell death induced by UV radiation or hydrogen peroxide. Aloe emodin inhibited both basal and TNF-triggered activation of extracellular signal-regulated kinase (ERK), and a selective blockade of ERK activation mimicked the cytoprotective action of the drug. On the other hand, aloe emodin did not affect TNF-induced activation of p38 mitogen-activated protein kinase or generation of reactive oxygen species. The combination of aloe emodin and TNF caused an intracellular appearance of acidified autophagic vesicles, and the inhibition of autophagy with bafilomycin or 3-methyladenine efficiently blocked the cytoprotective action of aloe emodin. These data indicate that aloe emodin could prevent TNF-triggered cell death through mechanisms involving induction of autophagy and blockade of ERK activation.

  5. A comparison of an interferon-gamma release assay and tuberculin skin test in refractory inflammatory disease patients screened for latent tuberculosis prior to the initiation of a first tumor necrosis factor α inhibitor.

    PubMed

    Kwakernaak, Arjan J; Houtman, Pieternella M; Weel, Jan F L; Spoorenberg, Johanna P L; Jansen, Tim L T A

    2011-04-01

    Treatment with TNFα inhibitors increases risk of reactivating a latent tuberculosis\\infection (LTBI). Therefore screening, prior to therapy with TNFα inhibitors, has been recommended, even in low-endemic areas such as well-developed Western Europe countries. We evaluated interferon-gamma release assay (IGRA), as opposed to tuberculin skin test (TST), for detection of LTBI in refractory inflammatory disease patients prior to the initiation of a first TNFα inhibitor. In addition, we evaluated the impact of impaired cellular immunity on IGRA. Patients starting on TNFα inhibition were screened for LTBI by TST and IGRA (Quantiferon-TB Gold). Data on tuberculosis exposure and Bacillus Calmette-Guérin (BCG) vaccination were obtained. Cellular immunity was assessed by CD4(+) T lymphocyte cell count. Nine out of 56 patients (16.1%) tested positive for LTBI. A concordant positive result was present in three patients with a medical history of tuberculosis exposure. Six patients with discordant test results had either: (1) a negative TST and positive IGRA in combination with a medical history of tuberculosis exposure (n = 1) or (2) a positive TST and negative IGRA in combination with BCG vaccination (n = 3) or a medical history of tuberculosis exposure (n = 2). CD4(+) T lymphocyte cell counts were within normal limits, and no indeterminate results of IGRA were present. IGRA appears reliable for confirming TST and excluding a false positive TST (due to prior BCG vaccination) in this Dutch serie of patients. In addition, IGRA may detect one additional case of LTBI out of 56 patients that would otherwise be missed using solely TST. Immune suppression appears not to result significantly in lower CD4(+) T lymphocyte cell counts and indeterminate results of IGRA, despite systemic corticosteroid treatment in half of the patients. Confirmation in larger studies, including assessment of cost-effectiveness, is required.

  6. 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

  7. Tumour necrosis factor-α in nasal allergy

    PubMed Central

    Ganbo, T.; Nakazawa, T.; Nakajima, T.; Ko, J.; Goto, R.; Murakami, Y.; Misui, K.

    1995-01-01

    Tumour necrosis factor-α (TNF-α) was measured by enzyme-linked immunosorbent assay and eosinophil cationic protein (ECP) by radio-immunoassay to evaluate TNF-α in nasal allergy. There was no significant difference either between the mean concentrations of TNF-α in nasal secretions from the patients with perennial nasal allergy and those of normal subjects, or between the TNF-α and ECP concentrations. However, reverse transcription polymerase chain reaction showed a specific increase of TNF-α mRNA and IFN-γ mRNA in allergic nasal mucosa after allergen challenge in vitro. These findings suggest a possibility that T cell-derived IFN-γ up-regulates macrophages to elaborate TNF-α, which may play a role in amplifying allergic inflammation in the nose through the cytokine network. PMID:18475667

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

    PubMed

    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.

  9. Tumor necrosis factor alpha and lymphotoxin production in Hodgkin's disease.

    PubMed

    Kretschmer, C; Jones, D B; Morrison, K; Schlüter, C; Feist, W; Ulmer, A J; Arnoldi, J; Matthes, J; Diamantstein, T; Flad, H D

    1990-08-01

    It is likely that the characteristic histologic features of Hodgkin's disease reflect cytokine production by the tumor cell population. Tumor necrosis factor alpha (TNF-alpha) and lymphotoxin (tumor necrosis factor beta [TNF-beta]) are important inflammatory mediators with wide-ranging effects within the lymphoreticular system. The aim of the present study was to investigate TNF-alpha and lymphotoxin production in the Hodgkin's disease-derived cell lines L428 and L540. At the product level, both cytokines could be demonstrated by immunostaining with specific monoclonal antibodies. TNF-alpha could be demonstrated by means of an enzyme-linked immunosorbent assay in culture supernatants from both cell lines as well as in cell lysates of L428 and L540 cells. Cytotoxic activity could be achieved only in L428 supernatants. This cytotoxic activity could not be blocked by the addition of a polyclonal antibody against TNF-alpha, but was partially inhibited with the monoclonal antibody against lymphotoxin. Synthesis of TNF-alpha and lymphotoxin in both L428 and L540 was confirmed by demonstrating the intracellular-specific messenger RNA (mRNA) using specific cDNA clones in Northern blot analysis. In situ hybridization studies with the TNF-alpha cDNA probe gave positive hybridization signals in L428 and in L540. These results demonstrate the transcription, translation, and export of TNF-alpha and lymphotoxin in cultured Hodgkin's disease-derived cell lines. In addition, results of preliminary experiments are presented in which we demonstrate Reed-Sternberg cells positive for TNF-alpha protein and mRNA in different Hodgkin's disease tissue biopsies, indicating that, at least for TNF-alpha, our cell line data are relevant to the neoplastic population present in Hodgkin's disease tissue.

  10. 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.

  11. Tumor necrosis factor receptor-associated protein 1 improves hypoxia-impaired energy production in cardiomyocytes through increasing activity of cytochrome c oxidase subunit II.

    PubMed

    Xiang, Fei; Ma, Si-Yuan; Zhang, Dong-Xia; Zhang, Qiong; Huang, Yue-Sheng

    2016-10-01

    Tumor necrosis factor receptor-associated protein 1 protects cardiomyocytes against hypoxia, but the underlying mechanisms are not completely understood. In the present study, we used gain- and loss-of-function approaches to explore the effects of tumor necrosis factor receptor-associated protein 1 and cytochrome c oxidase subunit II on energy production in hypoxic cardiomyocytes. Hypoxia repressed ATP production in cultured cardiomyocytes, whereas overexpression of tumor necrosis factor receptor-associated protein 1 significantly improved ATP production. Conversely, knockdown of tumor necrosis factor receptor-associated protein 1 facilitated the hypoxia-induced decrease in ATP synthesis. Further investigation revealed that tumor necrosis factor receptor-associated protein 1 induced the expression and activity of cytochrome c oxidase subunit II, a component of cytochrome c oxidase that is important in mitochondrial respiratory chain function. Moreover, lentiviral-mediated overexpression of cytochrome c oxidase subunit II antagonized the decrease in ATP synthesis caused by knockdown of tumor necrosis factor receptor-associated protein 1, whereas knockdown of cytochrome c oxidase subunit II attenuated the increase in ATP synthesis caused by overexpression of tumor necrosis factor receptor-associated protein 1. In addition, inhibition of cytochrome c oxidase subunit II by a specific inhibitor sodium azide suppressed the ATP sy nthesis induced by overexpressed tumor necrosis factor receptor-associated protein 1. Hence, tumor necrosis factor receptor-associated protein 1 protects cardiomyocytes from hypoxia at least partly via potentiation of energy generation, and cytochrome c oxidase subunit II is one of the downstream effectors that mediates the tumor necrosis factor receptor-associated protein 1-mediated energy generation program.

  12. Risk factors associated with intestinal necrosis in children with failed non-surgical reduction for intussusception.

    PubMed

    Huang, Hui-Ya; Huang, Xiao-Zhong; Han, Yi-Jiang; Zhu, Li-Bin; Huang, Kai-Yu; Lin, Jing; Li, Zhong-Rong

    2017-05-01

    Intestinal necrosis is the most serious complication of intussusception. The risk factors associated with intestinal necrosis in pediatric patients with intussusception have not been well characterized. This study aimed to investigate the risk factors associated with intestinal necrosis in pediatric patients with failed non-surgical reduction for intussusception. Hospitalized patients who failed the air-enema reduction for intussusception in the outpatient department and subsequently underwent surgery were retrospectively reviewed. All cases were categorized into two groups: intestinal necrosis group and non-intestinal necrosis group based on the surgical findings. Demographic and clinical features including the findings from the surgery were recorded and analyzed. Factors associated with intestinal necrosis were analyzed using univariate and multivariate unconditional logistic regression analyses. A total of 728 cases were included. Among them, 171 had intestinal necrosis at the time of surgery. The group with intestinal necrosis had a longer duration of symptom or length of illness (P = 0.000), and younger (P = 0.000) than the non-intestinal necrosis group. Complex/compound type of intussusceptions is more likely to have intestinal necrosis. Multivariate analysis showed that the presence of grossly bloody stool (OR = 2.12; 95% CI 1.19-3.76, P = 0.010) and duration of symptom (OR = 1.07; 95% CI 1.06-1.08, P = 0.000) were independent risk factors for intestinal necrosis in patients hospitalized for surgical reduction for intussusceptions. At time of admission, the presence of bloody stools and duration of symptom are the important risk factors for developing intestinal necrosis for those patients who failed non-surgical reduction. The length of illness has the highest sensitivity and specificity to correlate with intestinal necrosis. This finding may suggest that we should take the intussusception cases that have the longer duration of

  13. Anticoagulation by factor Xa inhibitors

    PubMed Central

    Orfeo, Thomas; Butenas, Saulius; Brummel-Ziedins, Kathleen E.; Gissel, Matthew; Mann, Kenneth G.

    2010-01-01

    Summary Background Therapeutic agents that regulate blood coagulation are critical to the management of thrombotic disorders, with the selective targeting of factor (f)Xa emerging as a promising approach. Objective To assess anticoagulant strategies targeting fXa. Methods A deterministic computational model of tissue factor (Tf)-initiated thrombin generation and two empirical experimental systems (a synthetic coagulation proteome reconstruction using purified proteins and a whole blood model) were used to evaluate clinically relevant examples of the two available types of fXa directed anticoagulants (an antithrombin (AT)-dependent agent, fondaparinux, and an AT-independent inhibitor, Rivaroxaban) in experimental regimens relevant to long term (suppression of new Tf-initiated events) and acute (suppression of ongoing coagulation processes) clinical applications. Results Computational representations of each anticoagulant’s efficacy in suppressing thrombin generation over a range of anticoagulant concentrations in both anticoagulation regimens were validated by results from corresponding empirical reconstructions and were consistent with those recommended for long term and acute clinical applications respectively. All three model systems suggested that Rivaroxaban would prove more effective in the suppression of an ongoing coagulation process than fondaparinux, reflecting its much higher reactivity toward the prothrombinase complex. Conclusion The success of fondaparinux in acute settings in vivo is not explained solely by its properties as an fXa inhibitor. We have reported that fIXa contributes to the long term capacity of clot-associated catalysts to restart a coagulation process [Orfeo T et al. J Biol Chem 2008;283:9776], suggesting that the enhanced anti-fIXa activity of fondaparinux-AT may be critical to its success in acute settings in vivo. PMID:20492473

  14. Effects of tumour necrosis factor on protein metabolism.

    PubMed

    Evans, D A; Jacobs, D O; Wilmore, D W

    1993-08-01

    Increased skeletal muscle breakdown and negative nitrogen balance are features of sepsis that may be mediated by cytokines. The effects of tumour necrosis factor (TNF) on protein metabolism were studied. When administered to anaesthetized dogs (0.57 x 10(5) units per kg body-weight over 6h), TNF caused urinary nitrogen excretion to increase (mean(s.e.m.) 165(15) mg kg-1 for dogs that received TNF versus 113(8) mg kg-1 for control animals, P < 0.01). Amino acid nitrogen release from the hindlimbs showed no change over the study period, indicating that the additional urinary nitrogen was not derived from peripheral protein stores. In a second study the same dose of TNF or saline was infused after the intestine had been removed. The mean(s.e.m.) urinary nitrogen excretion in control dogs that had undergone enterectomy (101(7) mg kg-1) was similar to that of intact animals, and addition of TNF did not significantly increase nitrogen excretion (86(18) mg kg-1). The results suggest that nitrogen excreted in the urine during administration of TNF is derived, at least initially, from the intestinal tract.

  15. Endothelial cell activation induced by tumor necrosis factor and lymphotoxin.

    PubMed Central

    Cavender, D. E.; Edelbaum, D.; Ziff, M.

    1989-01-01

    Alterations in the morphology and histochemistry of vascular endothelial cells (EC) have been repeatedly observed at sites of chronic inflammation and immune reactions. These changes, which are most prominent in the EC postcapillary venules present in areas with large lymphocytic infiltrates, include the acquisition of a columnar or cuboidal morphology, the development of ribonuclease-sensitive metachromasia, and an increase in intracellular organelles. Thus, EC at sites of inflammation appear to be activated and to demonstrate increased metabolic activity. This study reports that both tumor necrosis factor-alpha (TNF) and lymphotoxin (LT) can activate cultured human umbilical vein EC, as measured by: 1) increased adhesiveness for lymphocytes, 2) increased cell metabolism, as measured by RNA and protein synthesis, and 3) increased cell volume. Although gamma interferon (IFN-gamma) and interleukin-1 (IL-1) have been shown previously to stimulate EC adhesiveness for lymphocytes, these two cytokines had only marginal effects on EC RNA and protein synthesis, and both caused a decrease in EC volume. These findings suggest that TNF and LT play a role in the type of activation of EC in vivo that leads to the development of tall endothelium and increased lymphocyte emigration. PMID:2466402

  16. Production of polyclonal antibodies to feline tumor necrosis factor.

    PubMed Central

    Otto, C M; Niagro, F; McGraw, R A; Rawlings, C A

    1997-01-01

    Two 13-amino-acid peptides were synthesized based on the putative feline tumor necrosis factor (FeTNF) sequence. The synthesized peptides were conjugated to keyhole limpet hemocyanin, emulsified in complete Freund's adjuvant, and injected into rabbits. The gene for FeTNF was cloned into the FLAG (International Biotechnologies Inc. [IBI], Kodak, New Haven, Conn.) fusion protein expression vector. The expressed fusion protein was purified by using the M-1 anti-FLAG octapeptide monoclonal antibody (IBI, Kodak). The fusion protein was emulsified in complete Freund's adjuvant and injected into chickens. The immune sera generated to the synthetic peptides and the fusion protein recognized the recombinant FeTNF fusion protein on Western or dot blot assay. The preimmune and immune sera were incubated with naturally occurring FeTNF (supernatants from lipopolysaccharide-stimulated cultured feline peritoneal exudate or peripheral mononuclear cells). The antibody raised to the recombinant FeTNF fusion protein and N-terminal synthetic peptide neutralized bioactivity of native FeTNF and recombinant human TNF. Preimmune sera did not have any neutralizing activity. The polyclonal antibodies were not specific for FeTNF, since both porcine and human recombinant TNF were neutralized by the fusion protein antibodies. The synthetic peptide antibodies recognized recombinant feline and equine TNF on a Western blot. PMID:9220170

  17. Tumor necrosis factor blockade and the risk of viral infection

    PubMed Central

    Kim, Seo Young; Solomon, Daniel H.

    2011-01-01

    Tumor necrosis factor (TNF)-α blockers have been widely used to treat rheumatoid arthritis and other inflammatory diseases. An increased risk of tuberculosis and opportunistic infections with TNF-α blockers has been well reported because of the primary role of TNF-α in host defense and immune response. However, little is known about the association between TNF-α blockers and viral infections. Because interferon-γ and TNF-α play critical roles in the control of viral infection, depletion of TNF by treatment with TNF-α blockade may facilitate the risk of or reactivation of viral infection. Several large observational studies have recently found an increased risk of herpes zoster in patients receiving TNF-α blockers for rheumatoid arthritis. This review draws attention to several important viral infections such as human immunodeficiency, varicella-zoster and Epstein-Barr viruses, cytomegalovirus, and human papillomavirus in patients receiving TNF-α blocking therapy, their implications in clinical practice, and possible preventative approach with vaccination. PMID:20142812

  18. Tumor necrosis factor production by human sarcoid alveolar macrophages.

    PubMed Central

    Bachwich, P. R.; Lynch, J. P.; Larrick, J.; Spengler, M.; Kunkel, S. L.

    1986-01-01

    Tumor necrosis factor (TNF) is an oncolytic peptide that may also exert many other biologic effects. Experimentally, immunologically activated mononuclear phagocytes stimulated with endotoxin (LPS) produce TNF, while resting mononuclear phagocytes stimulated with LPS produce little TNF. To date, the ability of human alveolar macrophages (AMs) to produce TNF has not been clearly delineated. As pulmonary sarcoidosis is a granulomatous inflammatory disorder characterized by immunologically activated AMs, we investigated the production of TNF by AMs obtained by bronchoalveolar lavage from 7 normal volunteers and 13 patients with pulmonary sarcoidosis. The AMs were cultured with and without LPS, and TNF production was assessed by an in vitro cytotoxicity assay. Unstimulated sarcoid and normal AMs produced little TNF, but LPS stimulation enhanced TNF production by both normal and sarcoid AMs. Furthermore, LPS-stimulated sarcoid AMs produced more TNF than normal AMs (84.9 +/- 16.7 versus 32.5 +/- 10.2 units/million cells, P less than 0.05). It is concluded that human AMs can produce TNF and that sarcoid AMs are primed and can produce significantly more TNF, compared with normal AMs. PMID:3799813

  19. 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

  20. PULMONARY COMPLICATIONS OF TUMOR NECROSIS FACTOR-TARGETED THERAPY

    PubMed Central

    Thavarajah, Krishna; Wu, Peggy; Rhew, Elisa J.; Yeldandi, Anjana K; Kamp, David W.

    2009-01-01

    Tumor necrosis factor (TNF)-targeted therapies are increasingly being prescribed in the management of a variety of inflammatory and autoimmune diseases. The use of this class of medications also pose risks of developing an assortment of pulmonary side effects including infections (TB, bacterial, and fungal infections), pulmonary nodules, chronic pneumonitis/fibrosis, SLE-like reactions, vasculitis, and exacerbations of underlying lung disease. In addition to surveillance for tuberculosis prior to initiation of TNF-targeted therapy, a high level of vigilance should be maintained during administration for infectious and non-infectious complications, even years into a patient’s course. The available evidence argues for caution in using these agents in patients with pre-existing lung disease and heightened suspicion of accelerated nodule formation in those with preexisting rheumatoid nodules. Management centers on excluding infection, identifying confounders (especially methotrexate or pre-existing lung disease), and promptly discontinuing TNF-targeted therapy. In some instances, invasive procedures (e.g. bronchoscopy or VATS lung biopsy) will be necessary to establish the proper diagnosis, and the administration of steroids may be beneficial. PMID:19201589

  1. Immunoregulation by tumor necrosis factor superfamily member LIGHT

    PubMed Central

    Wang, Yugang; Zhu, Mingzhao; Miller, Mendy; Fu, Yang-Xin

    2015-01-01

    Summary LIGHT (homologous to lymphotoxins, inducible expression, competes with herpesvirus glycoprotein D for herpesvirus entry mediator, a receptor expressed on T lymphocytes) is a member of the tumor necrosis factor superfamily that contributes to the regulation of immune responses. LIGHT can influence T-cell activation both directly and indirectly by engagement of various receptors that are expressed on T cells and on other types of cells. LIGHT, LIGHT receptors, and their related binding partners constitute a complicated molecular network in the regulation of various processes. The molecular cross-talk among LIGHT and its related molecules presents challenges and opportunities for us to study and to understand the full extent of the LIGHT function. Previous research from genetic and functional studies has demonstrated that dysregulation of LIGHT expression can result in the disturbance of T-cell homeostasis and activation, changing the ability of self-tolerance and of the control of infection. Meanwhile, blockade of LIGHT activity can ameliorate the severity of various T-cell-mediated diseases. These observations indicate the importance of LIGHT and its involvement in many physiological and pathological conditions. Understanding LIGHT interactions offers promising new therapeutic strategies that target LIGHT-engaged pathways to fight against cancer and various infectious diseases. PMID:19426225

  2. 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

  3. Role of Agents other than Tumor Necrosis Factor Blockers in the Treatment of Psoriatic Arthritis.

    PubMed

    Atzeni, Fabiola; Costa, Luisa; Caso, Francesco; Scarpa, Raffaele; Sarzi-Puttini, Piercarlo

    2015-11-01

    Psoriatic arthritis (PsA) is a systemic inflammatory disease characterized by possible peripheral and axial joint involvement, enthesitis, dactylitis, and skin and nail disease. It affects up to one-third of psoriatic patients, and may be associated with comorbidities such as cardiovascular and metabolic diseases. The usually prescribed initial treatment of moderate-severe PsA is methotrexate, which may be accompanied or replaced by a tumor necrosis factor (TNF) inhibitor such as etanercept, infliximab, or adalimumab. However, some patients may become unresponsive (or have contraindications) to available anti-TNF agents and require alternative treatment. The aim of this review is to describe the potential role of some new immunomodulatory agents.

  4. Tumor necrosis factor-alpha, Kidney function and hypertension.

    PubMed

    Mehaffey, Eamonn; Majid, Dewan Syed Abdul

    2017-07-19

    Hypertension is considered to be a low-grade inflammatory condition characterized by the presence of various pro-inflammatory cytokines. The inflammatory cytokine Tumor Necrosis Factor-alpha (TNF-α) is a constituent of the pro-inflammatory environment that is associated with salt-sensitive hypertension (SSH) and related renal injury. Elevated angiotensin II (AngII) and other factors such as oxidative stress conditions promote TNF-α formation. Many recent studies have provided evidence that TNF-α exerts a direct renal action by regulating hemodynamic and excretory function in the kidney. The cytokine incites a strong natriuretic response and plays a part in regulation of the intrarenal renin-angiotensin system. The exact mechanistic role of TNF-α in the development of SSH is yet poorly understood. While TNF-α antagonism has been shown to attenuate hypertensive responses in many hypertensive animal models, contrasting findings demonstrate that the direct systemic administration of TNF-α usually induces hypotensive as well as natriuretic responses, indicating a counter-regulatory role of TNF-α in SSH. Differential activities of two cell surfaced receptors of TNF-α (receptor type 1 and type 2) may explain the contradictory functions of TNF-α in the setting of hypertension. This mini-review will evaluate ongoing research studies that investigate the action of TNF-α within the kidney and its role as an influential pathophysiologic variable in the development of SSH and renal injury. This information may help to develop specific TNF-α receptor targeting as an effective treatment strategy in this clinical condition. Copyright © 2016, American Journal of Physiology-Renal Physiology.

  5. Regulation of bitter taste responses by tumor necrosis factor

    PubMed Central

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

    2015-01-01

    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

  6. 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.

  7. Tumor necrosis factor-inducing activities of Cryptococcus neoformans components.

    PubMed Central

    Delfino, D; Cianci, L; Migliardo, M; Mancuso, G; Cusumano, V; Corradini, C; Teti, G

    1996-01-01

    Cryptococcus neoformans-induced tumor necrosis factor alpha (TNF-alpha) production may lead to increased human immunodeficiency virus replication in patients with AIDS. In order to identify cryptococcal components that are predominantly responsible for stimulating TNF production, various concentrations of glucuronoxylomannan (GXM), galactoxylomannan (GalXM), mannoproteins (MP), and alpha(1-3) [corrected] glucan were added to whole-blood cultures. All of the cryptococcal components tested, as well as whole heat-killed cryptococci, were capable of inducing TNF-alpha release in a dose-dependent manner. MP were significantly more potent than any of the other cryptococcal components tested or heat-killed cryptococci in stimulating TNF-alpha production (P < 0.05). GXM, in contrast, was significantly less potent in this activity than either GalXM or MP (P < 0.05). As little as 0.5 microg of MP per ml was sufficient to produce moderate but significant elevations of TNF-alpha release. Maximal MP-induced TNF-alpha levels were similar to those induced by Salmonella enteritidis lipopolysaccharide, our positive control. Further experiments using isolated leukocytes suggested that monocytes were the cell population mainly responsible for TNF-alpha production, although the participation of other cell types could not be excluded. The presence of complement-sufficient plasma was a necessary requirement for TNF-alpha induction by GXM, GalXM, and low doses of MP. High MP concentrations (100 microg/ml) were also capable of stimulating TNF-alpha production in the absence of plasma. These data indicate that soluble products released by C. neoformans are capable of inducing TNF-alpha secretion in human leukocytes. This may be clinically relevant, since high concentrations of such products are frequently found in the body fluids of AIDS patients infected with C. neoformans. PMID:8945566

  8. Tumour necrosis factor-alpha in diastolic dysfunction.

    PubMed

    Kilickap, Mustafa; Gurlek, Adalet; Dandachi, Rabih; Dincer, Irem; Tutkak, Huseyin; Oral, Dervis

    2004-10-01

    Active relaxation develops as a result of sequestration of calcium into the sarcoplasmic reticulum, and is controlled mainly by sarcoplasmic reticulum calcium ATPase (SERCA) and phospholamban.Tumour necrosis factor-alpha (TNF-alpha) downregulates both of these proteins, so it may play a role in the development of abnormal relaxation. However, a possible relationship between TNF-alpha and diastolic dysfunction has not been sufficiently evaluated in vivo. We investigated whether circulating levels of TNF-alpha increased in patients with relaxation abnormality. Forty hypertensive patients with normal left ventricular systolic function were enrolled in the study. Age-adjusted values of echocardiographically measured mitral inflow velocities, E-wave deceleration time and isovolemic relaxation time were used to define normal and abnormal relaxation. Twenty of the patients (mean age 59.2 +/- 10.6) had a relaxation abnormality (group I), and the twenty other patients (mean age 45.9 +/- 7.9) had a normal diastolic function (group II). TNF-alpha levels were measured by ELISA. There were no significant differences between the two groups in terms of interventricular septal thickness, posterior wall thickness, left ventricular mass, ejection fraction, plasma creatinin level, and medication. Patients with a relaxation abnormality were older than those with a normal diastolic function (p < 0.001). TNF-alpha levels were similar in both groups (62.1 +/- 46.0 pg/ml for group I, and 48.7 +/- 51.4 pg/ml for group II, p = 0.089). In this preliminary study, we demonstrated that TNF-alpha levels did not increase in patients with a relaxation abnormality. However, we think that a possible relationship between TNF-alpha and diastolic dysfunction should be clarified by further studies involving a larger number of patients with a wider spectrum of diastolic dysfunction.

  9. A third distinct tumor necrosis factor receptor of orthopoxviruses

    PubMed Central

    Loparev, Vladimir N.; Parsons, Joseph M.; Knight, Janice C.; Panus, Joanne Fanelli; Ray, Caroline A.; Buller, R. Mark L.; Pickup, David J.; Esposito, Joseph J.

    1998-01-01

    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-α (LTα) and blocked their in vitro cytolytic activity. Secreted viral CrmD bound TNF and LTα 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

  10. Relapsed Pulmonary Cryptococcosis during Tumor Necrosis Factor α Inhibitor Treatment.

    PubMed

    Takazono, Takahiro; Sawai, Toyomitsu; Tashiro, Masato; Saijo, Tomomi; Yamamoto, Kazuko; Imamura, Yoshifumi; Miyazaki, Taiga; Suyama, Naofumi; Izumikawa, Koichi; Kakeya, Hiroshi; Yanagihara, Katsunori; Mukae, Hiroshi; Kohno, Shigeru

    A 35-year-old non-HIV patient developed pulmonary cryptococcosis after the initiation of infliximab. He recovered by fluconazole treatment and completed the therapy for a total of 6 months. However, he experienced a relapse 16 months later during retreatment with infliximab, revealing an interesting clinical course contradicting retreatment. This case also represents the first case of relapsed pulmonary cryptococcosis suspected during treatment with a biologic agent. Both of these aspects generated important clinical questions about the length of pulmonary cryptococcosis treatment and the necessity of introducing a second prophylaxis for such patients.

  11. Relapsed Pulmonary Cryptococcosis during Tumor Necrosis Factor α Inhibitor Treatment

    PubMed Central

    Takazono, Takahiro; Sawai, Toyomitsu; Tashiro, Masato; Saijo, Tomomi; Yamamoto, Kazuko; Imamura, Yoshifumi; Miyazaki, Taiga; Suyama, Naofumi; Izumikawa, Koichi; Kakeya, Hiroshi; Yanagihara, Katsunori; Mukae, Hiroshi; Kohno, Shigeru

    2016-01-01

    A 35-year-old non-HIV patient developed pulmonary cryptococcosis after the initiation of infliximab. He recovered by fluconazole treatment and completed the therapy for a total of 6 months. However, he experienced a relapse 16 months later during retreatment with infliximab, revealing an interesting clinical course contradicting retreatment. This case also represents the first case of relapsed pulmonary cryptococcosis suspected during treatment with a biologic agent. Both of these aspects generated important clinical questions about the length of pulmonary cryptococcosis treatment and the necessity of introducing a second prophylaxis for such patients. PMID:27725552

  12. 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.

  13. 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.

  14. 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.

  15. An ent-kaurene diterpene enhances apoptosis induced by tumor necrosis factor in human leukemia cells.

    PubMed

    Suzuki, Ikue; Kondoh, Masuo; Harada, Motoki; Koizumi, Naoya; Fujii, Makiko; Nagashima, Fumihiro; Asakawa, Yoshinori; Watanabe, Yoshiteru

    2004-08-01

    Some antitumor agents, including tumor necrosis factor-alpha (TNF-alpha) and camptothecin (CPT), often cause resistance of tumor cells to antitumor agents through activation of the nuclear factor-kappa B (NF-kappa B) pathway that leads to up-regulation of anti-apoptotic proteins. Therefore, co-treatment of an inhibitor of the NF-kappa B pathway with antitumor agents is a useful strategy for chemotherapy. Here we report that ent-11 alpha-hydroxy-16-kauren-15-one (KD) selectively inhibits NF-kappa B-dependent gene expression due to treatment with TNF-alpha. KD in combination with TNF-alpha caused a dramatic increase in apoptosis in human leukemia cells accompanied by activation of caspases. A broad-spectrum inhibitor of caspases decreased the apoptosis induced by treatment with KD and TNF-alpha. KD in combination with CPT also caused an increase in apoptosis. These results suggest that the apoptotic potency of co-treatment of KD with TNF-alpha or CPT is elicited through selective inhibition of NF-kappa B-dependent anti-apoptotic proteins and thus may provide a basis for the development of useful approaches to the treatment of leukemia.

  16. 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

  17. Purification of human immunoglobulin G autoantibodies to tumor necrosis factor using affinity chromatography and magnetic separation.

    PubMed

    Sennikov, S V; Golikova, E A; Kireev, F D; Lopatnikova, J A

    2013-04-30

    Autoantibodies to cytokines are important biological effector molecules that can regulate cytokine activities. The aim of the study was to develop a protocol to purify autoantibodies to tumor necrosis factor from human serum, for use as a calibration material to determine the absolute content of autoantibodies to tumor necrosis factor by enzyme-linked immunosorbent assay. The proposed protocol includes a set of affinity chromatography methods, namely, Bio-Gel P6DG sorbent to remove albumin from serum, Protein G Sepharose 4 Fast Flow to obtain a total immunoglobulin G fraction of serum immunoglobulins, and Affi-Gel 15 to obtain specifically antibodies to tumor necrosis factor. The addition of a magnetic separation procedure to the protocol eliminated contaminant tumor necrosis factor from the fraction of autoantibodies to tumor necrosis factor. The protocol generated a pure fraction of autoantibodies to tumor necrosis factor, and enabled us to determine the absolute concentrations of different subclasses of immunoglobulin G autoantibodies to tumor necrosis factor in apparently healthy donors.

  18. Tumour necrosis factor-α/interleukin-10 ratio in patients with obstructive sleep apnoea hypopnoea syndrome.

    PubMed

    Jiang, H; Cao, H; Wang, P; Liu, W; Cao, F; Chen, J

    2015-01-01

    To explore the significance of the tumour necrosis factor-α/interleukin-10 ratio and the effect of continuous positive airway pressure in patients with different degrees of obstructive sleep apnoea hypopnoea syndrome severity. This study comprised 135 patients with obstructive sleep apnoea hypopnoea syndrome and 94 control subjects. Tumour necrosis factor-α and tumour necrosis factor-α/interleukin-10 ratio values were significantly higher in the obstructive sleep apnoea hypopnoea syndrome group than in the control group, but interleukin-10 was significantly lower. Tumour necrosis factor-α/interleukin-10 ratio values increased in line with the severity of obstructive sleep apnoea hypopnoea syndrome. In multivariate analysis, the tumour necrosis factor-α/interleukin-10 ratio correlated positively with the apnoea-hypopnoea index and all indices of obstructive sleep apnoea hypopnoea syndrome, except for age, body mass index and neck circumference. After one month of continuous positive airway pressure therapy, levels of tumour necrosis factor-α decreased; interleukin-10 showed no change. The results suggest that inflammation is activated and anti-inflammatory cytokines are decreased in obstructive sleep apnoea hypopnoea syndrome patients. Tumour necrosis factor-α/interleukin-10 ratio may prove useful for severity monitoring and management of obstructive sleep apnoea hypopnoea syndrome patients, and may reduce the need for polysomnography.

  19. Involvement of Mst1 in tumor necrosis factor-{alpha}-induced apoptosis of endothelial cells

    SciTech Connect

    Ohtsubo, Hideki; Ichiki, Toshihiro Imayama, Ikuyo; Ono, Hiroki; Fukuyama, Kae; Hashiguchi, Yasuko; Sadoshima, Junichi; Sunagawa, Kenji

    2008-03-07

    Mammalian sterile 20-kinase 1 (Mst1), a member of the sterile-20 family protein kinase, plays an important role in the induction of apoptosis. However, little is know about the physiological activator of Mst1 and the role of Mst1 in endothelial cells (ECs). We examined whether Mst1 is involved in the tumor necrosis factor (TNF)-{alpha}-induced apoptosis of ECs. Western blot analysis revealed that TNF-{alpha} induced activation of caspase 3 and Mst1 in a time- and dose-dependent manner. TNF-{alpha}-induced Mst1 activation is almost completely prevented by pretreatment with Z-DEVD-FMK, a caspase 3 inhibitor. Nuclear staining with Hoechst 33258 and fluorescence-activated cell sorting of propidium iodide-stained cells showed that TNF-{alpha} induced apoptosis of EC. Diphenyleneiodonium, an inhibitor of NADPH oxidase, and N-acetylcysteine, a potent antioxidant, also inhibited TNF-{alpha}-induced activation of Mst1 and caspase 3, as well as apoptosis. Knockdown of Mst1 expression by short interfering RNA attenuated TNF-{alpha}-induced apoptosis but not cleavage of caspase 3. These results suggest that Mst1 plays an important role in the induction of TNF-{alpha}-induced apoptosis of EC. However, positive feedback mechanism between Mst1 and caspase 3, which was shown in the previous studies, was not observed. Inhibition of Mst1 function may be beneficial for maintaining the endothelial integrity and inhibition of atherogenesis.

  20. 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

  1. Discovery of novel heterocyclic factor VIIa inhibitors.

    PubMed

    Rai, Roopa; Kolesnikov, Aleksandr; Sprengeler, Paul A; Torkelson, Steven; Ton, Tony; Katz, Bradley A; Yu, Christine; Hendrix, John; Shrader, William D; Stephens, Robin; Cabuslay, Ronnell; Sanford, Ellen; Young, Wendy B

    2006-04-15

    Structure-activity relationships and binding mode of novel heterocyclic factor VIIa inhibitors will be described. In these inhibitors, a highly basic 5-amidinoindole moiety has been successfully replaced with a less basic 5-aminopyrrolo[3,2-b]pyridine scaffold.

  2. 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.

  3. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and kidney disease.

    PubMed

    Ruiz-Ortega, Marta; Ortiz, Alberto; Ramos, Adrian M

    2014-01-01

    The tumor necrosis factor-like weak inducer of apoptosis (TWEAK) cytokine has been linked to kidney injury by functional studies in experimental animals, and has biomarker potential in kidney disease. TWEAK was known to promote tubular cell injury and kidney inflammation. Recent studies have expanded these observations, identifying additional targets of TWEAK relevant to kidney injury. Thus, TWEAK upregulates the chemokine and cholesterol scavenger receptor CXCL16 and downregulates the antiaging and antifibrotic molecule Klotho in tubular cells. Furthermore, fibrogenic TWEAK actions on renal fibroblasts were described. TWEAK or factor-inducible molecule 14 targeting decreased the kidney fibrosis resulting from immune and nonimmune kidney injury induced by transient tubular or glomerular insults or by persistent urinary tract obstruction. TWEAK might also contribute to the link between chronic kidney disease and kidney cancer, as suggested by its role in other genitourinary cancers. Progress has also been made in TWEAK targeting. A phase I clinical trial showed that TWEAK targeting is well tolerated in humans, and an ongoing trial is exploring efficacy in lupus nephritis. Nanomolecules and inhibitors of epidermal growth factor receptor pathway may also protect from the adverse effects of TWEAK in the kidney. These findings suggest that TWEAK targeting has clinical potential in kidney injury of immune and nonimmune origin.

  4. Tumor necrosis factor SNP haplotypes are associated with iron deficiency anemia in West African children

    PubMed Central

    Rockett, Kirk A.; Morgan, Gareth; Bejon, Philip A.; Sirugo, Giorgio; O'Connell, Maria A.; Hanchard, Neil; Kwiatkowski, Dominic P.; Prentice, Andrew M.

    2008-01-01

    Plasma levels of tumor necrosis factor-α (TNF-α) are significantly raised in malaria infection and TNF-α is thought to inhibit intestinal iron absorption and macrophage iron release. This study investigated putative functional single nucleotide polymorphisms (SNPs) and haplotypes across the major histocompatibility complex (MHC) class III region, including TNF and its immediate neighbors nuclear factor of κ light polypeptide gene enhancer in B cells (lκBL), inhibitor-like 1 and lymphotoxin alpha (LTA), in relation to nutritional iron status and anemia, in a cohort of 780 children across a malaria season. The prevalence of iron deficiency anemia (IDA) increased over the malaria season (P < .001). The TNF−308 AA genotype was associated with an increased risk of iron deficiency (adjusted OR 8.1; P = .001) and IDA (adjusted OR 5.1; P = .01) at the end of the malaria season. No genotypes were associated with IDA before the malaria season. Thus, TNF appears to be a risk factor for iron deficiency and IDA in children in a malaria-endemic environment and this is likely to be due to a TNF-α–induced block in iron absorption. PMID:18716131

  5. Heavy chain transfer by tumor necrosis factor-stimulated gene 6 to the bikunin proteoglycan.

    PubMed

    Lamkin, Elliott; Cheng, Georgiana; Calabro, Anthony; Hascall, Vincent C; Joo, Eun Ji; Li, Lingyun; Linhardt, Robert J; Lauer, Mark E

    2015-02-20

    We present data that hyaluronan (HA) polysaccharides, about 14-86 monosaccharides in length, are capable of accepting only a single heavy chain (HC) from inter-α-inhibitor via transfer by tumor necrosis factor-stimulated gene 6 (TSG-6) and that this transfer is irreversible. We propose that either the sulfate groups (or the sulfation pattern) at the reducing end of the chondroitin sulfate (CS) chain of bikunin, or the core protein itself, enables the bikunin proteoglycan (PG) to accept more than a single HC and permits TSG-6 to transfer these HCs from its relatively small CS chain to HA. To test these hypotheses, we investigated HC transfer to the intact CS chain of the bikunin PG, and to the free chain of bikunin. We observed that both the free CS chain and the intact bikunin PG were only able to accept a single HC from inter-α-inhibitor via transfer by TSG-6 and that HCs could be swapped from the bikunin PG and its free CS chain to HA. Furthermore, a significant portion of the bikunin PG was unable to accept a single heavy chain. We discuss explanations for these observations, including the intracellular assembly of inter-α-inhibitor. In summary, these data demonstrate that the sulfation of the CS chain of bikunin and/or its core protein promote HC transfer by TSG-6 to its relatively short CS chain, although they are insufficient to enable the CS chain of bikunin to accept more than one HC in the absence of other cofactors. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Heavy Chain Transfer by Tumor Necrosis Factor-stimulated Gene 6 to the Bikunin Proteoglycan*

    PubMed Central

    Lamkin, Elliott; Cheng, Georgiana; Calabro, Anthony; Hascall, Vincent C.; Joo, Eun Ji; Li, Lingyun; Linhardt, Robert J.; Lauer, Mark E.

    2015-01-01

    We present data that hyaluronan (HA) polysaccharides, about 14–86 monosaccharides in length, are capable of accepting only a single heavy chain (HC) from inter-α-inhibitor via transfer by tumor necrosis factor-stimulated gene 6 (TSG-6) and that this transfer is irreversible. We propose that either the sulfate groups (or the sulfation pattern) at the reducing end of the chondroitin sulfate (CS) chain of bikunin, or the core protein itself, enables the bikunin proteoglycan (PG) to accept more than a single HC and permits TSG-6 to transfer these HCs from its relatively small CS chain to HA. To test these hypotheses, we investigated HC transfer to the intact CS chain of the bikunin PG, and to the free chain of bikunin. We observed that both the free CS chain and the intact bikunin PG were only able to accept a single HC from inter-α-inhibitor via transfer by TSG-6 and that HCs could be swapped from the bikunin PG and its free CS chain to HA. Furthermore, a significant portion of the bikunin PG was unable to accept a single heavy chain. We discuss explanations for these observations, including the intracellular assembly of inter-α-inhibitor. In summary, these data demonstrate that the sulfation of the CS chain of bikunin and/or its core protein promote HC transfer by TSG-6 to its relatively short CS chain, although they are insufficient to enable the CS chain of bikunin to accept more than one HC in the absence of other cofactors. PMID:25561734

  7. Lactulose inhibits endotoxin induced tumour necrosis factor production by monocytes. An in vitro study.

    PubMed Central

    Greve, J W; Gouma, D J; von Leeuwen, P A; Buurman, W A

    1990-01-01

    Preoperative oral treatment with lactulose is used to prevent complications after surgery in patients with obstructive jaundice. The effect is perhaps the result of an inactivation of gut derived endotoxins but the exact mechanism of action is, however, unknown. Tumour necrosis factor is an important mediator of endotoxin toxicity. The cytokine tumour necrosis factor is mainly produced by mononuclear phagocytes. In this study, the effect of lactulose on the endotoxin induced tumour necrosis factor release by monocytes was investigated. The direct effect of lactulose on endotoxin was tested in a chromogenic limulus amoebocyte lysate assay. Polymyxin B a known inactivator of endotoxin was used as control in both experiments. Lactulose has a limited capacity to inactivate endotoxin as measured in the endotoxin assay. In contrast lactulose significantly reduced endotoxin induced tumour necrosis factor production by monocytes. In conclusion lactulose inhibits tumour necrosis factor production by a direct inhibitory effect on monocytes, rather than by inactivation of endotoxin. Because tumour necrosis factor is an important mediator of endotoxin toxicity, this inhibitory effect could explain the beneficial effect of lactulose in obstructive jaundice. PMID:2311978

  8. Cardiotrophin-1 induces tumor necrosis factor alpha synthesis in human peripheral blood mononuclear cells.

    PubMed

    Fritzenwanger, Michael; Meusel, Katharina; Jung, Christian; Franz, Marcus; Wang, Zhenhua; Foerster, Martin; Figulla, Hans-R

    2009-01-01

    Chronic heart failure (CHF) is associated with elevated concentrations of tumor necrosis factor (TNF) alpha and cardiotrophin-1 (CT-1) and altered peripheral blood mononuclear cell (PBMC) function. Therefore, we tested whether CT-1 induces TNFalpha in PBMC of healthy volunteers. CT-1 induced in PBMC TNFalpha protein in the supernatant and TNFalpha mRNA in a concentration- and time-dependent manner determined by ELISA and real-time PCR, respectively. Maximal TNFalpha protein was achieved with 100 ng/mL CT-1 after 3-6 hours and maximal TNFalpha mRNA induction after 1 hour. ELISA data were confirmed using immunofluorescent flow cytometry. Inhibitor studies with actinomycin D and brefeldin A showed that both protein synthesis and intracellular transport are essential for CT-1 induced TNFalpha expression. CT-1 caused a dose dependent nuclear factor (NF) kappaB translocation. Parthenolide inhibited both NFkappaB translocation and TNFalpha protein expression indicating that NFkappaB seems to be necessary. We revealed a new mechanism for elevated serum TNFalpha concentrations and PBMC activation in CHF besides the hypothesis of PBMC activation by bacterial translocation from the gut.

  9. [Factors of avascular necrosis of femoral head and osteoporosis in SARS patients' convalescence].

    PubMed

    Li, Yu-ming; Wang, Shi-xin; Gao, Hong-sheng; Wang, Jing-gui; Wei, Chuan-she; Chen, Li-ming; Hui, Wu-li; Yuan, Shu-ling; Jiao, Zhen-shan; Yang, Zhen; Su, Bin

    2004-08-17

    To explore the factors affecting the pathogenesis of avascular necrosis of femoral head and osteoporosis of SARS patients during convalescent stage. The clinical data of 40 SARS patients, 12 males and 28 females, aged 29 +/- 9, hospitalized from April to June 2003, were reviewed, targeted on the use of glucocorticoids. Three months after the discharge ELISA and indirect immunofluorescent antibody (IFA) assay were used to detect the serum IgG. Magnetic resonance imaging (MRI) was used to detect the damage of the head of femur and quantitative ultrasound (QUS) was used to detect osteoporosis at the left heel. The average total dosage of methylprednisolone was (4949 +/- 2959) mg, and the average course of treatment was (24 +/- 5) days (16 to 30 days). Twenty-three patients underwent ictus therapy of corticosteroids for (8 +/- 4) days. The extenuation time of corticosteroid' dosage was (33 +/- 26) mg/d. Of the 40 patients, 36 were IgG positive with an average A value of (0.91 +/- 0.24) and 4 patients were IgG negative. Twelve patients (30%) were with type I avascular necrosis of femoral head, including 3 cases with unilateral left--necrosis and 9 cases of bilateral necrosis. The other 28 patients were without necrosis. Two patients were suffering from osteoporosis and 30 patients were with bone density decrement. The average Z values of the parameter BUA and VOS were (-1.26 +/- 0. 53) and (-0.53 +/- 0.30) respectively. The corresponding T values of the parameter BUA and VOS were (-1.49 +/- 0.59) and (-0.65 +/- 0.05) respectively. The influencing factors of femoral necrosis included the degree of healing activity, the dosage summation of corticosteroids, and length of ictus therapy. The influencing factors of bone density included age, dosage summation, and length of ictus therapy. The influencing factors of the bone fabric and flexibility included the use and length of ictus therapy. Statistics showed that serum IgG was not related with avascular necrosis of femoral

  10. Analysis of risk factors for femoral head necrosis after internal fixation in femoral neck fractures.

    PubMed

    Wang, Tao; Sun, Jun-Ying; Zha, Guo-Chun; Jiang, Tao; You, Zhen-Jun; Yuan, De-Jing

    2014-12-01

    Femoral head necrosis is a rare but devastating complication following femoral neck fracture. The reported incidence of avascular necrosis after femoral neck fracture fixation varies widely, and there is no consensus regarding its risk factors. The aim of this study was to analyze the risk factors for femoral head necrosis after internal fixation in femoral neck fracture. This retrospective study included 166 patients with femoral neck fractures treated with surgical reduction and internal fixation at the authors' institution from January 2004 to December 2008. Eight patients died for reasons unrelated to the surgery, and 12 patients were lost to follow-up. The remaining 146 patients (146 fractures) were followed until union or until conversion to total hip arthroplasty. The patients included 61 males and 85 females with an average age of 47.5 years (range, 18-68 years). The authors analyzed the following factors: age, sex, Garden classification, reduction quality, surgical methods, injury-to-surgery interval, preoperative traction, weight-bearing time, and implant removal. All patients were followed for a mean of 52 months (range, 6-90 months). The incidence of femoral head necrosis was 14.4% (21/146). Garden classification (P=.012), reduction quality (P=.008), implant removal (P=.020), and preoperative traction (P=.003) were significantly associated with femoral head necrosis. Patient age (P=.990), sex (P=.287), injury-to-surgery interval (P=.360), weight-bearing time (P=.868), and surgical methods (P=.987) were not significantly associated with femoral head necrosis. In multivariate logistic regression analysis, implant removal was not a significant risk factor for femoral head necrosis development (P=.498). Garden classification, reduction quality, and preoperative traction had a significant effect on femoral head necrosis development. Copyright 2014, SLACK Incorporated.

  11. Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy.

    PubMed

    Jiang, Xi; Deng, Ke-Qiong; Luo, Yuxuan; Jiang, Ding-Sheng; Gao, Lu; Zhang, Xiao-Fei; Zhang, Peng; Zhao, Guang-Nian; Zhu, Xueyong; Li, Hongliang

    2015-08-01

    Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways. Here, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II- or phenylephrine-induced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli. This interaction between TRAF3 and TBK1 further activated AKT signaling, which ultimately promoted the development of cardiac hypertrophy. Our findings not only reveal a key role of TRAF3 in regulating the hypertrophic response but also uncover TRAF3-TBK1-AKT as a novel signaling pathway in the development of cardiac hypertrophy and heart failure. This pathway may represent a potential therapeutic target for this pathological process.

  12. Tumor necrosis factor receptor-associated factor 5 is an essential mediator of ischemic brain infarction.

    PubMed

    Wang, Lang; Lu, Yanyun; Guan, Hongjing; Jiang, Dingsheng; Guan, Yu; Zhang, Xin; Nakano, Hiroyasu; Zhou, Yan; Zhang, Yan; Yang, Li; Li, Hongliang

    2013-08-01

    Tumor necrosis factor receptor-associated factor 5 (TRAF5) is an adaptor protein of the tumor necrosis factor (TNF) receptor superfamily and the interleukin-1 receptor/Toll-like receptor superfamily and plays important roles in regulating multiple signaling pathways. This study was conducted to investigate the role of TRAF5 in the context of brain ischemia/reperfusion (I/R) injury. Transient occlusion of the middle cerebral artery was performed on TRAF5 knockout mice (KO), neuron-specific TRAF5 transgene (TG), and the appropriate controls. Compared with the WT mice, the TRAF5 KO mice showed lower infarct volumes and better outcomes in the neurological tests. A low neuronal apoptosis level, an attenuated blood-brain barrier (BBB) disruption and an inhibited inflammatory response were exhibited in TRAF5 KO mice. TRAF5 TG mice exhibited an opposite phenotype. Moreover, the Akt/FoxO1 signaling pathway was enhanced in the ischemic brains of the TRAF5 KO mice. These results provide the first demonstration that TRAF5 is a critical mediator of I/R injury in an experimental stroke model. The Akt /FoxO1 signaling pathway probably plays an important role in the biological function of TRAF5 in this model. © 2013 International Society for Neurochemistry.

  13. 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.

  14. Nitric oxide mediates angiogenesis induced in vivo by platelet-activating factor and tumor necrosis factor-alpha.

    PubMed Central

    Montrucchio, G.; Lupia, E.; de Martino, A.; Battaglia, E.; Arese, M.; Tizzani, A.; Bussolino, F.; Camussi, G.

    1997-01-01

    We evaluated the role of an endogenous production of nitric oxide (NO) in the in vitro migration of endothelial cells and in the in vivo angiogenic response elicited by platelet-activating factor (PAF), tumor necrosis factor-alpha (TNF), and basic fibroblast growth factor (bFGF). The NO synthase inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME), but not its enantiomer D-NAME, prevented chemotaxis of endothelial cells induced in vitro by PAF and by TNF. The motogenic activity of TNF was also inhibited by WEB 2170, a specific PAF-receptor antagonist. In contrast, chemotaxis induced by bFGF was not prevented by L-NAME or by WEB 2170. Angiogenesis was studied in vivo in a murine model in which Matrigel was used as a vehicle for the delivery of mediators. In this model, the angiogenesis induced by PAF and TNF was inhibited by WEB 2170 and L-NAME but not by D-NAME. In contrast, angiogenesis induced by bFGF was not affected by L-NAME or by WEB 2170. TNF, but not bFGF, induced PAF synthesis within Matrigel. These results suggest that NO mediates the angiogenesis induced by PAF as well as that induced by TNF, which is dependent on the production of PAF. In contrast, the angiogenic effect of bFGF appears to be both PAF and NO independent. Images Figure 3 Figure 4 PMID:9250168

  15. Regulatory Roles of the Tumor Necrosis Factor Receptor BCMA

    PubMed Central

    Coquery, Christine M.; Erickson, Loren D.

    2012-01-01

    B cell maturation antigen (BCMA) is a tumor necrosis family receptor (TNFR) member that is predominantly expressed on terminally differentiated B cells and, upon binding to its ligands B cell activator of the TNF family (BAFF) and a proliferation inducing ligand (APRIL), delivers pro-survival cell signals. Thus, BCMA is most known for its functional activity in mediating the survival of plasma cells that maintain long-term humoral immunity. The expression of BCMA has been also linked to a number of cancers, autoimmune disorders, and infectious diseases that suggest additional roles for BCMA activity. Despite the recent advances in our understanding of the roles for the related TNFR members BAFF-R and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), the signaling pathway used by BCMA for mediating plasma cell survival as well as its putative function in certain disease states are not well understood. By examining the expression, regulation, and signaling targets of BCMA we may gain further insight into this receptor and how it operates within cells in both health and disease. This information is important for identifying new therapeutic targets that may be relevant in treating diseases that involve the BAFF/APRIL cytokine network. PMID:23237506

  16. 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.

  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.

  19. Molecular Mechanisms of Hepatocellular Apoptosis Induced by Trovafloxacin-Tumor Necrosis Factor-alpha Interaction

    PubMed Central

    Roth, Robert A.

    2014-01-01

    Idiosyncratic drug-induced liver injury (IDILI) continues to be a significant human health problem. IDILI is characterized as occurring in a minority of individuals exposed to a drug, yet it accounts for as much as 17% of all cases of acute liver failure. Despite these concerns, the mechanisms underlying IDILI remain unknown. Trovafloxacin (TVX), which causes IDILI in humans, also causes hepatocellular death in vitro when combined with tumor necrosis factor-alpha (TNF) treatment. However, the molecular mechanisms involved in this toxicity are not fully characterized. The purpose of this study was to identify mechanisms by which TVX and TNF interact to cause hepatocellular death, with a focus on a human hepatocyte cell line. TVX and TNF interacted to cause cytotoxicity in HepG2 cells at drug concentrations similar to those in people undergoing TVX therapy. TVX/TNF treatment caused apoptosis and DNA damage in HepG2 cells that depended on caspase activation. Prolonged activation of JNK occurred in TVX/TNF-induced cytotoxicity, and treatment with the JNK selective inhibitor SP600125 attenuated cytotoxicity. TVX/TNF cotreatment also caused cytotoxicity in isolated primary murine hepatocytes that was dependent on caspase activation. These results increase understanding of molecular signaling pathways involved in hepatocellular death caused by a drug with idiosyncratic liability in the presence of TNF. PMID:24097668

  20. 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

  1. Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts.

    PubMed

    Mirshahi, Alireza; Hoehn, René; Lorenz, Katrin; Kramann, Christina; Baatz, Holger

    2012-01-01

    Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine produced by macrophages and T-cells. It plays an important role both in inflammation and apoptosis. In the eye, TNF-α appears to have a role in the pathogenesis of inflammatory, edematous, neovascular and neurodegenerative disorders. Several TNF-blocking drugs have been developed and approved, and are in clinical use for inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis. TNF-α blockers are widely used in ophthalmology as an off-label alternative to "traditional" immunosuppressive and immune-modulatory treatments in noninfectious uveitis. Preliminary studies suggest a positive effect of intravenously administered TNF-α blockers, mainly infliximab, for treating refractory diabetic macular edema and neovascular age-related macular degeneration. Unfortunately, much of the current data raises considerable safety concerns for intravitreal use of TNF-α inhibitors, in particular, intraocular inflammatory responses have been reported after intravitreal injection of infliximab. Results of dose-finding studies and humanized antibody or antibody fragments (e.g. adalimumab) are anticipated in the coming years; these will shed light on potential benefits and risks of local and systemic TNF-α blockers used for treatment of diseases of the retina and choroid.

  2. Emerging ideas: prevention of posttraumatic arthritis through interleukin-1 and tumor necrosis factor-alpha inhibition.

    PubMed

    Lawrence, J Todd R; Birmingham, James; Toth, Alison P

    2011-12-01

    Despite surgical and mechanical stabilization of an acutely injured joint through ligament reconstruction, meniscus repair, or labral repair, the risk of posttraumatic arthritis remains high. Joint injury triggers three phases of pathogenic events: the early (acute) phase involves joint swelling, hemarthrosis, expression of inflammatory cytokines (especially interleukin-1 [IL-1] and tumor necrosis factor-α [TNF-α]), and biomarkers of cartilage catabolism; an intermediate phase is characterized by reduction of joint inflammation, ongoing joint catabolism, but no evidence yet for typical features of radiographic osteoarthritis (OA); and a late phase characterized by radiographic OA. We hypothesize that the early phase of acute knee injury represents a window of opportunity for providing biologic treatment to promote healing and to slow or prevent a subsequent cascade of destructive joint processes leading to OA. We propose a phase II, randomized, placebo-controlled, double-blinded, clinical trial to treat acute knee injuries with intraarticular injection of an IL-1 inhibitor. Patient-centered outcomes will include pain reduction and improvement of knee function. MR imaging and measurement of biochemical markers will be monitored during the subsequent 2 years to determine if the structural response to injury can be reversed. If this model is validated, modulation of the molecular pathways responsible for articular cartilage breakdown will augment current reconstructive procedures in the treatment of acute joint injuries and prevent the development of injury-related arthritis.

  3. A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus.

    PubMed

    Alejo, Alí; Ruiz-Argüello, M Begoña; Ho, Yin; Smith, Vincent P; Saraiva, Margarida; Alcami, Antonio

    2006-04-11

    Variola virus (VaV) is the causative agent of smallpox, one of the most devastating diseases encountered by man, that was eradicated in 1980. The deliberate release of VaV would have catastrophic consequences on global public health. However, the mechanisms that contribute to smallpox pathogenesis are poorly understood at the molecular level. The ability of viruses to evade the host defense mechanisms is an important determinant of viral pathogenesis. Here we show that the tumor necrosis factor receptor (TNFR) homologue CrmB encoded by VaV functions not only as a soluble decoy TNFR but also as a highly specific binding protein for several chemokines that mediate recruitment of immune cells to mucosal surfaces and the skin, sites of virus entry and viral replication at late stages of smallpox. CrmB binds chemokines through its C-terminal domain, which is unrelated to TNFRs, was named smallpox virus-encoded chemokine receptor (SECRET) domain and uncovers a family of poxvirus chemokine inhibitors. An active SECRET domain was found in another viral TNFR (CrmD) and three secreted proteins encoded by orthopoxviruses. These findings identify a previously undescribed chemokine-binding and inhibitory domain unrelated to host chemokine receptors and a mechanism of immune modulation in VaV that may influence smallpox pathogenesis.

  4. A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus

    PubMed Central

    Alejo, Alí; Ruiz-Argüello, M. Begoña; Ho, Yin; Smith, Vincent P.; Saraiva, Margarida; Alcami, Antonio

    2006-01-01

    Variola virus (VaV) is the causative agent of smallpox, one of the most devastating diseases encountered by man, that was eradicated in 1980. The deliberate release of VaV would have catastrophic consequences on global public health. However, the mechanisms that contribute to smallpox pathogenesis are poorly understood at the molecular level. The ability of viruses to evade the host defense mechanisms is an important determinant of viral pathogenesis. Here we show that the tumor necrosis factor receptor (TNFR) homologue CrmB encoded by VaV functions not only as a soluble decoy TNFR but also as a highly specific binding protein for several chemokines that mediate recruitment of immune cells to mucosal surfaces and the skin, sites of virus entry and viral replication at late stages of smallpox. CrmB binds chemokines through its C-terminal domain, which is unrelated to TNFRs, was named smallpox virus-encoded chemokine receptor (SECRET) domain and uncovers a family of poxvirus chemokine inhibitors. An active SECRET domain was found in another viral TNFR (CrmD) and three secreted proteins encoded by orthopoxviruses. These findings identify a previously undescribed chemokine-binding and inhibitory domain unrelated to host chemokine receptors and a mechanism of immune modulation in VaV that may influence smallpox pathogenesis. PMID:16581912

  5. Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha.

    PubMed

    Brock, C; Brock, B; Aziz, Q; Møller, H J; Pfeiffer Jensen, M; Drewes, A M; Farmer, A D

    2016-12-12

    The vagus nerve is a central component of cholinergic anti-inflammatory pathways. We sought to evaluate the effect of bilateral transcutaneous cervical vagal nerve stimulation (t-VNS) on validated parameters of autonomic tone and cytokines in 20 healthy subjects. 24 hours after t-VNS, there was an increase in cardiac vagal tone and a reduction in tumor necrosis factor-α in comparison to baseline. No change was seen in blood pressure, cardiac sympathetic index or other cytokines. These preliminary data suggest that t-VNS exerts an autonomic and a subtle antitumor necrosis factor-α effect, which warrants further evaluation in larger controlled studies.

  6. Transmembrane tumor necrosis factor-alpha sensitizes adipocytes to insulin.

    PubMed

    Zhou, Wenjing; Yang, Peng; Liu, Li; Zheng, Shan; Zeng, Qingling; Liang, Huifang; Zhu, Yazhen; Zhang, Zunyue; Wang, Jing; Yin, Bingjiao; Gong, Feili; Wu, Yiping; Li, Zhuoya

    2015-05-05

    Transmembrane TNF-α (tmTNF-α) acts both as a ligand, delivering 'forward signaling' via TNFR, and as a receptor, transducing 'reverse signaling'. The contradiction of available data regarding the effect of tmTNF-α on insulin resistance may be due to imbalance in both signals. Here, we demonstrated that high glucose-induced impairment of insulin-stimulated glucose uptake by 3T3-L1 adipocytes was concomitant with decreased tmTNF-α expression and increased soluble TNF-α (sTNF-α) secretion. However, when TACE was inhibited, preventing the conversion of tmTNF-α to sTNF-α, this insulin resistance was partially reversed, indicating a salutary role of tmTNF-α. Treatment of 3T3-L1 adipocytes with exogenous tmTNF-α promoted insulin-induced phosphorylation of IRS-1 and Akt, facilitated GLUT4 expression and membrane translocation, and increased glucose uptake while addition of sTNF-α resulted in the opposite effect. Furthermore, tmTNF-α downregulated the production of IL-6 and MCP-1 via NF-κB inactivation, as silencing of A20, an inhibitor for NF-κB, by siRNA, abolished this effect of tmTNF-α. However, tmTNF-α upregulated adiponectin expression through the PPAR-γ pathway, as inhibition of PPAR-γ by GW9662 abrogated both tmTNF-α-induced adiponectin transcription and glucose uptake. Our data suggest that tmTNF-α functions as an insulin sensitizer via forward signaling. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Inhibitors of the Metalloproteinase Anthrax Lethal Factor

    PubMed Central

    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 LF-inhibitor 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 high-throughput 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

  8. Eicosapentaenoic acid inhibits tumour necrosis factor-α-induced lipolysis in murine cultured adipocytes.

    PubMed

    Lorente-Cebrián, Silvia; Bustos, Matilde; Marti, Amelia; Fernández-Galilea, Marta; Martinez, J Alfredo; Moreno-Aliaga, Maria J

    2012-03-01

    Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid with beneficial effects in obesity and insulin resistance. High levels of proinflammatory cytokine tumour necrosis factor-α (TNF-α) in obesity promote lipolysis in adipocytes, leading to the development of insulin resistance. Thus, the aims of the present study were to analyze the potential antilipolytic properties of EPA on cytokine-induced lipolysis and to investigate the possible mechanisms involved. The EPA effects on basal and TNF-α-induced lipolysis were determined in both primary rat and 3T3-L1 adipocytes. Treatment of primary rat adipocytes with EPA (100 and 200 μM) significantly decreased basal glycerol release (P<.01) and prevented cytokine-induced lipolysis in a dose-dependent manner (P<.001). Moreover, EPA decreased TNF-α-induced activation of nuclear factor-κB and extracellular-related kinase 1/2 phosphorylation. In addition, the antilipolytic action of EPA was stimulated by the AMP-kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-b-d-ribofuranoside and blocked by the AMPK-inhibitor compound C. Moreover, we found that EPA stimulated hormone-sensitive lipase (HSL) phosphorylation on serine-565, which further supports the involvement of AMPK in EPA's antilipolytic actions. Eicosapentaenoic acid treatment (24 h), alone and in the presence of TNF-α, also decreased adipose triglyceride lipase (ATGL) protein content in cultured adipocytes. However, oral supplementation with EPA for 35 days was able to partially reverse the down-regulation of HSL and ATGL messenger RNA observed in retroperitoneal adipose tissue of high-fat-diet-fed rats. These findings suggest that EPA inhibits proinflammatory cytokine-induced lipolysis in adipocytes. This effect might contribute to explain the insulin-sensitizing properties of EPA. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. 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.

  10. 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.

  11. Binding Mode Analysis of Zerumbone to Key Signal Proteins in the Tumor Necrosis Factor Pathway

    PubMed Central

    Fatima, Ayesha; Abdul, Ahmad Bustamam Hj.; Abdullah, Rasedee; Karjiban, Roghayeh Abedi; Lee, Vannajan Sanghiran

    2015-01-01

    Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF) α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway initiated by the binding of the protein to its receptor. Zerumbone, an active constituent of Zingiber zerumbet, Smith, is known to act on the tumor necrosis factor pathway upregulating tumour necrosis factor related apoptosis inducing ligand (TRAIL) death receptors and inducing apoptosis in cancer cells. Zerumbone is a sesquiterpene that is able to penetrate into the hydrophobic pockets of proteins to exert its inhibiting activity with several proteins. We found a good binding with the tumor necrosis factor, kinase κB (IKKβ) and the Nuclear factor κB (NF-κB) component proteins along the TNF pathway. Our results suggest that zerumbone can exert its apoptotic activities by inhibiting the cytoplasmic proteins. It inhibits the IKKβ kinase that activates the NF-κB and also binds to the NF-κB complex in the TNF pathway. Blocking both proteins can lead to inhibition of cell proliferating proteins to be downregulated and possibly ultimate induction of apoptosis. PMID:25629232

  12. Induction of tumor necrosis factor in human peripheral-blood mononuclear cells by proteolytic enzymes.

    PubMed

    Desser, L; Rehberger, A

    1990-01-01

    We could demonstrate that polyenzyme preparations as well as bromelain and papain stimulate the production of tumor necrosis factor-alpha in human peripheral-blood mononuclear cell cultures in a time-dependent manner. We give evidence that immunomodulation and especially the release of cytokines may contribute to the therapeutic effect of these preparations.

  13. Reduction of Burn Progression with Topical Delivery of (Antitumor Necrosis Factor-alpha )-Hyaluronic Acid Conjugates

    DTIC Science & Technology

    2012-01-01

    and are used to treat a broad range of inflammatory conditions, such as psoriasis , rheuma- toid arthritis, and inflammatory bowel disease. That each...Reactive oxygen species in tumor necrosis factor- alpha-activated primary human keratinocytes: implications for psoriasis and inflammatory skin

  14. Leishmaniasis, Autoimmune Rheumatic Disease, and Anti–Tumor Necrosis Factor Therapy, Europe

    PubMed Central

    Xynos, Ioannis D.; Tektonidou, Maria G.; Pikazis, Dimitrios

    2009-01-01

    We report 2 cases of leishmaniasis in patients with autoimmune rheumatic diseases in Greece. To assess trends in leishmaniasis reporting in this patient population, we searched the literature for similar reports from Europe. Reports increased during 2004–2008, especially for patients treated with anti–tumor necrosis factor agents. PMID:19523302

  15. 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…

  16. 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…

  17. Roles of interleukin-1 and tumor necrosis factor in lipopolysaccharide-induced hypoglycemia.

    PubMed Central

    Vogel, S N; Henricson, B E; Neta, R

    1991-01-01

    In this study, hypoglycemia induced by injection of lipopolysaccharide (LPS) or the recombinant cytokine interleukin-1 alpha or tumor necrosis factor alpha (administered alone or in combination) was compared. LPS-induced hypoglycemia was reversed significantly by recombinant interleukin-1 receptor antagonist. PMID:1828792

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. Arg972 insulin receptor substrate-1 enhances tumor necrosis factor-α-induced apoptosis in osteoblasts.

    PubMed

    You, Yunhui; Liu, Shiqing; Peng, Lijuan; Long, Mei; Deng, Hongxiang; Zhao, Hongjun

    2015-07-01

    The presence of Arg972 insulin receptor substrate-1 (IRS-1) is associated with impaired insulin/IRS-1 signaling to activate phosphatidylinositol-3 kinase (PI3K). Tumor necrosis factor-α (TNF-α), an inflammatory cytokine with a central role in the pathogenesis of rheumatoid arthritis (RA), induces apoptosis in osteoblasts, which are the principal cell type responsible for bone loss in RA. In our previous study, an association between Arg972 IRS-1 and a high risk and severity of RA was identified. In the present study, the effects of Arg972 IRS-1 and IRS-1 on TNF-α-induced apoptosis in human osteoblasts were examined. Normal and RA osteoblasts were stably transfected with Arg972 IRS-1 and IRS-1. In addition, cells were stably transduced with IRS-1-shRNA to knock down IRS1. Following stimulation with 10 nM insulin for 30 min, the stable overexpression of Arg972 IRS-1 and knock down of IRS-1 significantly decreased IRS-1-associated PI3K activity and Akt activation/phosphorylation at serine 473 (ser473) and enhanced TNF-α-induced apoptosis in normal and in RA osteoblasts. By contrast, the stable overexpression of IRS-1 significantly increased the levels of IRS-1-associated PI3K activity and Akt phosphorylation (ser473) and inhibited TNF-α-induced apoptosis, which was eliminated by pretreatment with 50 µn BJM120, a selective PI3K inhibitor, for 30 min. In conclusion, the present study provided the first evidence, to the best of our knowledge, that insulin stimulation of Arg972 IRS-1 and IRS-1 enhanced and inhibited TNF-α-induced apoptosis, respectively in normal and RA osteoblasts by a PI3K‑dependent mechanism. These findings suggest that insulin/IRS-1 signaling is important in the pathogenesis of RA.

  3. Transfection of influenza A virus nuclear export protein induces the expression of tumor necrosis factor alpha.

    PubMed

    Lara-Sampablo, Alejandra; Flores-Alonso, Juan Carlos; De Jesús-Ortega, Nereyda; Santos-López, Gerardo; Vallejo-Ruiz, Verónica; Rosas-Murrieta, Nora; Reyes-Carmona, Sandra; Herrera-Camacho, Irma; Reyes-Leyva, Julio

    2014-06-24

    Influenza A virus genomic segments eight codes for non-structural 1 (NS1) protein that is involved in evasion of innate antiviral response, and nuclear export protein (NEP) that participates in the export of viral ribonucleoprotein (RNP) complexes, transcription and replication. Tumor necrosis factor alpha (TNF-α) is highly expressed during influenza virus infections and is considered an anti-infective cytokine. NS1 and NEP proteins were overexpressed and their role on TNF-α expression was evaluated. Both TNF-α mRNA and protein increased in cells transfected with NEP but not with NS1. We further investigate if NS1 or NEP regulates the activity of TNF-α promoter. In the presence of NEP the activity of TNF-α promoter increased significantly compared with the control (83.5±2.9 vs. 30.9±2.8, respectively; p=0.001). This effect decreased 15-fold when the TNF-α promoter distal region was deleted, suggesting the involvement of mitogen-activated protein kinases (MAPK) and NF-kB response elements. This was corroborated by testing the effect produced on TNF-α promoter by the treatment with Raf/MEK/ERK (U0126), NF-kB (Bay-11-7082) and PI3K (Ly294-002) cell signaling inhibitors. Treatment with U0126 and Bay-117082 reduced the activity of TNF-α promoter mediated by NEP (41.5±3.2, 70% inhibition; and 80.6±7.4, 35% inhibition, respectively) compared to mock-treated control. The results suggest a new role for NEP protein that participates in the transcriptional regulation of human TNF-α expression.

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

    PubMed

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

    2015-12-01

    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. 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. Copyright © 2015

  5. DR3 signaling protects against cisplatin nephrotoxicity mediated by tumor necrosis factor.

    PubMed

    Al-Lamki, Rafia S; Lu, WanHua; Finlay, Sarah; Twohig, Jason P; Wang, Eddie C Y; Tolkovsky, Aviva M; Bradley, John R

    2012-04-01

    The expression of death receptor 3 (DR3), a member of the tumor necrosis factor (TNF) receptor superfamily, is up-regulated in human tubular epithelial cells (TECs) during renal injury, but its function in this setting remains unknown. We used cisplatin to induce renal injury in wild-type (DR3(+/+)) or congenitally deficient DR3(-/-) mice to examine the in vivo role of DR3. Cisplatin induced the expression of DR3, its ligand, TNF-like ligand 1A (TL1A), and TNF in TECs, as observed in human renal injury. Cisplatin increased apoptotic death of DR3(-/-) TECs by twofold compared with DR3(+/+) TECs, whereas it reduced the number of tubules expressing phospho-NF-κBp65(Ser276) by 50% at 72 hours. Similar degrees of induction of DR3, TL1A, and TNF, and changes in apoptosis and phospho-NF-κBp65(Ser276), were obtained in mouse kidney organ cultures treated with cisplatin for 3 hours, suggesting a direct effect on TECs. TNF was implicated in mediating cisplatin-induced tubular damage given that the in vivo co-administration of GM6001, an inhibitor of TNF maturation and release, significantly reduced TNF production and tubular damage. Moreover, TNF exacerbated, whereas TL1A reduced, cisplatin-induced apoptosis in the DR3(+/+) mouse proximal tubule cell line, TKPTS. Our data demonstrate that cisplatin-induced nephrotoxicity is mitigated by DR3 signaling, suggesting that this occurs by antagonizing pro-apoptotic signals induced by TNF. Therefore, activating DR3 may be beneficial in reducing acute kidney injury. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. Tumor necrosis factor-α mediates JNK activation response to intestinal ischemia-reperfusion injury

    PubMed Central

    Yang, Qi; Zheng, Feng-Ping; Zhan, Ya-Shi; Tao, Jin; Tan, Si-Wei; Liu, Hui-Ling; Wu, Bin

    2013-01-01

    AIM: To investigate whether tumor necrosis factor-α (TNF-α) mediates ischemia-reperfusion (I/R)-induced intestinal mucosal injury through c-Jun N-terminal kinase (JNK) activation. METHODS: In this study, intestinal I/R was induced by 60-min occlusion of the superior mesenteric artery in rats followed by 60-min reperfusion, and the rats were pretreated with a TNF-α inhibitor, pentoxifylline, or the TNF-α antibody infliximab. After surgery, part of the intestine was collected for histological analysis. The mucosal layer was harvested for RNA and protein extraction, which were used for further real-time polymerase chain reaction, enzyme-linked immunosorbent assay and Western blotting analyses. The TNF-α expression, intestinal mucosal injury, cell apoptosis, activation of apoptotic protein and JNK signaling pathway were analyzed. RESULTS: I/R significantly enhanced expression of mucosal TNF-α at both the mRNA and protein levels, induced severe mucosal injury and cell apoptosis, activated caspase-9/caspase-3, and activated the JNK signaling pathway. Pretreatment with pentoxifylline markedly downregulated TNF-α at both the mRNA and protein levels, whereas infliximab pretreatment did not affect the expression of TNF-α induced by I/R. However, pretreatment with pentoxifylline or infliximab dramatically suppressed I/R-induced mucosal injury and cell apoptosis and significantly inhibited the activation of caspase-9/3 and JNK signaling. CONCLUSION: The results indicate there was a TNF-α-mediated JNK activation response to intestinal I/R injury. PMID:23946597

  7. Tumor necrosis factor-mediated release of platelet-derived growth factor from cultured endothelial cells

    PubMed Central

    1987-01-01

    Platelet-derived growth factor (PDGF) is a 30,000-Mr glycoprotein that is chemotactic and mitogenic for vascular smooth muscle cells (SMC). It is also a potent vasoconstrictor. In the present study, we found that the macrophage-derived polypeptide, tumor necrosis factor (TNF), releases a factor from human umbilical vein endothelial cells (EC) that is mitogenic for SMC. Postculture medium from TNF-stimulated EC induced a 90% increase in mitogenesis is compared with controls. This effect was half-maximal at a TNF dose of 114 pM, reflected a 2.5-fold increase in PDGF-specific mRNA synthesis, and peaked at 15 h of TNF stimulation. Mitogenic activity was completely abrogated by preincubation of postculture medium with antibody to platelet PDGF. Stimulation of EC with IL-1 (60-240 pM) led to the release of similar mitogenic activity. Thus, in addition to its effects on the hemostatic and adhesive properties of EC, TNF also promotes release of PDGF, which may serve to modulate proliferation of vascular SMC during wound healing, inflammation, and atherogenesis. PMID:3598461

  8. Radiation necrosis of the mandible: a 10 year study. Part II. Dental factors; onset, duration and management of necrosis

    SciTech Connect

    Murray, C.G.; Herson, J.; Daly, T.E.; Zimmerman, S.

    1980-05-01

    In a review of patients receiving radiation for cancer in the oral region the rate of radiation necrosis of the mandible was found to be similar for patients who had dental extractions before radiation therapy and for the remainder of the dentate population. It was suggested that diseased teeth should be removed prior to irradiation and sufficient healing time should be allowed. Teeth should not be extracted after irradiation. Dental prostheses can be provided for most irradiated patients if adequate care is exercised. The probability of necrosis commencing was highest three to twelve months after the start of therapy; it diminished gradually after that period. The duration of necrosis was depicted as an exponential curve with a constant probability of necrosis termination at each time point after onset. In 46.8% of the patients in study II (1971-1975), the necrosis was healed by conservative means. This was a significant increase over study I (1966-1969), and a complementary reduction in the necessity for surgical intervention was also found.

  9. Regulatory mechanisms of interleukin-8 production induced by tumour necrosis factor-α in human hepatocellular carcinoma cells

    PubMed Central

    Wang, Yaohui; Wang, Weimin; Wang, Lingyan; Wang, Xiangdong; Xia, Jinglin

    2012-01-01

    Abstract Interleukin (IL)-8 plays the critical role in the initiation of micro-environmental inflammation responsible for tumour growth and patient prognosis. This study aimed at investigating the molecular mechanisms of IL-8 production from human hepatocellular carcinoma (HCC) cells. The levels of IL-8 and phosphorylation of p38 mitogen-activated protein kinase (MAPK), ERK1/2 and Akt in MHCC-97H cells were measured by ELISA, Western blot and immunofluorescence. NF-κB p65 protein nuclear translocation was determined by non-radioactive NF-κB p50/p65 transcription factor activity kit and cell bio-behaviours were detected by the real-time cell-monitoring system. Tumour necrosis factor-α (TNF-α) significantly induced phosphorylation of p38 MAPK, ERK, Akt and production of IL-8 from HCC cells, which were prevented by SB203580 (p38 MAPK inhibitor), PD98059 (ERK inhibitor), LY294002 and Wortmannin (PI3K inhibitor) and SB328437 (CCR3 inhibitor). TNF-α could significantly increase the translocation of NF-κB p65 protein into the nucleus in a dose-dependent manner, while SB203580 partially inhibited. In inflammatory micro-environment, HCC auto-produced IL-8 through p38 MAPK, ERK and PI3K/Akt signalling pathways, where the p38 MAPK is a central factor to activate the NF-κB pathway and regulate the expression of IL-8 production. There was a potential cross-talking between receptors. PMID:21545687

  10. Human cobalamin deficiency: alterations in serum tumour necrosis factor-alpha and epidermal growth factor.

    PubMed

    Peracchi, M; Bamonti Catena, F; Pomati, M; De Franceschi, M; Scalabrino, G

    2001-08-01

    We have previously demonstrated that vitamin B12 (cobalamin)-deficient central neuropathy in the rat is associated with local overexpression of neurotoxic tumour necrosis factor (TNF)-alpha combined with locally decreased synthesis of neurotrophic epidermal growth factor (EGF). The aims of this study were to investigate whether a similar imbalance also occurs in the serum of adult patients with clinically confirmed cobalamin deficiency and whether it can be corrected by vitamin B12 replacement therapy. We studied 34 adult patients with severe cobalamin deficiency, 12 patients with pure iron deficiency anaemia and 34 control subjects. Haematological markers of cobalamin deficiency and serum TNF-alpha and EGF levels were measured using commercial kits. Thirteen cobalamin-deficient patients were re-evaluated after 3 and 6 months of parenteral vitamin B12 treatment. TNF-alpha was significantly higher (p < 0.01) and EGF significantly lower (p < 0.01) in the patients with cobalamin deficiency, but both were unchanged in patients with pure iron deficiency anaemia. In cobalamin-deficient patients the serum TNF-alpha levels correlated significantly with plasma total homocysteine levels (r = 0.425; p < 0.02). In the treated patients TNF-alpha and EGF levels normalised concomitantly with clinical and haematological disease remission. In humans, as in rats, cobalamin concentration appears to be correlated with the synthesis and release of TNF-alpha and EGF in a reciprocal manner, because cobalamin deficiency is accompanied by overproduction of TNF-alpha and underproduction of EGF.

  11. Neuroprotection in a rabbit model of intraventricular haemorrhage by cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-alpha inhibition

    PubMed Central

    Vinukonda, Govindaiah; Csiszar, Anna; Hu, Furong; Dummula, Krishna; Pandey, Nishi Kant; Zia, Muhammad T.; Ferreri, Nicholas R.; Ungvari, Zoltan; LaGamma, Edmund F.

    2010-01-01

    Intraventricular haemorrhage is a major complication of prematurity that results in neurological dysfunctions, including cerebral palsy and cognitive deficits. No therapeutic options are currently available to limit the catastrophic brain damage initiated by the development of intraventricular haemorrhage. As intraventricular haemorrhage leads to an inflammatory response, we asked whether cyclooxygenase-2, its derivative prostaglandin E2, prostanoid receptors and pro-inflammatory cytokines were elevated in intraventricular haemorrhage; whether their suppression would confer neuroprotection; and determined how cyclooxygenase-2 and cytokines were mechanistically-linked. To this end, we used our rabbit model of intraventricular haemorrhage where premature pups, delivered by Caesarian section, were treated with intraperitoneal glycerol at 2 h of age to induce haemorrhage. Intraventricular haemorrhage was diagnosed by head ultrasound at 6 h of age. The pups with intraventricular haemorrhage were treated with inhibitors of cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-α; and cell-infiltration, cell-death and gliosis were compared between treated-pups and vehicle-treated controls during the first 3 days of life. Neurobehavioural performance, myelination and gliosis were assessed in pups treated with cyclooxygenase-2 inhibitor compared to controls at Day 14. We found that both protein and messenger RNA expression of cyclooxygenase-2, prostaglandin E2, prostanoid receptor-1, tumour necrosis factor-α and interleukin-1β were consistently higher in the forebrain of pups with intraventricular haemorrhage relative to pups without intraventricular haemorrhage. However, cyclooxygenase-1 and prostanoid receptor 2–4 levels were comparable in pups with and without intraventricular haemorrhage. Cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-α inhibition reduced inflammatory cell infiltration, apoptosis, neuronal degeneration and gliosis

  12. 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

  13. miR-29a suppresses MCF-7 cell growth by downregulating tumor necrosis factor receptor 1.

    PubMed

    Zhao, Yiling; Yang, Fenghua; Li, Wenyuan; Xu, Chunyan; Li, Li; Chen, Lifei; Liu, Yancui; Sun, Ping

    2017-02-01

    Tumor necrosis factor receptor 1 is the main receptor mediating many tumor necrosis factor-alpha-induced cellular events. Some studies have shown that tumor necrosis factor receptor 1 promotes tumorigenesis by activating nuclear factor-kappa B signaling pathway, while other studies have confirmed that tumor necrosis factor receptor 1 plays an inhibitory role in tumors growth by inducing apoptosis in breast cancer. Therefore, the function of tumor necrosis factor receptor 1 in breast cancer requires clarification. In this study, we first found that tumor necrosis factor receptor 1 was significantly increased in human breast cancer tissues and cell lines, and knockdown of tumor necrosis factor receptor 1 by small interfering RNA inhibited cell proliferation by arresting the cell cycle and inducing apoptosis. In addition, miR-29a was predicted as a regulator of tumor necrosis factor receptor 1 by TargetScan and was shown to be inversely correlated with tumor necrosis factor receptor 1 expression in human breast cancer tissues and cell lines. Luciferase reporter assay further confirmed that miR-29a negatively regulated tumor necrosis factor receptor 1 expression by binding to the 3' untranslated region. In our functional study, miR-29a overexpression remarkably suppressed cell proliferation and colony formation, arrested the cell cycle, and induced apoptosis in MCF-7 cell. Furthermore, in combination with tumor necrosis factor receptor 1 transfection, miR-29a significantly reversed the oncogenic role caused by tumor necrosis factor receptor 1 in MCF-7 cell. In addition, we demonstrated that miR-29a suppressed MCF-7 cell growth by inactivating the nuclear factor-kappa B signaling pathway and by decreasing cyclinD1 and Bcl-2/Bax protein levels. Taken together, our results suggest that miR-29a is an important regulator of tumor necrosis factor receptor 1 expression in breast cancer and functions as a tumor suppressor by targeting tumor necrosis factor receptor 1 to

  14. Requirement of Tumor Necrosis Factor Receptor–Associated Factor (Traf)6 in Interleukin 17 Signal Transduction

    PubMed Central

    Schwandner, Ralf; Yamaguchi, Kyoko; Cao, Zhaodan

    2000-01-01

    Signaling through its widely distributed cell surface receptor, interleukin (IL)-17 enhances the transcription of genes encoding proinflammatory molecules. Although it has been well documented that IL-17 activates the transcription factor nuclear factor (NF)-κB and c-Jun NH2-terminal kinase (JNK), the upstream signaling events are largely unknown. Here we report the requirement of tumor necrosis factor receptor–associated factor (TRAF)6 in IL-17–induced NF-κB and JNK activation. In embryonic fibroblasts (EFs) derived from TRAF6 knockout mice, IL-17 failed to activate the IκB kinases (IKKs) and JNK. Consequently, IL-17–induced IL-6 and intercellular adhesion molecule 1 expression in the TRAF6-deficient cells was abolished. Lack of TRAF6 appeared to be the sole defect responsible for the observed failure to respond to IL-17, because transient transfection of TRAF6 expression plasmid into the TRAF6-deficient cells restored IL-17–induced NF-κB activation in a luciferase reporter assay. Furthermore, the levels of IL-17 receptor (IL-17R) on the TRAF6-deficient EFs were comparable to those on the wild-type control cells. Defect in IL-17 response was not observed in TRAF2-deficient EFs. Moreover, when TRAF6 and IL-17R were coexpressed in 293 cells, TRAF6 coimmunoprecipitated with IL-17R. Together, these results indicate that TRAF6, but not TRAF2, is a crucial component in the IL-17 signaling pathway leading to proinflammatory responses. PMID:10748240

  15. Tumor Necrosis Factor Receptor Associated Factor 2 Signaling Provokes Adverse Cardiac Remodeling in the Adult Mammalian Heart

    PubMed Central

    Divakaran, Vijay G.; Evans, Sarah; Topkara, Veli K.; Diwan, Abhinav; Burchfield, Jana; Gao, Feng; Dong, Jianwen; Tzeng, Huei-Ping; Sivasubramanian, Natarajan; Barger, Philip M.; Mann, Douglas L.

    2013-01-01

    Background Tumor necrosis factor (TNF) superfamily ligands that provoke a dilated cardiac phenotype signal through a common scaffolding protein termed TNF receptor associated factor 2 (TRAF2); however, virtually nothing is known with regard to TRAF2 signaling in the adult mammalian heart. Methods and Results We generated multiple founder lines of mice with cardiac restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (MHC-TRAF2HC). MHC-TRAF2HC transgenic mice developed a time-dependent increase in cardiac hypertrophy, LV dilation and adverse LV remodeling, and a significant decrease in LV +dP/dt and −dP/dt when compared to littermate (LM) controls (p < 0.05 compared to LM). During the early phases of LV remodeling there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2HC mice aged, there was a significant decrease in total MMP activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in NF-κB activation at 4 – 12 weeks and JNK activation at 4 weeks in the MHCs TRAF2HC mice. Transciptional profiling revealed that > 95% of the hypertrophic/dilated cardiomyopathy-related genes that were significantly upregulated genes in the MHC-TRAF2HC hearts contained κB elements in their promoters. Conclusions These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart. PMID:23493088

  16. Crystallization and preliminary X-ray analysis of the tumour necrosis factor alpha-tumour necrosis factor receptor type 2 complex.

    PubMed

    Mukai, Yohei; Nakamura, Teruya; Yoshioka, Yasuo; Tsunoda, Shin-ichi; Kamada, Haruhiko; Nakagawa, Shinsaku; Yamagata, Yuriko; Tsutsumi, Yasuo

    2009-03-01

    Tumour necrosis factor receptor type 2 (TNFR2, TNFRSF1B) is an essential receptor for various host-defence functions of tumour necrosis factor alpha (TNF). As part of studies to determine the structure of TNFR2, the formation, crystallization and preliminary X-ray diffraction analysis of the TNF-TNFR2 complex are described. The TNF-TNFR2 complex, which comprises one TNF trimer and three TNFR2 monomers, was confirmed and purified by size-exclusion chromatography. Crystals of the TNF-TNFR2 complex were obtained using polyethylene glycol 3350 as a precipitant. The crystal belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 74.5, b = 117.4, c = 246.8 A. Assuming the presence of two TNF-TNFR2 complexes in the asymmetric unit, the Matthews coefficient V(M) was 2.49 A(3) Da(-1) and the solvent content of the crystal was 50.7%. The crystal diffracted to 2.95 A resolution.

  17. A novel tumor necrosis factor-responsive transcription factor which recognizes a regulatory element in hemopoietic growth factor genes

    SciTech Connect

    Shannon, M.F.; Pell, L.M.; Kuczek, E.S.; Occhiodoro, F.S.; Dunn, S.M.; Vadas, M.A. ); Lenardo, M.J. )

    1990-06-01

    A conserved DNA sequence element, termed cytokine 1 (CK-1), is found in the promoter regions of many hemopoietic growth factor (HGF) genes. Mutational analyses and modification interference experiments show that this sequence specifically binds a nuclear transcription factor, NF-GMa, which is a protein with a molecular mass of 43 kilodaltons. It interacts with different affinities with the CK-1-like sequence from a number of HGF genes, including granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte (G)-CSF, interleukin 3 (IL-3), and IL-5. The authors show that the level of NF-GMa binding is induced in embryonic fibroblasts by tumor necrosis factor {alpha} (TNF-{alpha}) treatment and that the CK-1 sequence from the G-CSF gene is a TNF-{alpha}-responsive enhancer in these cells.

  18. 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

  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. Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis.

    PubMed Central

    Nickoloff, B. J.; Karabin, G. D.; Barker, J. N.; Griffiths, C. E.; Sarma, V.; Mitra, R. S.; Elder, J. T.; Kunkel, S. L.; Dixit, V. M.

    1991-01-01

    The importance of immunologic mechanisms in psoriasis has been deduced from the ability of immunosuppressive therapies to ameliorate this common and chronic skin disease. Certainly the histology of psoriatic lesions suggests a dialogue between the hyperplastic keratinocytes and infiltrating T lymphocytes and macrophages. To begin dissecting the cytokine network involved in the pathophysiology of psoriasis, the location, in both epidermal and dermal compartments, of tumor necrosis factor-alpha, interleukin-8, intercellular adhesion molecule-1, and transforming growth factor-alpha at the protein and/or mRNA levels were identified. Tumor necrosis factor-alpha was selected as a potentially key regulatory cytokine, first because it induces cultured keratinocyte interleukin-8, intercellular adhesion molecule-1, and transforming growth factor-alpha production, and second because intercellular adhesion molecule-1 expression by keratinocytes in psoriatic epidermis had been identified previously. Using immunohistochemical localization, tumor necrosis factor-alpha was identified in 12 psoriatic lesions as intense and diffuse expression by dermal dendrocytes (macrophages) in the papillary dermis (without significant staining of endothelial cells, mast cells, or dermal Langerhans cells), and focally by keratinocytes and intraepidermal Langerhans cells. Functional interaction between the dermal dendrocytes and keratinocytes was suggested by the presence of interleukin-8 expression of suprabasal keratinocytes immediately above the tumor necrosis factor-alpha-positive dermal dendrocytes. Interleukin-8 mRNA and transforming growth factor-alpha mRNA were detectable in the epidermal roof of psoriatic lesions, but neither was detectable at the protein or mRNA levels in any normal skin specimens. Treatment of cultured human keratinocytes with phorbol ester (which experimentally produces psoriasiform changes on mouse skin) or tumor necrosis factor-alpha also increased interleukin-8 and

  1. Lysophosphatidic Acid Triggers Apoptosis in HeLa Cells through the Upregulation of Tumor Necrosis Factor Receptor Superfamily Member 21

    PubMed Central

    2017-01-01

    Lysophosphatidic acid (LPA), a naturally occurring bioactive phospholipid, activates G protein-coupled receptors (GPCRs), leading to regulation of diverse cellular events including cell survival and apoptosis. Despite extensive studies of the signaling pathways that mediate LPA-regulated cell growth and survival, the mechanisms underlying the apoptotic effect of LPA remain largely unclear. In this study, we investigated this issue in HeLa cells. Our data demonstrate that LPA induces apoptosis in HeLa cells at pathologic concentrations with a concomitant upregulation of the expression of TNFRSF21 (tumor necrosis factor receptor superfamily member 21), also known as death receptor number 6 (DR6) involved in inflammation. Moreover, treatment of cells with LPA receptor (LPAR) antagonist abolished the DR6 upregulation by LPA. LPA-induced DR6 expression was also abrogated by pertussis toxin (PTX), an inhibitor of GPCRs, and by inhibitors of PI3K, PKC, MEK, and ERK. Intriguingly, LPA-induced DR6 expression was specifically blocked by dominant-negative form of PKCδ (PKCδ-DN). LPA-induced DR6 expression was also dramatically inhibited by knockdown of ERK or CREB. These results suggest that activation of the MEK/ERK pathway and the transcription factor CREB mediate LPA-induced DR6 expression. More interestingly, knockdown of DR6 using siRNA approach remarkably attenuated LPA-induced apoptosis. In conclusion, our results suggest that LPA-induced apoptosis in HeLa cells is mediated by the upregulation of DR6 expression. PMID:28348459

  2. 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

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

    PubMed Central

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

    2015-01-01

    Summary 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

  4. Kinetics of tumor necrosis factor production by photodynamic-therapy-activated macrophages

    NASA Astrophysics Data System (ADS)

    Pass, Harvey I.; Evans, Steven; Perry, Roger; Matthews, Wilbert

    1990-07-01

    The ability of photodynamic therapy (PDT) to activate macrophages and produce cytokines, specifically tumor necrosis factor (TNF), is unknown. Three day thioglycolate elicited macrophages were incubated with 25 ug/mi Photofrin II (P11) for 2 hour, after which they were subjected to 630 nm light with fluences of 0-1800 J/m. The amount of TNF produced in the system as well as macrophage viability was measured 1, 3, 6, and 18 hours after POT. The level of TNF produced by the macrophages was significantly elevated over control levels 6 hours after POT and the absolute level of tumor necrosis factor production was influenced by the treatment energy and the resulting macrophage cytotoxicity. These data suggest that POT therapy induced cytotoxicity in vivo may be amplified by macrophage stimulation to secrete cytokines and these cytokines may also participate in other direct/indirect photodynamic therapy effects, i.e. immunosuppression, vascular effects.

  5. 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

  6. 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

    2015-07-08

    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.

  7. 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.

  8. Role of Tumor Necrosis Factor Alpha in Gnotobiotic Mice Infected with an Escherichia coli O157:H7 Strain

    PubMed Central

    Isogai, Emiko; Isogai, Hiroshi; Kimura, Koichi; Hayashi, Shunji; Kubota, Toru; Fujii, Nobuhiro; Takeshi, Koichi

    1998-01-01

    Gnotobiotic mice inoculated with an enterohemorrhagic Escherichia coli (EHEC) O157:H7 strain developed a flaccid paresis, usually culminating in death. The bacteria colonized feces at 109 to 1010 CFU per g (inoculum size: 2.0 × 109 CFU/mouse), and Shiga-like toxins (SLTs) were detected in the feces. A microscopic examination of colons showed mild inflammatory cell infiltration, thinning of the intestinal wall, or necrotic foci. Necrosis of tubular cells was noted in these symptomatic mice. Microhemorrhage, thrombosis, and edematous changes of the brain were also seen. Inflammatory cytokines, tumor necrosis factor alpha (TNF-α), interleukin 1α (IL-1α), and IL-6, were detected in the kidney after EHEC infection, but not in the serum. In the brain, only TNF-α was detected. When 2.0 × 102 CFU of EHEC O157:H7 was fed to germ-free mice, the number of bacteria began to rise rapidly on day 1 and was maintained at 108 to 109 CFU/g of feces. SLTs were detected in the feces of the mice. However, the mice showed no histological changes and no cytokine responses, similar to what was found for controls. Treatment with TNF-α modified the clinical neural signs, histopathological changes, and cytokine responses; mice treated with TNF-α developed severe neurotoxic symptoms and had higher frequencies of systemic symptoms and glomerular pathology. Strong cytokine responses were seen in the kidney and brain. Serum cytokines were also detected in this group. In contrast, a TNF-α inhibitor (protease inhibitor) inhibited these responses, especially in the brain. However, local synthesis of the cytokines was observed in the kidney. Thus, TNF-α and the other proinflammatory cytokines could be important in modifying the disease caused by EHEC. PMID:9423858

  9. Role of Tumor Necrosis Factor Alpha in Development of Immunity against Cryptosporidium parvum Infection

    PubMed Central

    Lean, I-Sarah; Lacroix-Lamandé, Sonia; Laurent, Fabrice; McDonald, Vincent

    2006-01-01

    Tumor necrosis factor (TNF-α) significantly reduced Cryptosporidium parvum development in a murine enterocyte cell line, and a key mechanism of action appeared to be inhibition of parasite invasion. However, TNF-α-deficient mice controlled infection as effectively as wild-type mice. This suggests that TNF-α might have only a redundant role for establishing immunity against C. parvum. PMID:16790816

  10. Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion

    PubMed Central

    de Wilt, J H W; ten Hagen, T L M; de Boeck, G; van Tiel, S T; de Bruijn, E A; Eggermont, A M M

    2000-01-01

    Several possible mechanisms for the synergistic anti-tumour effects between tumour necrosis factor alpha (TNF-α) and melphalan after isolated limb perfusion (ILP) have been presented. We found a significant sixfold increase in melphalan tumour tissue concentration after ILP when TNF-α was added to the perfusate, which provides a straightforward explanation for the observed synergism between melphalan and TNF-α in ILP. © 2000 Cancer Research Campaign PMID:10737379

  11. The tumour necrosis factor/TNF receptor superfamily: therapeutic targets in autoimmune diseases

    PubMed Central

    Vinay, D S; Kwon, B S

    2011-01-01

    Autoimmune diseases are characterized by the body's ability to mount immune attacks on self. This results from recognition of self-proteins and leads to organ damage due to increased production of pathogenic inflammatory molecules and autoantibodies. Over the years, several new potential therapeutic targets have been identified in autoimmune diseases, notable among which are members of the tumour necrosis factor (TNF) superfamily. Here, we review the evidence that certain key members of this superfamily can augment/suppress autoimmune diseases. PMID:21401577

  12. Myometrial tumor necrosis factor-α receptors increase with gestation and labor and modulate gene expression through mitogen-activated kinase and nuclear factor-κB.

    PubMed

    Alexander, Helen A; Sooranna, Suren R; Myatt, Leslie; Johnson, Mark R

    2012-01-01

    Previously, we found that myometrial tumor necrosis factor-α (TNF-α) messenger RNA (mRNA) expression did not increase with preterm or term labor. To further investigate the role of TNF-α in human labor, we studied TNF-α receptor (TNFR1A and B) expression, regulation, and associated intracellular signaling pathways in human myometrial samples obtained both before and after the onset of labor and in primary cultures of uterine smooth muscle cells (USMCs). We found that the mRNA expression of both receptors increased with advancing gestation and labor and protein levels of TNFR1B were significantly higher in term laboring myometrial samples than in nonlabor controls. Tumor necrosis factor- treatment of USMCs activated all mitogen-activated protein kinase (MAPK) subtypes and nuclear factor κ-B (NF-κB). The TNF-α induced increases in the expression of TNFR1B and prostaglandin H synthase type 2 were reduced by inhibitors of NF-κB and MAPKs, respectively. The TNF-α induced increase in interleukin 8 (IL-8) appeared to be independent of MAPK and NF-κB pathway. These data suggest that the uterus may become more sensitive to the action of TNF-α with advancing gestation and labor and that TNF-α acts via MAPK and NF-κB to promote labor-associated gene expression.

  13. Activation of the neutrophil bactericidal activity for nontypable Haemophilus influenzae by tumor necrosis factor and lymphotoxin.

    PubMed

    Tan, A M; Ferrante, A; Goh, D H; Roberton, D M; Cripps, A W

    1995-02-01

    Previous studies have suggested that, in vivo, activated T lymphocytes and neutrophils are important in immunity to nontypable Haemophilus influenzae. We now extend this work by showing that neutrophils pretreated with products of activated T lymphocytes or activated macrophages show significantly enhanced killing of nontypable H. influenzae. Lymphotoxin, a product of activated T lymphocytes, significantly enhanced the neutrophil-mediated killing of nontypable H. influenzae, and tumor necrosis factor, produced by activated T lymphocytes as well as macrophages stimulated by activated T lymphocytes, also significantly increased the bactericidal activity of neutrophils. These cytokine-induced effects were seen with short pretreatment times of neutrophils and were maximal by 30 min. The killing of H. influenzae by neutrophils required the presence of heat-labile opsonins. In the absence of these opsonins, both tumor necrosis factor and lymphotoxin were unable to promote the killing of the bacteria by neutrophils. Furthermore, the results showed that tumor necrosis factor-primed neutrophils displayed significantly increased expression of CR3 and CR4 that was associated with increased phagocytosis of complement-opsonized nontypable H. influenzae. These cytokines may play an important role in immunity toward nontypable H. influenzae by stimulating neutrophil bactericidal activity.

  14. Interferon-γ differentially modulates the impact of tumor necrosis factor-α on human endometrial stromal cells.

    PubMed

    Spratte, Julia; Oemus, Anne; Zygmunt, Marek; Fluhr, Herbert

    2015-09-01

    The pro-inflammatory T helper (Th)-1 cytokines, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), are immunological factors relevant at the feto-maternal interface and involved in the pathophysiology of implantation disorders. The synergistic action of the two cytokines has been described with regard to apoptotic cell death and inflammatory responses in different cell types, but little is known regarding the human endometrium. Therefore, we examined the interaction of TNF-α and IFN-γ in human endometrial stromal cells (ESCs). ESCs were isolated from specimens obtained during hysterectomy and decidualized in vitro. Cells were incubated with TNF-α, IFN-γ or signaling-inhibitor. Insulin-like growth factor binding protein (IGFBP)-1, prolactin (PRL), leukemia inhibitory factor (LIF), interleukin (IL)-6, IL-8, regulated on activation normal T-cell expressed and secreted protein (RANTES) and monocyte chemotactic protein (MCP)-1 were measured using ELISA and real-time RT-PCR. Nuclear factor of transcription (NF)-κB and its inhibitor (IκBα) were analyzed by in-cell western assay and transcription factor assay. TNF-α inhibited and IFN-γ did not affect the decidualization of ESCs. In contrast, IFN-gamma differentially modulated the stimulating effect of TNF-alpha on cytokines by enhancing IL-6, RANTES and MCP-1 and attenuating LIF mRNA expression. These effects were time- and dose-dependent. IFN-γ had no impact on the initial activation of NF-κB signaling. Histone-deacetylase activity was involved in the modulating effect of IFN-γ on RANTES secretion. These observations showed a distinct pattern of interaction of the Th-1 cytokines, TNF-α and IFN-γ in the human endometrium, which could play an important role in the pathophysiology of implantation disorders.

  15. Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-[alpha

    SciTech Connect

    Carter, Percy H.; Scherle, Peggy A.; Muckelbauer, Jodi K.; Voss, Matthew E.; Liu, Rui-qin; Thompson III, Lorin A.; Xu, Meizhong; Lo, Yvonne C.; Li, Zhong; Strzemienski, Paul; Yang, Gengjie; Falahatpishen, Nikoo; Farrow, Neil A.; Tebben, Andrew J.; Underwood, Denis; Trzaskos, James M.; Friedman, Steven M.; Newton, Robert C.; Decicco, Carl P.

    2010-03-05

    The binding of tumor necrosis factor alpha (TNF-{alpha}) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein-protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-{alpha} to TNFRc1 (IC{sub 50} = 50 nM) and also blocked TNF-stimulated phosphorylation of I{kappa}-B in Ramos cells (IC{sub 50} = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 {micro}M. Detailed evaluation of this and related molecules revealed that compounds in this class are 'photochemically enhanced' inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity (ca. 40-100 mM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-{alpha} to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-{alpha}-TNFRc1 interaction.

  16. Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-alpha.

    PubMed

    Carter, P H; Scherle, P A; Muckelbauer, J K; Voss, M E; Liu, R Q; Thompson, L A; Tebben, A J; Solomon, K A; Lo, Y C; Li, Z; Strzemienski, P; Yang, G; Falahatpisheh, N; Xu, M; Wu, Z; Farrow, N A; Ramnarayan, K; Wang, J; Rideout, D; Yalamoori, V; Domaille, P; Underwood, D J; Trzaskos, J M; Friedman, S M; Newton, R C; Decicco, C P; Muckelbauer, J A

    2001-10-09

    The binding of tumor necrosis factor alpha (TNF-alpha) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein-protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-alpha to TNFRc1 (IC(50) = 50 nM) and also blocked TNF-stimulated phosphorylation of Ikappa-B in Ramos cells (IC(50) = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 microM. Detailed evaluation of this and related molecules revealed that compounds in this class are "photochemically enhanced" inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity (ca. 40-100 microM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-alpha to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-alpha-TNFRc1 interaction.

  17. Risk Factor Analysis for Mastectomy Skin Flap Necrosis: Implications for Intraoperative Vascular Analysis.

    PubMed

    Reintgen, Christian; Leavitt, Adam; Pace, Elizabeth; Molas-Pierson, Justine; Mast, Bruce A

    2016-06-01

    Skin flap necrosis after mastectomy can be a devastating complication significantly affecting patient outcomes. Routine vascular analysis (fluorescein or laser angiography) of mastectomy skin flaps in all patients has been advocated but is of questionable cost-effectiveness. The purpose of this study was to identify the incidence and causative risk factors for mastectomy skin flap necrosis and thereby calculate the fiscal reality of intraoperative vascular screening. This is an institutional review board-approved retrospective study of all patients from 2007 to 2013 who underwent mastectomy related to breast cancer. Skin flap necrosis was defined as major if it necessitated return to the operating room. Data analysis was done for determination of causative factors of necrosis, including age, body mass index, smoking, previous irradiation, coronary artery disease, chronic obstructive pulmonary disorder, hypertension, gastroesophageal reflux disease, hyperlipidemia, obstructive sleep apnea, asthma, diabetes, thyroid disease, history of lumpectomy, and breast reduction or augmentation. During this time, intraoperative vascular screening was not done. Five hundred eighty-one patients underwent 616 mastectomies with a total of 34 necrotic events (5.5%)-16 major and 18 minor. Analyses via Student t tests, univariate analyses, χ testing, and logistic regression showed that history of smoking was the only patient factor associated with postoperative necrosis (P = 0.008). More frequently represented in the necrosis group, but without statistical significance, are previous lumpectomy (P = 0.069) and immediate reconstruction (P = 0.078).For the entire study period, the actual cost to the hospital for major necrotic events was $7,123.10 or $445.19 for each of the 16 major necrotic events and $209.50 for all 34 necrotic events. Per-patient cost-effective screening would need to be less than $11.54 for all patients, $100.33 for highest risk patients (smokers), and $21.65 for

  18. Epstein-Barr virus immediate-early protein BZLF1 inhibits tumor necrosis factor alpha-induced signaling and apoptosis by downregulating tumor necrosis factor receptor 1.

    PubMed

    Morrison, Thomas E; Mauser, Amy; Klingelhutz, Aloysius; Kenney, Shannon C

    2004-01-01

    Tumor necrosis factor alpha (TNF-alpha) is a key mediator of host immune and inflammatory responses and inhibits herpesvirus replication by cytolytic and noncytolytic mechanisms. TNF-alpha effects are primarily mediated through the major TNF-alpha receptor, TNF-R1, which is constitutively expressed in most cell types. Here we show that the Epstein-Barr virus (EBV) immediate-early protein BZLF1 prevents TNF-alpha activation of target genes and TNF-alpha-induced cell death. These effects are mediated by down-regulation of the promoter for TNF-R1. Additionally, we demonstrate that expression of TNF-R1 is downregulated during the EBV lytic replication cycle. Thus, EBV has developed a novel mechanism for evading TNF-alpha antiviral effects during lytic reactivation or primary infection.

  19. Vitamin B12 deficiency, tumor necrosis factor-alpha, and epidermal growth factor: a novel function for vitamin B12?

    PubMed

    Miller, Joshua W

    2002-05-01

    Vitamin B12 deficiency was recently shown to be associated with elevated levels of tumor necrosis factor-alpha and decreased levels of epidermal growth factor in both rats and humans. These findings suggest a novel pathogenetic mechanism underlying the neuropathology of vitamin B12 deficiency. They may also explain putative relationships between vitamin B12 deficiency and certain disorders, including Alzheimer's disease, rheumatoid arthritis, and AIDS.

  20. Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1

    PubMed Central

    2013-01-01

    Background Tumor invasion and metastasis are the major reasons for leading death of patients with hepatocellular carcinoma (HCC). Therefore, to identify molecules that can suppress invasion and metastasis of tumor will provide novel targets for HCC therapies. Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2, TIPE2, is a novel immune negative molecule and an inhibitor of the oncogenic Ras in mice but its function in human is unclear. Our previous research has shown that TIPE2 is downregulated in human primary HCC compared with the paired adjacent non-tumor tissues. Results In present study, we provide evidence that TIPE2 inhibits effectively human hepatocellular carcinoma metastasis. The forced expression of TIPE2 in HCC-derived cell lines markedly inhibits tumor cell growth, migration and invasion in vitro and suppresses growth and metastasis of HCC in vivo. Clinical information from a cohort of 112 patients reveals that loss or reduced expression of TIPE2 in primary HCC tissues is significantly associated with tumor metastasis. Mechanically, TIPE2 inhibits the migration and invasion through targeting Rac1 and then reduces F-actin polymerization and expression of matrix metallopeptidase 9 (MMP9) and urokinase plasminogen activator (uPA). Conclusion Our results indicate that human TIPE2 is endogenous inhibitor of Rac1 in HCC by which it attenuates invasion and metastasis of HCC. The data suggest that TIPE2 will be a new target for HCC therapy. PMID:24274578

  1. Reduction by cobra venom factor of myocardial necrosis after coronary artery occlusion.

    PubMed

    Maroko, P R; Carpenter, C B; Chiariello, M; Fishbein, M C; Radvany, P; Knostman, J D; Hale, S L

    1978-03-01

    Components of the complement system are known to play an important role in the cytolytic process and in chemotaxis of leukocytes. Cobra venom factor specifically cleaves C3 activity via activation of the alternative (properdin) complement pathway. It does not act directly on C3. If C3 is involved in tissue necrosis after ischemic injury, cobra venom factor might reduce tissue damage after acute coronary occlusion. Accordingly, in 14 control dogs occlusion of the left anterior descending artery was carried out for 24 h. Epicardial electrograms were recorded 15 min after occlusion, and 24 h later transmural specimens for creatine phosphokinase activity (CPK) and for histological analysis were obtained from the same sites. In another 14 experimental dogs, 20 U/kg cobra venom factor was given intravenously 30 min after occlusion. Serum complement levels fell within 2-4 h to <20% of normal. In the control dogs, the relationship between ST-segment elevation and CPK activity 24 h later was: log CPK = -0.06 ST + 1.48 (n = 111 specimens, 14 dogs, r = 0.77). In the experimental dogs, log CPK = -0.024 ST + 1.46 (n = 111 specimens, 14 dogs, r = 0.60), showing significantly different slopes (P < 0.001), i.e., less CPK depression for any level of ST-segment elevation. Histologically, 69 of 71 sites (97%) with ST-segment elevation exceeding 2 mV in the control dogs showed signs of necrosis 24 h later, whereas in the experimental group only 43 of 79 sites (54%) with abnormal ST-segment elevations showed signs of necrosis (P < 0.0005). At the same time, it was shown that the administration of cobra venom factor did not alter cardiac performance, collateral blood flow to the ischemic myocardium or the clotting system, but infiltration of polymorphonuclear leukocytes into the myocardium was decreased. It is concluded that cobra venom factor, by reducing the amount of C3 and C5 substrate available for chemotactic factor generation, or other as yet undefined mechanisms, protects the

  2. Augmentation of the effect of doxorubicin with low-dose tumor necrosis factor in experimental liver metastasis.

    PubMed

    Bloom, N D; Norbergs, D A; Sherman, B; Sadjadi, M; Ramaswamy, G; Jacobs, R; Ackerman, N

    1990-06-01

    The antitumor activity of recombinant human tumor necrosis factor was studied in vivo as a single agent and in combination with a conventional chemotherapeutic agent. Dosages of tumor necrosis factor of 100 micrograms, 50 micrograms, and 25 micrograms were injected intraportally in Sprague-Dawley rats containing hepatic implants of Walker carcinosarcoma. An effect on the tumor was seen but was associated with a significant acute mortality. Lower dosages of tumor necrosis factor, 10 micrograms, 5 micrograms, and 1 microgram, administered with 10 mg/kg of doxorubicin (Adriamycin) significantly enhanced the antitumor effect of doxorubicin without an acute mortality. This suggests that lower dosages of tumor necrosis factor with conventional chemotherapy may augment the latter's effect without any added toxicity.

  3. Tumor necrosis factor (TNF)-neuropeptide Y (NPY) crosstalk regulates inflammation, epithelial barrier functions and colonic motility

    PubMed Central

    Chandrasekharan, Bindu; Jeppsson, Sabrina; Pienkowski, Stefan; Belsham, Denise D; Sitaraman, Shanthi V.; Merlin, Didier; Kokkotou, Efi; Nusrat, Asma; Tansey, Malu G.; Srinivasan, Shanthi

    2014-01-01

    Background Neuro-immune interactions play a significant role in regulating the severity of inflammation. Our previous work demonstrated that neuropeptide Y (NPY) is up regulated in the enteric nervous system (ENS) during murine colitis, and that NPY knockout mice exhibit reduced inflammation. Here we investigated if NPY expression during inflammation is induced by tumor necrosis factor (TNF), the main pro-inflammatory cytokine. Methods Utilizing primary enteric neurons and colon explant cultures from WT and NPY knockout (NPY−/−) mice, we determined if NPY knockdown modulates TNF release and epithelial permeability. Further we assessed if NPY expression is inducible by TNF in enteric neuronal cells and mouse model of experimental colitis, utilizing the TNF inhibitors-etanercept (blocks transmembrane and soluble TNF) and XPro1595 (blocks soluble TNF only). Results We found that enteric neurons express TNF receptors (TNFR1 and R2). Primary enteric neurons from NPY−/− mice produced less TNF compared to WT. Further, TNF activated NPY promoter in enteric neurons via phospho-c-jun. NPY−/− mice had decreased intestinal permeability. In vitro, NPY increased epithelial permeability via phosphatidyl inositol-3-kinase (PI3-K)-induced pore-forming claudin-2. TNF inhibitors attenuated NPY expression in vitro and in vivo. TNF-inhibitor-treated colitic mice exhibited reduced NPY expression and inflammation, reduced oxidative stress, enhanced neuronal survival and improved colonic motility. XPro1595 had more protective effects on neuronal survival and motility compared to etanercept. Conclusions We demonstrate a novel TNF-NPY cross talk that modulates inflammation, barrier functions and colonic motility during inflammation. It is also suggested that selective blocking of soluble TNF maybe a better therapeutic option than using anti-TNF antibodies. PMID:24108115

  4. 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

  5. Tumour necrosis factor-alpha gene promoter polymorphism in chronic obstructive pulmonary disease.

    PubMed

    Higham, M A; Pride, N B; Alikhan, A; Morrell, N W

    2000-02-01

    Tumour necrosis factor(TNF)-alpha levels are elevated in airways of patients with chronic obstructive pulmonary disease (COPD) and may contribute to its pathogenesis. A guanine to adenine substitution at position -308 of the TNF-alpha gene promoter (TNF1/2) has been associated with chronic bronchitis of various aetiologies in a Taiwanese population. The authors performed a study investigating association of the polymorphism with smoking-related COPD in Caucasians. Frequencies of TNF1/2 alleles in 86 Caucasians (52 males) with COPD were compared with 63 (52 males) asymptomatic smoker/exsmoker control subjects and a population control of 199 (99 males) blood donors. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism technique on genomic deoxyribonucleic acid (DNA) obtained from peripheral blood. There were no significant differences in TNF1/2 allele frequencies between groups: 0.85/0.15 in COPD, 0.85/0.15 in smoker control subjects, 0.83/0.17 in population control subjects. Within the COPD group there was no association of TNF1/2 alleles with indices of airflow obstruction (% predicted forced expiratory volume in one second (FEV1) and % predicted FEV1/vital capacity ratio) nor gas transfer (% predicted carbon monoxide transfer coefficient and % predicted carbon monoxide diffusing capacity of the lung). It is concluded that: 1) the tumour necrosis factor gene promoter allele does not influence the risk of developing chronic obstructive pulmonary disease in a Caucasian population of smokers; and 2) there is no association of the tumour necrosis factor gene promoter genotype with severity of airflow obstruction nor degree of emphysema in chronic obstructive pulmonary disease.

  6. [Profile of use of anti tumor necrosis factor in Colombian patients].

    PubMed

    Machado, Jorge; Moncada, Juan Carlos; Pineda, Ricardo

    2011-06-01

    Tumor necrosis factor-alpha antagonists (anti-TNFα) have shown an increasing consumption and generate a significant economic burden on health systems. The prescribing patterns of tumor necrosis factor-alpha antagonists were determined in a patient population associated with the Sistema General de Seguridad Social en Salud in Colombia. A descriptive observational study was conducted in 316 patients with respect to use of tumor necrosis factor-alpha antagonists during a treatment period from January 2008 to June 2009. The database examined contained indications of use, inclusion criteria to medication, duration of illness, co-morbidities and adverse reactions. The data were retrieved from the clinical histories. Student's t test was used for the comparison of quantitative variables, and the chi-square test was used to establish associations between categorical variables and multivariate analysis were used. Mean age was 44.613.9 years; 63.9% of participants were female. Of the 316 patients, 17.1% received monotherapy. The order of prescription drugs was as follows: adalimumab (37.3%), infliximab (37.3%) and etanercept (25.4%), all were prescribed in appropriately defined daily doses. Co-medication drugs most frequently prescribed were: disease-modifying anti-rheumatic (82.9%), NSAIDs (29.1%), omeprazole (22.5%), antihypertensives (21.2%), folic acid (19.9%) calcium plus vitamin D (9.8%), calcitriol (6.0%). 10.4% of patients had a record of some adverse drug reaction. The average cost of therapy per patient per year was US$23,464. Anti-TNFα are being used at recommended doses, particularly in rheumatoid arthritis and in combination with other anti-rheumatic drugs. The direct cost of therapy was high for the country's health system.

  7. 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.

  8. The role of tumor necrosis factor-alpha in systemic lupus erythematosus

    PubMed Central

    Aringer, Martin; Smolen, Josef S

    2008-01-01

    Murine models of systemic lupus erythematosus (SLE) have shown apparently contradictory evidence in that either (a) tumor necrosis factor (TNF) expression was low and TNF administration helpful or (b) TNF was high and TNF blockade of therapeutic benefit, depending on the mouse model investigated. In fact, TNF apparently has both effects, checking autoimmunity, at least to some degree, and fostering inflammation. TNF blockade regularly, but transiently, induces or increases autoantibodies to chromatin and to phospholipids. At the same time, open-label data suggest that TNF blockade suppresses inflammatory manifestations of SLE, and long-term benefit was seen in patients with lupus nephritis. A controlled clinical trial is under way. PMID:18226185

  9. Grepafloxacin inhibits tumor necrosis factor-alpha-induced interleukin-8 expression in human airway epithelial cells.

    PubMed

    Hashimoto, S; Matsumoto, K; Gon, Y; Maruoka, S; Hayashi, S; Asai, Y; Machino, T; Horie, T

    2000-01-01

    We examined the effect of grepafloxacin (GPFX), a new fluoroquinolone antimicrobial agent, on interleukin-8 (IL-8) expression in tumor necrosis factor-alpha (TNF-alpha)-stimulated human airway epithelial cells (AEC). GPFX inhibited IL-8 protein production as well as mRNA expression in a concentration-dependent manner (2.5 - 25 micro g/ml), but the inhibition of IL-8 expression by corresponding concentrations of GPFX to serum and airway lining fluids was not complete. We discuss the modulatory effect of GPFX on IL-8 production in the context of its efficacy on controlling chronic airway inflammatory diseases.

  10. Tumour necrosis factor (TNF alpha) in leishmaniasis. I. TNF alpha mediates host protection against cutaneous leishmaniasis.

    PubMed Central

    Liew, F Y; Parkinson, C; Millott, S; Severn, A; Carrier, M

    1990-01-01

    Genetically resistant CBA mice developed significantly larger lesions to Leishmania major infection when they were injected with rabbit anti-tumour necrosis factor (TNF)-specific antibodies compared to control mice injected with normal rabbit immunoglobulin. BALB/c mice recovered from a previous infection following prophylactic sublethal irradiation also developed exacerbated lesions when treated with the anti-TNF antibody. Injection of TNF into the lesion of infected CBA mice significantly reduced the lesion development. Furthermore, TNF activates macrophages to kill Leishmania in vitro. These data demonstrate that TNF plays an important role in mediating host-protection against cutaneous leishmaniasis. PMID:2335376

  11. High Serum Interleukin-10 and Tumor Necrosis Factor Alpha Levels in Chronic Paracoccidioidomycosis

    PubMed Central

    Fornari, M. C.; Bava, A. J.; Guereño, M. T.; Berardi, V. E.; Silaf, M. R.; Negroni, R.; Diez, R. A.

    2001-01-01

    In patients with chronic paracoccidioidomycosis (n = 10), levels of tumor necrosis factor alpha, interleukin-10, and interleukin-2 in serum, measured by enzyme-linked immunosorbent assay (in picograms per milliliter, as mean ± standard error of the mean), were higher than in normal controls (n = 8): 186 ± 40 versus 40 ± 7 (P < 0.05), 203 ± 95 versus 20 ± 8 (P = 0.001), and 96.3 ± 78.57 versus 1.19 ± 1.19 (P = 0.045), respectively. Gamma interferon and interleukin-4 levels were similar in patients and controls. PMID:11527826

  12. Tumour necrosis factor blockade and the risk of osteoporosis: back to the future.

    PubMed

    Sambrook, Philip

    2007-01-01

    Osteoporosis is a common clinical problem, especially in patients with rheumatoid arthritis (RA). A reduction in bone mineral density (BMD) of the axial and appendicular skeleton ranging from 7% to 15% has been reported in RA in studies employing a variety of densitometric techniques. Reports consistent with a beneficial effect of tumour necrosis factor blockade on BMD have begun to emerge in recent years, and in Arthritis Research and Therapy, a case control study reports that patients treated with infliximab for RA had preservation of BMD in the lumbar spine and femoral neck compared to those treated with methotrexate.

  13. 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.

  14. Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation.

    PubMed Central

    Hallahan, D E; Spriggs, D R; Beckett, M A; Kufe, D W; Weichselbaum, R R

    1989-01-01

    We report that tumor necrosis factor alpha (TNF-alpha) mRNA is increased after treatment with x-rays in certain human sarcoma cells. An increase in TNF-alpha mRNA is accompanied by the increased production of TNF-alpha protein. TNF-alpha enhances radiation lethality in both TNF-alpha-producing and -nonproducing tumor cells. These data suggest that, in addition to the direct cytotoxic effects of x-rays, production of TNF-alpha may add to radiation lethality through autocrine and paracrine mechanisms. Combinations of TNF-alpha and therapeutic radiation may be useful in clinical cancer therapy. Images PMID:2602359

  15. Raised serum levels of cachectin/tumor necrosis factor alpha in renal allograft rejection

    PubMed Central

    1987-01-01

    A sensitive radioimmunoassay was used for monitoring serum levels of endogenous cachectin/tumor necrosis factor alpha (TNF) in 10 renal transplant recipients. Acute allograft rejections were associated with marked elevations of circulating TNF. The peak levels of TNF (median 140 pg/ml) were in the same concentration range as previously reported in parasitic infections. The results show that the release of TNF into circulation is an early event in renal allograft rejection and that raised levels of TNF in man can also be induced by noninfectious stimuli. PMID:3309124

  16. Effects of Tumor Necrosis Factor Alpha on Sin Nombre Virus Infection In Vitro

    PubMed Central

    Khaiboullina, Svetlana F.; Netski, Dale M.; Krumpe, Peter; St. Jeor, Stephen C.

    2000-01-01

    Previous data indicate that immune mechanisms may be involved in developing capillary leakage during Sin Nombre virus (SNV) infection. Therefore, we investigated production of tumor necrosis factor alpha (TNF-α) by human alveolar macrophages and human umbilical vein endothelial cells (HUVEC) after infection with SNV. In addition, we examined the effect of TNF-α on HUVEC monolayer leakage. Our results reveal that although TNF-α decreases accumulation of viral nucleoproteins, TNF-α levels do not change in SNV-infected cells. In addition, supernatants from SNV-infected human alveolar macrophages did not cause a significant increase in endothelial monolayer permeability. PMID:11090198

  17. Interleukin 6 and tumour necrosis factor alpha serum levels in monoclonal gammopathy of undetermined significance.

    PubMed

    Bladé, Joan; Filella, Xabier; Montoto, Silvia; Bosch, Francesc; Rosiñol, Laura; Coca, Francesca; Giné, Eva; Nadal, Elisabeth; Aymerich, Marta; Rozman, María; Montserrat, Emili

    2002-05-01

    The objectives of the present study were to compare the interleukin 6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) serum levels of individuals with monoclonal gammopathy of undetermined significance (MGUS) with those of healthy controls, and to ascertain the predictor value of these cytokines in the evolution from MGUS to multiple myeloma. After a median follow-up of 7 years from the initial cytokine measurements, nine patients with MGUS have evolved to a malignant condition. The actuarial probability of malignant transformation in patients with increased IL-6 and TNF-alpha was not significantly higher than in those with normal values.

  18. Neutrophil Recruitment by Tumor Necrosis Factor from Mast Cells in Immune Complex Peritonitis

    NASA Astrophysics Data System (ADS)

    Zhang, Yan; Ramos, Bernard F.; Jakschik, Barbara A.

    1992-12-01

    During generalized immune complex-induced inflammation of the peritoneal cavity, two peaks of tumor necrosis factor (TNF) were observed in the peritoneal exudate of normal mice. In mast cell-deficient mice, the first peak was undetected, and the second peak of TNF and neutrophil influx were significantly reduced. Antibody to TNF significantly inhibited neutrophil infiltration in normal but not in mast cell-deficient mice. Mast cell repletion of the latter normalized TNF, neutrophil mobilization, and the effect of the antibody to TNF. Thus, in vivo, mast cells produce the TNF that augments neutrophil emigration.

  19. 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.

  20. Insulin alleviates posttrauma cardiac dysfunction by inhibiting tumor necrosis factor-α-mediated reactive oxygen species production.

    PubMed

    Feng, Yafei; Liu, Yi; Wang, Dexin; Zhang, Xing; Liu, Wenchong; Fu, Feng; Dong, Ling; Zhang, Haifeng; Li, Jia; Gao, Feng

    2013-06-01

    Clinical evidence indicates that intensive insulin treatment prevents the incidence of multiple organ failures in surgical operation and severe trauma, but the mechanisms involved remain elusive. This study was designed to test the hypothesis that insulin may exert anti-inflammatory and antioxidative effects and thus alleviate cardiac dysfunction after trauma. Prospective, randomized experimental study. Animal research laboratory. Sprague Dawley rats. Anesthetized rats were subjected to 200 revolutions at a rate of 35 rpm in Noble-Collip drum to induce a nonlethal mechanical trauma and were randomized to receive vehicle, insulin, and insulin + wortmannin treatments. An in vitro study was performed on cultured cardiomyocytes subjected to sham-traumatic serum (SS), traumatic serum (TS), SS + tumor necrosis factor (TNF)-α, SS + H2O2, TS + neutralizing anti-TNF-α antibody, or TS + tempol treatments. Immediate cardiac dysfunction occurred 0.5 hr after trauma without significant cardiomyocyte necrosis and apoptosis, while serum TNF-α and cardiac reactive oxygen species (ROS) production was increased. Importantly, incubation of cardiomyocytes with TS or SS + TNF-α significantly increased ROS generation together with dampened cardiomyocyte contractility and Ca transient, all of which were rescued by TNF-α antibody. Administration of insulin inhibited TNF-α and ROS overproduction and alleviated cardiac dysfunction 2 hours after trauma. Scavenging ROS with tempol also attenuated cardiac dysfunction after trauma, whereas insulin combined with tempol failed to further improve cardiac functional recovery compared with insulin treatment alone. Moreover, the aforementioned anti-TNF-α, antioxidative, and cardioprotective effects afforded by insulin were almost abolished by the phosphatidylinositol 3-kinase inhibitor wortmannin. These results demonstrate for the first time that mechanical trauma induces a significant increase in TNF-α and ROS production, resulting in

  1. Reduction of NO Synthase Expression and Tumor Necrosis Factor Alpha Production in Macrophages by Amphotericin B Lipid Carriers

    PubMed Central

    Larabi, Malika; Legrand, Philippe; Appel, Martine; Gil, Sophie; Lepoivre, Michel; Devissaguet, Jean-Philippe; Puisieux, Francis; Barratt, Gillian

    2001-01-01

    The present study compared the abilities of different lipid carriers of amphotericin B (AMB) to activate murine peritoneal macrophages, as assessed by their capacities to produce nitric oxide (NO) and tumor necrosis factor alpha (TNF-α). Although AMB alone did not induce NO production, synergy was observed with gamma interferon but not with lipopolysaccharide. This synergy could not be explained by the mobilization of the nuclear activation factor NF-κB by AMB. On the other hand, AMB induced TNF-α production without a costimulator and no synergy was observed. Anti-TNF-α antibodies did not influence NO production, and an inhibitor of NO synthase did not affect TNF-α production, indicating that the production of one of these effector molecules was independent of that of the other. The incorporation of AMB into lipid carriers reduced NO and TNF-α production with all formulations but more so with liposomes than with lipid complexes. NO production was correlated with the induction of NO synthase II, revealed by Western blotting. The extent of association of AMB with macrophages depended on the formulation, especially on the AMB/lipids ratio: the higher the ratio was, the greater the AMB association with macrophages. However, there was no clear correlation between AMB association with macrophages, whether internalized or bound to the membrane, and immunostimulating effects. These results may explain the reduced toxicities of lipid-based formulations of AMB. PMID:11158754

  2. Tumor Necrosis Factor-α Sensitizes Breast Cancer Cells to Natural Products with Proteasome-Inhibitory Activity Leading to Apoptosis

    PubMed Central

    Lu, Li; Shi, Wenli; Deshmukh, Rahul R.; Long, Jie; Cheng, Xiaoli; Ji, Weidong; Zeng, Guohua; Chen, Xianliang; Zhang, Yajie; Dou, Q. Ping

    2014-01-01

    The inflammatory microenvironment plays an important role in the process of tumor development. Tumor necrosis factor-α (TNF-α), a key pro-inflammatory cytokine, has a significant role in this process. Natural medicinal products such as Withaferin A (WA) and Celastrol (Cel) have shown anti-cancer and anti-inflammatory properties that can be attributed to multiple mechanisms including, but not limited to, apoptosis induction due to the inhibition of proteasomal activities. This study aimed to investigate the effects of TNF-α in combination with WA or Cel in vitro in MDA-MB-231 breast cancer cells. TNF-α, when combined with WA or Cel, activated caspase-3 and -9 and downregulated XIAP in a dose-dependent manner, leading to induction of apoptosis in MDA-MB-231 breast cancer cells. The combination also caused accumulation of the proteasomal target protein IκBα, resulting in inhibition of the nuclear translocation of nuclear factor-κB (NF-κB). Taken together, these results suggest that TNF-α could sensitize breast cancer cells MDA-MB-231 to WA and Cel, at least in part, through inhibiting the activation of NF-κB signaling, leading to XIAP inhibition with subsequent upregulation of caspase-3 and -9 activities. Thus, the anti-cancer activities of TNF-α are enhanced when combined with the natural proteasome inhibitors, WA or Cel. PMID:25419573

  3. Factor 8 (F8) gene mutation profile of Turkish hemophilia A patients with inhibitors.

    PubMed

    Fidanci, Inanç D; Kavakli, Kaan; Uçar, Canan; Timur, Cetin; Meral, Adalet; Kilinç, Yurdanur; Sayilan, Hülya; Kazanci, Elif; Cağlayan, S Hande

    2008-07-01

    Factor VIII (FVIII) replacement therapy is ineffective in hemophilia A patients who develop alloantibodies (inhibitors) against FVIII. The type of factor 8 (F8) gene mutation, genes in the major histocompatibility complex loci, and also polymorphisms in IL-10 and tumor necrosis factor-alpha are the major predisposing factors for inhibitor formation. The present study was initiated to reveal the F8 gene mutation profile of 30 severely affected high-responder patients with inhibitor levels of more than 5 Bethesda U (BU)/ml and four low-responder patients with inhibitors less than 5 BU/ml. Southern blot and PCR analysis were performed to detect intron 22 and intron 1 inversions, respectively. Point mutations were screened by DNA sequence analysis of all coding regions, intron/exon boundaries, promoter and 3' UTR regions of the F8 gene. The prevalent mutation was the intron 22 inversion among the high-responder patients followed by large deletions, small deletions, and nonsense mutations. Only one missense and one splicing error mutation was seen. Among the low-responder patients, three single nucleotide deletions and one intron 22 inversion were found. All mutation types detected were in agreement with the severe hemophilia A phenotype, most likely leading to a deficiency of and predisposition to the development of alloantibodies against FVIII. It is seen that Turkish hemophilia A patients with major molecular defects have a higher possibility of developing inhibitors.

  4. Computational modeling of tuberculous meningitis reveals an important role for tumor necrosis factor

    PubMed Central

    El-Kebir, M.; van der Kuip, M.; van Furth, A.M.; Kirschner, D.E.

    2013-01-01

    Tuberculosis is a global health issue with annually about 1.5 million deaths and 2 billion infected people worldwide. Extra pulmonary tuberculosis comprises 13% of all cases of which tuberculous meningitis is the most severe. It has a high mortality and is often diagnosed once irreversible neurological damage has already occurred. Development of diagnostic and treatment strategies requires a thorough understanding of the pathogenesis of tuberculous meningitis. This disease is characterized by the formation of a cerebral granuloma, which is a collection of immune cells that attempt to immunologically restrain, and physically contain bacteria. The cytokine tumor necrosis factor-α is known for its important role in granuloma formation. Because traditional experimental animal studies exploring tuberculous meningitis are difficult and expensive, another approach is needed to begin to address this important and significant disease outcome. Here, we present an in silico model capturing the unique immunological environment of the brain that allows us to study the key mechanisms driving granuloma formation in time. Uncertainty and sensitivity analysis reveal a dose-dependent effect of tumor necrosis factor-α on bacterial load and immune cell numbers thereby influencing the onset of tuberculous meningitis. Insufficient levels result in bacterial overgrowth, whereas high levels lead to uncontrolled inflammation being detrimental to the host. These findings have important implications for the development of immuno-modulating treatment strategies for tuberculous meningitis. PMID:23542051

  5. 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.

  6. Tumor necrosis factor and interleukin 1 as mediators of endotoxin-induced beneficial effects

    SciTech Connect

    Urbaschek, R.; Urbaschek, B.

    1987-09-01

    Bacterial lipopolysaccharides or endotoxins are known to induce tumor necrosis; enhanced nonspecific resistance to bacterial, viral, and parasitic infections and to radiation sickness; and tolerance to lethal doses of endotoxin. These beneficial effects are achieved by pretreatment with minute amounts of endotoxin. Recombinant tumor necrosis factor (TNF) and interleukin 1 (IL-1) are among the mediators capable of invoking radioprotection or resistance to the consequences of cecal ligation and puncture. Both cytokines are potent inducers of serum colony-stimulating factor (CSF) in C3H/HeJ mice (low responders to endotoxin). The number of splenic granulocyte-macrophage precursors was found to increase 5 days after injection of TNF in these mice. Although with IL-1 no increase in the number of granulocyte-macrophage colonies occurred in culture in the presence of serum CSF, a marked stimulation was observed when TNF was added. This stimulation of myelopoiesis observed in vivo and in vitro may be related to the radioprotective effect of TNF. The data presented suggest that TNF and IL-1 released after injection of endotoxin participate in the mediation of endotoxin-induced enhancement of nonspecific resistance and stimulation of hematopoiesis. 76 references.

  7. Computational modeling of tuberculous meningitis reveals an important role for tumor necrosis factor-α.

    PubMed

    El-Kebir, M; van der Kuip, M; van Furth, A M; Kirschner, D E

    2013-07-07

    Tuberculosis is a global health issue with annually about 1.5 million deaths and 2 billion infected people worldwide. Extra-pulmonary tuberculosis comprises 13% of all cases of which tuberculous meningitis is the most severe. It has a high mortality and is often diagnosed once irreversible neurological damage has already occurred. Development of diagnostic and treatment strategies requires a thorough understanding of the pathogenesis of tuberculous meningitis. This disease is characterized by the formation of a cerebral granuloma, which is a collection of immune cells that attempt to immunologically restrain, and physically contain bacteria. The cytokine tumor necrosis factor-α is known for its important role in granuloma formation. Because traditional experimental animal studies exploring tuberculous meningitis are difficult and expensive, another approach is needed to begin to address this important and significant disease outcome. Here, we present an in silico model capturing the unique immunological environment of the brain that allows us to study the key mechanisms driving granuloma formation in time. Uncertainty and sensitivity analysis reveals a dose-dependent effect of tumor necrosis factor-α on bacterial load and immune cell numbers thereby influencing the onset of tuberculous meningitis. Insufficient levels result in bacterial overgrowth, whereas high levels lead to uncontrolled inflammation being detrimental to the host. These findings have important implications for the development of immuno-modulating treatment strategies for tuberculous meningitis.

  8. Tumor necrosis factor and the pathogenesis of Pichinde virus infection in guinea pigs.

    PubMed

    Aronson, J F; Herzog, N K; Jerrells, T R

    1995-03-01

    Pichinde virus (PIC) is a reticuloendothelial arenavirus of the New World tropics. A guinea pig passage-adapted strain of this virus (adPIC) is uniformly lethal for inbred guinea pigs, while the related, prototype strain (PIC3739) has attenuated virulence. The abilities of adPIC and PIC3739 to induce tumor necrosis factor (TNF) in vivo and in cultured macrophages were compared. Infection with adPIC, but not PIC3739, was associated with detectable serum TNF that peaked in week 2 of infection. Tumor necrosis factor was found in the spleens of adPIC- and PIC3739-infected animals in week 1 of infection; TNF alpha mRNA levels in spleens and livers of adPIC infected animals increased and remained high throughout infection, whereas PIC3739-infected organs showed down regulation of TNF alpha mRNA late in infection. Peritoneal macrophages explanted from adPIC-infected animals showed enhanced lipopolysaccharide-inducible TNF production. Altered regulation of TNF production may play a role in the pathogenesis of guinea pig arenavirus disease.

  9. Tumor Necrosis Factor and the Pathogenesis of Pichinde Virus Infection in Guinea Pigs

    PubMed Central

    Aronson, Judith F.; Herzog, Norbert K.; Jerrells, Thomas R.

    1995-01-01

    Pichinde virus (PIC) is a reticuloendothelial arenavirus of the New World tropics. A guinea pig passage–adapted strain of this virus (adPIC) is uniformly lethal for inbred guinea pigs, while the related, prototype strain (PIC3739) has attenuated virulence. The abilities of adPIC and PIC3739 to induce tumor necrosis factor (TNF) in vivo and in cultured macrophages were compared. Infection with adPIC, but not PIC3739, was associated with detectable serum TNF that peaked in week 2 of infection. Tumor necrosis factor was found in the spleens of adPIC- and PIC3739-infected animals in week 1 of infection ; TNFα mRNA levels in spleens and livers of adPIC infected animals increased and remained high throughout infection, whereas PIC3739-infected organs showed down regulation of TNFα mRNA late in infection. Peritoneal macrophages explanted from adPIC-infected animals showed enhanced lipopolysaccharide-inducible TNF production. Altered regulation of TNF production may play a role in the pathogenesis of guinea pig arenavirus disease. PMID:7694969

  10. 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. © 2015 John Wiley & Sons Ltd.

  11. In vivo role of tumor necrosis-like factor in Eimeria tenella infection.

    PubMed

    Zhang, S; Lillehoj, H S; Ruff, M D

    1995-01-01

    The effect of tumor necrosis-like factor (TNLF) on the pathogenesis of coccidiosis was investigated. Injection of crude chicken TNLF enhanced the weight loss caused by Eimeria tenella infection. Rabbit polyclonal antibody against recombinant human tumor necrosis factor-alpha (rhTNF) partially restored E. tenella-induced weight loss in SC chickens, but not in TK chickens. However, injection of chickens with chicken TNLF, rhTNF, and rabbit serum against rhTNF had no significant effect on cecal lesions. Both SC and TK chickens produced circulating TNLF following primary, but not secondary infection, and SC chickens showed higher level of TNLF production than TK chickens. Peripheral blood leukocyte-derived macrophages from SC and TK chickens produced a significant amount of TNLF compared to the preinfection condition when cocultured with sporozoites. In general, macrophages from SC chickens produced higher levels of TNLF than those from TK chickens. No significant difference was observed between primary and secondary infection. These results suggest that the excessive TNF production may be involved in weight loss caused by E. tenella infection in SC chickens.

  12. Familial clustering of recurrent pericarditis may disclose tumour necrosis factor receptor-associated periodic syndrome.

    PubMed

    Cantarini, Luca; Lucherini, Orso Maria; Baldari, Cosima Tatiana; Laghi Pasini, Franco; Galeazzi, Mauro

    2010-01-01

    Although several causes of recurrent pericarditis have been identified, the etiology remains obscure in most cases. The tumour necrosis factor receptor-1 associated periodic syndrome (TRAPS) is the most common autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene encoding the 55-kD receptor for tumour necrosis factor-(TNF)-alpha. Serosal membrane inflammation is a common feature of TRAPS, usually in the form of polyserositis. In addition, patients affected with recurrent pericarditis as the only clinical manifestation of TRAPS have been recently described. Our aim was to investigate the possible involvement of mutations in the TNFRSF1A gene in a cohort of patients affected with idiopathic recurrent pericarditis. Twenty consecutive patients diagnosed with idiopathic recurrent pericarditis were enrolled. Each patient underwent detailed examinations in order to rule out underlying diseases such as infections, connective tissue disorders and malignancies, and mutations of the TNFRSF1A gene were searched for by amplifying, using polymerase chain reaction (PCR), genomic DNA, and direct sequencing. TNFRSF1A mutations were found in 2 of the 20 patients. They were siblings, and they both carried a heterozygous low-penetrance R92Q mutation in the TNFRSF1A gene. Familial clustering has been recently reported in up to 10% of patients with recurrent pericarditis, thus suggesting in some cases a possible genetic predisposition. Our study suggests that familial clustering may represent a clue for investigating mutations in the TNFRSF1A gene in these patients and eventually disclose TRAPS.

  13. Brefeldin A-Inhibited Guanine Nucleotide-Exchange Factor 1 (BIG1) Governs the Recruitment of Tumor Necrosis Factor Receptor-Associated Factor 2 (TRAF2) to Tumor Necrosis Factor Receptor 1 (TNFR1) Signaling Complexes

    PubMed Central

    Noguchi, Takuya; Tsuchida, Mei; Kogue, Yosuke; Spadini, Christian; Hirata, Yusuke; Matsuzawa, Atsushi

    2016-01-01

    Tumor necrosis factor receptor-associated factor 2 (TRAF2) is a critical mediator of tumor necrosis factor-α (TNF-α) signaling. However, the regulatory mechanisms of TRAF2 are not fully understood. Here we show evidence that TRAF2 requires brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) to be recruited into TNF receptor 1 (TNFR1) signaling complexes. In BIG1 knockdown cells, TNF-α-induced c-Jun N-terminal kinase (JNK) activation was attenuated and the sensitivity to TNF-α-induced apoptosis was increased. Since these trends correlated well with those of TRAF2 deficient cells as previously demonstrated, we tested whether BIG1 functions as an upstream regulator of TRAF2 in TNFR1 signaling. As expected, we found that knockdown of BIG1 suppressed TNF-α-dependent ubiquitination of TRAF2 that is required for JNK activation, and impaired the recruitment of TRAF2 to the TNFR1 signaling complex (complex I). Moreover, we found that the recruitment of TRAF2 to the death-inducing signaling complex termed complex II was also impaired in BIG1 knockdown cells. These results suggest that BIG1 is a key component of the machinery that drives TRAF2 to the signaling complexes formed after TNFR1 activation. Thus, our data demonstrate a novel and unexpected function of BIG1 that regulates TNFR1 signaling by targeting TRAF2. PMID:27834853

  14. Insulin-like growth factor I accelerates recovery from ischemic acute tubular necrosis in the rat.

    PubMed Central

    Miller, S B; Martin, D R; Kissane, J; Hammerman, M R

    1992-01-01

    The effects of administering insulin-like growth factor I (IGF-I) were examined in a model of ischemic acute tubular necrosis in rats. Injury was induced by 75 min of bilateral renal artery occlusion. Compared to rats administered vehicle, rats administered IGF-I (100 micrograms/day via continuous subcutaneous infusion) had significantly lower serum creatinine and blood urea nitrogen levels over the course of 7 days postocclusion. Glomerular filtration rate as determined by inulin clearance was examined on day 2 postocclusion and was significantly increased in IGF-I-treated animals (0.16 +/- 0.02 ml per min per 100 g of body weight) compared to vehicle-treated controls (0.08 +/- 0.02 ml per min per 100 g of body weight). The weight loss that occurred during the course of acute tubular necrosis was ameliorated by IGF-I. Mortality was reduced from 36.7% in vehicle-treated rats to 7.1% in rats administered IGF-I. Histologically, there was much less renal injury evident at day 7 postocclusion in the IGF-I-treated rats compared to vehicle-treated controls. In contrast, growth hormone (200 micrograms administered subcutaneously for 4 days) did not affect recovery of renal function or reduce mortality postreperfusion. This report demonstrates a beneficial effect of IGF-I administration in the setting of acute tubular necrosis. Several properties of IGF-I render it a pharmacological agent with excellent potential for treatment of this condition in humans. Images PMID:1465411

  15. Insulin-like growth factor I accelerates recovery from ischemic acute tubular necrosis in the rat.

    PubMed

    Miller, S B; Martin, D R; Kissane, J; Hammerman, M R

    1992-12-15

    The effects of administering insulin-like growth factor I (IGF-I) were examined in a model of ischemic acute tubular necrosis in rats. Injury was induced by 75 min of bilateral renal artery occlusion. Compared to rats administered vehicle, rats administered IGF-I (100 micrograms/day via continuous subcutaneous infusion) had significantly lower serum creatinine and blood urea nitrogen levels over the course of 7 days postocclusion. Glomerular filtration rate as determined by inulin clearance was examined on day 2 postocclusion and was significantly increased in IGF-I-treated animals (0.16 +/- 0.02 ml per min per 100 g of body weight) compared to vehicle-treated controls (0.08 +/- 0.02 ml per min per 100 g of body weight). The weight loss that occurred during the course of acute tubular necrosis was ameliorated by IGF-I. Mortality was reduced from 36.7% in vehicle-treated rats to 7.1% in rats administered IGF-I. Histologically, there was much less renal injury evident at day 7 postocclusion in the IGF-I-treated rats compared to vehicle-treated controls. In contrast, growth hormone (200 micrograms administered subcutaneously for 4 days) did not affect recovery of renal function or reduce mortality postreperfusion. This report demonstrates a beneficial effect of IGF-I administration in the setting of acute tubular necrosis. Several properties of IGF-I render it a pharmacological agent with excellent potential for treatment of this condition in humans.

  16. Tumour necrosis factor receptor trafficking dysfunction opens the TRAPS door to pro-inflammatory cytokine secretion

    PubMed Central

    Turner, Mark D.; Chaudhry, Anupama; Nedjai, Belinda

    2011-01-01

    Cytokines are secreted from macrophages and other cells of the immune system in response to pathogens. Additionally, in autoinflammatory diseases cytokine secretion occurs in the absence of pathogenic stimuli. In the case of TRAPS [TNFR (tumour necrosis factor receptor)-associated periodic syndrome], inflammatory episodes result from mutations in the TNFRSF1A gene that encodes TNFR1. This work remains controversial, however, with at least three distinct separate mechanisms of receptor dysfunction having been proposed. Central to these hypotheses are the NF-κB (nuclear factor κB) and MAPK (mitogen-activated protein kinase) families of transcriptional activators that are able to up-regulate expression of a number of genes, including pro-inflammatory cytokines. The present review examines each proposed mechanism of TNFR1 dysfunction, and addresses how these processes might ultimately impact upon cytokine secretion and disease pathophysiology. PMID:22115362

  17. Dehydrocostus lactone enhances tumor necrosis factor-alpha-induced apoptosis of human leukemia HL-60 cells.

    PubMed

    Oh, G S; Pae, H O; Chung, H T; Kwon, J W; Lee, J H; Kwon, T O; Kwon, S Y; Chon, B H; Yun, Young Gab

    2004-05-01

    Sesquiterpene lactones have raised considerable interest because of their ability to block the activation of nuclear transcription factor-kappaB (NF-kappaB). NF-kappaB plays an important role in the resistance of cancer cells to the induction of apoptosis by anticancer drugs and tumor necrosis factor-alpha (TNF-alpha). Pharmacological inhibition of NF-kappaB offers the promise of enhancing the efficacy of anticancer therapies. Here, we demonstrate that dehydrocostus lactone (DL), the major sesquiterpene lactone isolated from the roots of Saussurea lappa, inhibits NF-kappaB activation by preventing TNF-alpha-induced degradation and phosphorylation of its inhibitory protein I-kappaB alpha in human leukemia HL-60 cells and that DL renders HL-60 cells susceptible to TNF-alpha-induced apoptosis by enhancing caspase-8 and caspase-3 activities.

  18. Tumor necrosis factor negative bone marrow-derived dendritic cells exhibit deficient IL-10 expression.

    PubMed

    Roomberg, Alicia; Kling, Jessica; Fromm, Phillip; Körner, Heinrich

    2010-01-01

    The effective maturation of dendritic cells (DC) is complex and highly regulated and requires the presence of a variety of signals. Tumor necrosis factor (TNF) and its receptors or innate pattern recognition receptors such as the toll-like receptors have been shown to contribute to this process. DC derived from bone marrow cells in the presence of granulocyte/macrophage colony-stimulating factor can be used as a model to ascertain the contribution of different signals to DC maturation. Analysis of DC activated by addition of the mycobacterial vaccine strain Bacillus Calmette-Guérin showed that of the effector molecules studied only interleukin-10 expression was significantly reduced in TNF-negative (B6.TNF(-/-)) DC. Another effector molecule produced by DC, inducible nitric oxide synthase, was largely unchanged.

  19. Interferon and tumor necrosis factor as humoral mechanisms coupling hematopoietic activity to inflammation and injury.

    PubMed

    Askenasy, Nadir

    2015-01-01

    Enhanced hematopoiesis accompanies systemic responses to injury and infection. Tumor necrosis factor (TNF) produced by injured cells and interferons (IFNs) secreted by inflammatory cells is a co-product of the process of clearance of debris and removal of still viable but dysfunctional cells. Concomitantly, these cytokines induce hematopoietic stem and progenitor cell (HSPC) activity as an intrinsic component of the systemic response. The proposed scenario includes induction of HSPC activity by type I (IFNα/β) and II (IFNγ) receptors within the quiescent bone marrow niches rendering progenitors responsive to additional signals. TNFα converges as a non-selective stimulant of HSPC activity and both cytokines synergize with other growth factors in promoting differentiation. These physiological signaling pathways of stress hematopoiesis occur quite frequent and do not cause HSPC extinction. The proposed role of IFNs and TNFs in stress hematopoiesis commends revision of their alleged involvement in bone marrow failure syndromes.

  20. 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.

  1. Molecular design of conjugated tumor necrosis factor-alpha: synthesis and characteristics of polyvinyl pyrrolidone modified tumor necrosis factor-alpha.

    PubMed

    Kamada, H; Tsutsumi, Y; Tsunoda, S; Kihira, T; Kaneda, Y; Yamamoto, Y; Nakagawa, S; Horisawa, Y; Mayumi, T

    1999-04-13

    We conjugated tumor necrosis factor-alpha (TNF-alpha) with the synthetic polymeric modifier polyvinyl pyrrolidone (PVP) to facilitate its clinical use for anti-tumor therapy. TNF-alpha was chemically conjugated with the terminal carboxyl-bearing PVP at one end of its main chain, which was radically polymerized via the formation of an amide bond between the lysine amino groups of TNF-alpha and carboxyl group of PVP. In vitro specific bioactivity of PVP-conjugated TNF-alpha (PVP-TNF-alpha) relative to that of native TNF-alpha gradually decreased with increases in the degree of PVP attachment. In contrast, PVP-TNF-alpha in which 40% of TNF-alpha lysine residues were coupled with PVP (MPVP-TNF-alpha) exhibited the highest anti-tumor activity among the conjugated derivatives examined. MPVP-TNF-alpha had more than 200-fold higher anti-tumor efficacy than native TNF-alpha, and the anti-tumor activity of MPVP- TNF-alpha was more than 5-fold stronger than that MPEG- TNF-alpha which had the highest anti-tumor activity among PEG-conjugated TNF-alphas examined. Additionally, a high dose of native TNF-alpha induced toxic side-effects such as body weight reduction, piloerection and tissue inflammation, while no side effects were observed following i.v. administration of MPVP-TNF-alpha. The plasma half-life of MPVP-TNF-alpha (360 min) was about 80 and 3-fold longer than those of native TNF-alpha (4.6 min) and MPEG-TNF-alpha (122 min), respectively. These results suggested that PVP is a useful polymeric modifier for increasing the anti-tumor activity of PVP.

  2. Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.

    PubMed

    Molinsky, Jan; Klanova, Magdalena; Koc, Michal; Beranova, Lenka; Andera, Ladislav; Ludvikova, Zdenka; Bohmova, Martina; Gasova, Zdenka; Strnad, Miroslav; Ivanek, Robert; Trneny, Marek; Necas, Emanuel; Zivny, Jan; Klener, Pavel

    2013-02-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with selective antitumor activity. However, many primary tumors are TRAIL resistant. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. We show that roscovitine and TRAIL demonstrate synergistic cytotoxicity in hematologic malignant cell lines and primary cells. Pretreatment of TRAIL-resistant leukemia cells with roscovitine induced enhanced cleavage of death-inducing signaling complex-bound proximal caspases after exposure to TRAIL. We observed increased levels of both pro- and antiapoptotic BCL-2 proteins at the mitochondria following exposure to roscovitine. These results suggest that roscovitine induces priming of cancer cells for death by binding antiapoptotic BCL-2 proteins to proapoptotic BH3-only proteins at the mitochondria, thereby decreasing the threshold for diverse proapoptotic stimuli. We propose that the mitochondrial priming and enhanced processing of apical caspases represent major molecular mechanisms of roscovitine-induced sensitization to TRAIL in leukemia/lymphoma cells.

  3. The dietary flavonoid apigenin sensitizes malignant tumor cells to tumor necrosis factor-related apoptosis-inducing ligand.

    PubMed

    Horinaka, Mano; Yoshida, Tatsushi; Shiraishi, Takumi; Nakata, Susumu; Wakada, Miki; Sakai, Toshiyuki

    2006-04-01

    Dietary flavonoid apigenin is expected to have preventive and therapeutic potential against malignant tumors. In this report, we show for the first time that apigenin markedly induces the expression of death receptor 5 (DR5) and synergistically acts with exogenous soluble recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis in malignant tumor cells. TRAIL is a promising candidate for cancer therapeutics due to its ability to selectively induce apoptosis in cancer cells. The combined use of apigenin and TRAIL at suboptimal concentrations induces Bcl-2-interacting domain cleavage and the activation of caspases-8, -10, -9, and -3. Furthermore, human recombinant DR5/Fc chimera protein and caspase inhibitors dramatically inhibit apoptosis induced by the combination of apigenin and TRAIL. On the other hand, apigenin-mediated induction of DR5 expression is not observed in normal human peripheral blood mononuclear cells. Moreover, apigenin does not sensitize normal human peripheral blood mononuclear cells to TRAIL-induced apoptosis. These results suggest that this combined treatment with apigenin and TRAIL might be promising as a new therapy against malignant tumors.

  4. Malignancy risk of anti-tumor necrosis factor alpha blockers: an overview of systematic reviews and meta-analyses.

    PubMed

    Chen, Yuehong; Sun, Jianhong; Yang, Yuan; Huang, Yupeng; Liu, Gang

    2016-01-01

    The objective of the study is to systematically review the malignancy risk of anti-tumor necrosis factor alpha (anti-TNFα) agents. Databases of PubMed Medline, OVID EMBASE, and Cochrane Library were searched to identify published systematic reviews and meta-analyses of randomized control trials, observational studies, and case series that evaluated malignancy risk of anti-TNFα blockers. Search time duration was restricted from January 1st, 2000 to July 16th, 2015. Overview Quality Assessment Questionnaires were used to assess the quality of included reviews. Two methodology trained reviewers separately and repeatedly screened searched studies according to study selection criteria, collected data, and assessed quality. Totally, 42 reviews proved eligible with only one Cochrane review. Anti-TNFα antagonists were extensively used to treat various diseases; nevertheless, malignancy risks were most commonly described in patients with rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In RA patients, no increased risks of breast cancer, lymphoma, and non-melanoma skin cancer were found, but if the use of anti-TNFα agents was associated with elevated risk of overall malignancy was still uncertainty. In IBD patients, the use of anti-TNFα inhibitors was not connected with enhanced risk of overall cancer. No increased cancer risk was found in other disease conditions. Twenty-nine reviews were rated as good quality, 12 as moderate, and one as poor. There are no sufficient evidences to draw the conclusion that anti-TNFα blockers have relationship with increased malignancy risk.

  5. Hyaluronan synthase 3 mediated oncogenic action through forming inter-regulation loop with tumor necrosis factor alpha in oral cancer

    PubMed Central

    Kuo, Yi-Zih; Fang, Wei-Yu; Huang, Cheng-Chih; Tsai, Sen-Tien; Wang, Yi-Ching; Yang, Chih-Li; Wu, Li-Wha

    2017-01-01

    Hyaluronan (HA) is a major extracellular matrix component. However, its role and mediation in oral cancer remains elusive. Hyaluronan synthase 3 (HAS3), involved in pro-inflammatory short chain HA synthesis, was the predominant synthase in oral cancer cells and tissues. HAS3 overexpression significantly increased oral cancer cell migration, invasion and xenograft tumorigenesis accompanied with the increased expression of tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1). Conversely, HAS3 depletion abrogated HAS3-mediated stimulation. HAS3 induced oncogenic actions partly through activating EGFR-SRC signaling. HAS3-derived HA release into extracellular milieu enhanced transendothelial monocyte migration and MCP-1 expression, which was attenuated by anti-HAS3 antibodies or a HAS inhibitor, 4-Methylumbelliferone (4-MU). The NF-κB-binding site III at -1692 to -1682 bp upstream from the transcript 1 start site in HAS3 proximal promoter was the most responsive to TNF-α-stimulated transcription. ChIP-qPCR analysis confirmed the highest NF-κB-p65 enrichment on site III. Increased HAS3 mRNA expression was negatively correlated with the overall survival of oral cancer patients. A concomitant increase of TNF-α, a stimulus for HAS3 expression, with HAS3 expression was not only associated with lymph node metastasis but also negated clinical outcome. Together, HAS3 and TNF-α formed an inter-regulation loop to enhance tumorigenesis in oral cancer. PMID:28107185

  6. Hyaluronan synthase 3 mediated oncogenic action through forming inter-regulation loop with tumor necrosis factor alpha in oral cancer.

    PubMed

    Kuo, Yi-Zih; Fang, Wei-Yu; Huang, Cheng-Chih; Tsai, Sen-Tien; Wang, Yi-Ching; Yang, Chih-Li; Wu, Li-Wha

    2017-02-28

    Hyaluronan (HA) is a major extracellular matrix component. However, its role and mediation in oral cancer remains elusive. Hyaluronan synthase 3 (HAS3), involved in pro-inflammatory short chain HA synthesis, was the predominant synthase in oral cancer cells and tissues. HAS3 overexpression significantly increased oral cancer cell migration, invasion and xenograft tumorigenesis accompanied with the increased expression of tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1). Conversely, HAS3 depletion abrogated HAS3-mediated stimulation. HAS3 induced oncogenic actions partly through activating EGFR-SRC signaling. HAS3-derived HA release into extracellular milieu enhanced transendothelial monocyte migration and MCP-1 expression, which was attenuated by anti-HAS3 antibodies or a HAS inhibitor, 4-Methylumbelliferone (4-MU). The NF-κB-binding site III at -1692 to -1682 bp upstream from the transcript 1 start site in HAS3 proximal promoter was the most responsive to TNF-α-stimulated transcription. ChIP-qPCR analysis confirmed the highest NF-κB-p65 enrichment on site III. Increased HAS3 mRNA expression was negatively correlated with the overall survival of oral cancer patients. A concomitant increase of TNF-α, a stimulus for HAS3 expression, with HAS3 expression was not only associated with lymph node metastasis but also negated clinical outcome. Together, HAS3 and TNF-α formed an inter-regulation loop to enhance tumorigenesis in oral cancer.

  7. Inhibition of tumor necrosis factor-alpha signaling prevents human immunodeficiency virus-1 protein Tat and methamphetamine interaction.

    PubMed

    Theodore, Shaji; Cass, Wayne A; Nath, Avindra; Steiner, Joseph; Young, Kristie; Maragos, William F

    2006-09-01

    Our previous studies demonstrated that the psychostimulant methamphetamine (MA) and the human immunodeficiency virus-1 (HIV-1) protein Tat interacted to cause enhanced dopaminergic neurotoxicity. The present study examined whether tumor necrosis factor-alpha (TNF-alpha) mediates the interaction between Tat and MA. In Sprague-Dawley rats, injections of Tat caused a small but significant increase in striatal TNF-alpha level, whereas MA resulted in no change. The increase in TNF-alpha induced by Tat + MA was not significantly different from that induced by Tat alone. Temporal analysis of TNF-alpha levels revealed a 50-fold increase 4 h after Tat administration. In C57BL/6 mice, Tat + MA induced a 50% decline in striatal dopamine levels, which was significantly attenuated in mice lacking both receptors for TNF-alpha. TNF-alpha synthesis inhibitors significantly attenuated Tat + MA neurotoxicity in hippocampal neuronal culture. The results suggest that Tat-induced elevation of TNF-alpha may predispose the dopaminergic terminals to subsequent damage by MA.

  8. Trovafloxacin enhances lipopolysaccharide-stimulated production of tumor necrosis factor-α by macrophages: role of the DNA damage response.

    PubMed

    Poulsen, Kyle L; Olivero-Verbel, Jesus; Beggs, Kevin M; Ganey, Patricia E; Roth, Robert A

    2014-07-01

    Trovafloxacin (TVX) is a drug that has caused idiosyncratic, drug-induced liver injury (IDILI) in humans. In a murine model of IDILI, otherwise nontoxic doses of TVX and the inflammagen lipopolysaccharide (LPS) interacted to produce pronounced hepatocellular injury. The liver injury depended on a TVX-induced, small but significant prolongation of tumor necrosis factor-α (TNF) appearance in the plasma. The enhancement of TNF expression by TVX was reproduced in vitro in RAW 264.7 murine macrophages (RAW cells) stimulated with LPS. The current study was designed to identify the molecular target of TVX responsible for this response in RAW cells. An in silico analysis suggested a favorable binding profile of TVX to eukaryotic topoisomerase II-α (TopIIα), and a cell-free assay revealed that TVX inhibited eukaryotic TopIIα activity. Topoisomerase inhibition is known to lead to DNA damage, and TVX increased the DNA damage marker phosphorylated histone 2A.X in RAW cells. Moreover, TVX induced activation of the DNA damage sensor kinases, ataxia telangiectasia mutated (ATM) and Rad3-related (ATR). The ATR inhibitor NU6027 [6-(cyclohexylmethoxy)-5-nitrosopyrimidine-2,4-diamine] prevented the TVX-mediated increases in LPS-induced TNF mRNA and protein release, whereas a selective ATM inhibitor [2-(4-morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one (KU55933)] was without effect. TVX prolonged TNF mRNA stability, and this effect was largely attenuated by NU6027. These results suggest that TVX can inhibit eukaryotic topoisomerase, leading to activation of ATR and potentiation of TNF release by macrophages, at least in part through increased mRNA stability. This off-target effect might contribute to the ability of TVX to precipitate IDILI in humans. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  9. 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.

  10. Tumor necrosis factor-α potentiates long-term potentiation in the rat dentate gyrus after acute hypoxia

    PubMed Central

    Wall, Audrey M.; Mukandala, Gatambwa; Greig, Nigel H.; O’Connor, John J.

    2016-01-01

    An inadequate supply of oxygen in the brain may lead to the introduction of an inflammatory response through neuronal and glial cells that can result in neuronal damage. Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine that is released during acute hypoxia and can have neurotoxic or neuroprotective effects in the brain. Both TNF-α and interleukin-1β (IL-1β) have been shown by a number of research groups to alter synaptic scaling and also to inhibit long-term potentiation (LTP) in the hippocampus when induced by specific high frequency stimulation protocols. In this study we have examined the effects of TNF-α on synaptic transmission and plasticity in hippocampal slices after acute hypoxia using two high frequency stimulation protocols. Field excitatory postsynaptic potentials were elicited in the medial perforant pathway of the dentate gyrus. Exogenous TNF-α (5 ng/ml) attenuated LTP induced by theta burst stimulation but had no effect on LTP induced by a more prolonged high frequency stimulation (HFS). Pre-treatment with lipopolysaccharide (100 ng/ml) or TNF-α but not IL-1β (4 ng/ml) prior to a 30 min hypoxic insult resulted in a significant enhancement of LTP post hypoxia when induced by the HFS. Anti-TNF, 3,6 dithiothalidomide (a TNF-α synthesis inhibitor) and SB203580 (a p38 MAPK inhibitor) significantly reduced this effect. These results indicate an important modulatory role for elevated TNF-α levels on LTP in the hippocampus after an acute hypoxic event. PMID:25641742

  11. Ceramide sphingolipid signaling mediates Tumor Necrosis Factor (TNF)-dependent toxicity via caspase signaling in dopaminergic neurons

    PubMed Central

    2012-01-01

    Background Dopaminergic (DA) neurons in the ventral midbrain selectively degenerate in Parkinson’s disease (PD) in part because their oxidative environment in the substantia nigra (SN) may render them vulnerable to neuroinflammatory stimuli. Chronic inhibition of soluble Tumor Necrosis Factor (TNF) with dominant-negative TNF inhibitors protects DA neurons in rat models of parkinsonism, yet the molecular mechanisms and pathway(s) that mediate TNF toxicity remain(s) to be clearly identified. Here we investigated the contribution of ceramide sphingolipid signaling in TNF-dependent toxicity. Results Ceramide dose-dependently reduced the viability of DA neuroblastoma cells and primary DA neurons and pharmacological inhibition of sphingomyelinases (SMases) with three different inhibitors during TNF treatment afforded significant neuroprotection by attenuating increased endoplasmic reticulum (ER) stress, loss of mitochondrial membrane potential, caspase-3 activation and decreases in Akt phosphorylation. Using lipidomics mass spectrometry we confirmed that TNF treatment not only promotes generation of ceramide, but also leads to accumulation of several atypical deoxy-sphingoid bases (DSBs). Exposure of DA neuroblastoma cells to atypical DSBs in the micromolar range reduced cell viability and inhibited neurite outgrowth and branching in primary DA neurons, suggesting that TNF-induced de novo synthesis of atypical DSBs may be a secondary mechanism involved in mediating its neurotoxicity in DA neurons. Conclusions We conclude that TNF/TNFR1-dependent activation of SMases generates ceramide and sphingolipid species that promote degeneration and caspase-dependent cell death of DA neurons. Ceramide and atypical DSBs may represent novel drug targets for development of neuroprotective strategies that can delay or attenuate the progressive loss of nigral DA neurons in patients with PD. PMID:22973882

  12. Immunological effects of a tumor necrosis factor alpha-armed oncolytic adenovirus.

    PubMed

    Hirvinen, Mari; Rajecki, Maria; Kapanen, Mika; Parviainen, Suvi; Rouvinen-Lagerström, Noora; Diaconu, Iulia; Nokisalmi, Petri; Tenhunen, Mikko; Hemminki, Akseli; Cerullo, Vincenzo

    2015-03-01

    For long it has been recognized that tumor necrosis factor alpha (TNFa) has anticancer characteristics, and its use as a cancer therapeutic was proposed already in the 1980s. However, its systemic toxicity has limited its usability. Oncolytic viruses, selectively cancer-killing viruses, have shown great potency, and one of their most useful aspects is their ability to produce high amounts of transgene products locally, resulting in high local versus systemic concentrations. Therefore, the overall magnitude of tumor cell killing results from the combination of oncolysis, transgene-mediated direct effect such as TNFa-mediated apoptosis, and, perhaps most significantly, from activation of the host immune system against the tumor. We generated a novel chimeric oncolytic adenovirus expressing human TNFa, Ad5/3-D24-hTNFa, whose efficacy and immunogenicity were tested in vitro and in vivo. The hTNFa-expressing adenovirus showed increased cancer-eradicating potency, which was shown to be because of elevated apoptosis and necrosis rates and induction of various immune responses. Interestingly, we saw increase in immunogenic cell death markers in Ad5/3-d24-hTNFa-treated cells. Moreover, tumors treated with Ad5/3-D24-hTNFa displayed enhanced presence of OVA-specific cytotoxic T cells. We thus can conclude that tumor eradication and antitumor immune responses mediated by Ad5/3-d24-hTNFa offer a new potential drug candidate for cancer therapy.

  13. Role of tissue factor in the antitumor effect of recombinant human tumor necrosis factor-alpha in mice.

    PubMed

    Nishigaki, F; Miyayasu, K; Tsujimoto, S; Manda, T; Shimomura, K

    1994-01-01

    Recombinant tumor necrosis factor-alpha (rTNF-alpha) inhibited tumor growth of Meth A fibrosarcoma (Meth A) solid tumor in mice, and the antitumor effect of rTNF-alpha was significantly decreased by pretreatment with small doses or rTNF-alpha in mice. In in vitro experiments, incubation of human umbilical vein endothelial cells with rTNF-alpha enhanced procoagulant activity (PCA), which was drastically augmented after an addition of the conditioned medium of Meth A tumor cells. Furthermore, rTNF-alpha-induced PCA was decreased by pretreatment with rTNF-alpha in endothelial cells. This PCA was completely blocked after the addition of anti-human tissue factor (TF) murine monoclonal antibody. These results imply that in vivo antitumor effects of rTNF-alpha are mediated by expression of TF in endothelial cells, which is augmented by tumor released factor(s).

  14. Metabolic and lactational responses during recombinant bovine tumor necrosis factor-alpha treatment in lactating cows.

    PubMed

    Kushibiki, S; Hodate, K; Shingu, H; Obara, Y; Touno, E; Shinoda, M; Yokomizo, Y

    2003-03-01

    This study examined the effects of recombinant bovine tumor necrosis factor-alpha (rbTNF) administration on metabolic and hormonal responses and lactational performance in dairy cows. Twelve lactating Holstein cows were injected subcutaneously with rbTNF (2.5 microg per kg per d) or saline (3 ml per head per d) at 1200 h daily for 7 d (d 0-6) and used in a crossover design. The rbTNF treatment induced increases in plasma haptoglobin, nonesterified fatty acid, cortisol, and growth hormone levels compared with the control levels. The rbTNF-treated cows had lower triiodothyronine and insulin-like growth factor-1 concentrations than control cows. In a somatoliberin challenge on d 6, the somatotropin response to somatoliberin (0.25 microg/kg) was smaller in the rbTNF group than in the control. The rbTNF treatment also produced increases of the nitrite plus nitrate concentration in plasma and milk during the period between d 1 and 7. Milk yield was reduced by rbTNF administration from d 1 to 8. The percentage of milk fat was increased on d 1-7 by rbTNF treatment, but milk protein content in the rbTNF group was decreased on d 5 and 7 as compared with that in the control group. These results support the possibility that tumor necrosis factor-alpha is responsible for the changes in hormone secretion, milk production and composition, and inflammatory parameters observed during coliform mastitis.

  15. [Cardiovascular exercise on obese women: effects on adiponectine, leptine, and tumour necrosis factor-alpha].

    PubMed

    Landeros-Olvera, Erick; López-Alvarenga, Juan Carlos; Nava-González, Edna J; Gallegos-Cabriales, Esther; Lavalle-González, Fernando; Bastarrachea, Raúl A; Salazar González, Bertha Cecilia

    2014-01-01

    The relationship of hormones adiponectin, leptin and tumor necrosis factor-alpha in adipose tissue on the atherogenic process is one of the most promising models in preventive medicine. The numerous tests performed to identify the effect of exercise on these hormones have not been clear on the type of exercise routine and physical effort calculated to contribute to changing plasma concentrations in obese women. Analyze controlledcardiovascular exercise effect on serum level of adiponectin, leptin, and tumournecrosis factor-alpha in obese young women. A simple blind clinical essay. The intervention covered a 10-week controlled, cardiovascular exercise program by 34 women (cases n=17, controls n=17) with a body mass index>27kg/m(2). Molecular analysis was performed by immune-fluorescence. Following the intervention, cases and controls means were as follows: adiponectin 19.0 vs. 12.2μ/ml (P=.008); leptin 20.0 vs. 28.0μ/L (P=.02); and tumour necrosis factor-alpha 4.7 vs. 5.1pg/ml (P=.05). The established exercise (5 sessions a week of exercise of 40min each for 10 weeks with a heart rate reserve of 40 to 80%) improved plasma concentrations of these hormones in the expected direction. This finding highlights an unpublished amount of exercise, controlled by the reserve cardiac frequency that might contribute the cardiovascular and metabolic protection to obese women. Copyright © 2013 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

  16. Tumor necrosis factor-alpha inhibits pre-osteoblast differentiation through its type-1 receptor.

    PubMed

    Abbas, Sabiha; Zhang, Yan-Hong; Clohisy, John C; Abu-Amer, Yousef

    2003-04-01

    Tumor necrosis factor-alpha (TNF) is a pro-inflammatory cytokine with a profound role in many skeletal diseases. The cytokine has been described as a mediator of bone loss in osteolysis and other inflammatory bone diseases. In addition to its known bone resorptive action, TNF reduces bone formation by inhibiting osteoblast differentiation. Using primary and transformed osteoblastic cells, we first document that TNF inhibits expression of alkaline phosphatase and matrix deposition, both considered markers of osteoblast differentiation. The effects are dose- and time-dependent. Core-binding factor A1 (cbfa1) is a transcription factor critical for osteoblast differentiation, and we show here that it is activated by the osteoblast differentiation agent, beta-glycerophosphate. Therefore, we investigated whether the inhibitory effects of TNF were associated with altered activity of this transcription factor. Using retardation assays, we show that TNF significantly inhibits cbfal activation by beta-glycerophosphate, manifested by reduced DNA-binding activity. Next, we turned to determine the signaling pathway by which TNF inhibits osteoblast differentiation. Utilizing animals lacking individual TNF receptors, we document that TNFr1 is required for transmitting the cytokine's inhibitory effect. In the absence of this receptor, TNF failed to impact all osteoblast differentiation markers tested. In summary, TNF blocks expression of osteoblast differentiation markers and inhibits beta-glycerophosphate-induced activation of the osteoblast differentiation factor cbfa1. Importantly, these effects are mediated via a mechanism requiring the TNF type-1 receptor.

  17. Necrosis in yeast.

    PubMed

    Eisenberg, Tobias; Carmona-Gutierrez, Didac; Büttner, Sabrina; Tavernarakis, Nektarios; Madeo, Frank

    2010-03-01

    Necrosis was long regarded as an accidental cell death process resulting from overwhelming cellular injury such as chemical or physical disruption of the plasma membrane. Such a definition, however, proved to be inapplicable to many necrotic scenarios. The discovery that genetic manipulation of several proteins either protected or enhanced necrotic cell death argued in favor of a regulated and hence programmed process, as it is the case for apoptosis. For more than a decade, yeast has served as a model for apoptosis research; recently, evidence accumulated that it also harbors a necrotic program. Here, we summarize the current knowledge about factors that control necrotic cell death in yeast. Mitochondria, aging and a low pH are positive regulators of this process while cellular polyamines (e.g. spermidine) and endonuclease G as well as homeostatic organelles like the vacuole or peroxisomes are potent inhibitors of necrosis. Physiological necrosis may stimulate intercellular signaling via the release of necrotic factors that promote viability of healthy cells and, thus, assure survival of the clone. Together, the data obtained in yeast argue for the existence of a necrotic program, which controls longevity and whose physiological function may thus be aging.

  18. 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.

  19. Type I pityriasis rubra pilaris: upregulation of tumor necrosis factor alpha and response to adalimumab therapy.

    PubMed

    Zhang, Yao-Hua; Zhou, Youwen; Ball, Nigel; Su, Ming-Wan; Xu, Jin-Hua; Zheng, Zhi-Zhong

    2010-01-01

    pityriasis rubra pilaris (PRP) has unknown etiology and is often refractory to conventional therapies. to document a PRP patient's response to adalimumab therapy and to highlight the potential role of tumor necrosis factor (TNF) in the development of PRP skin lesions. a patient received adalimumab therapy at standard dosing intervals. In addition, the messenger ribonucleic acid (mRNA) of TNF in the lesional and perilesional normal skin was quantified in two patients with PRP. the patient responded to adalimumab therapy and achieved clinical remission by 4 months. There was a significant elevation of TNF mRNA in the lesional skin of PRP. TNF upregulation is detected in PRP lesional skin, consistent with the observed clinical efficacy of TNF blockade for the treatment of PRP.

  20. The role of tumor necrosis factor receptor superfamily members in mammalian brain development, function and homeostasis

    PubMed Central

    Twohig, Jason P.; Cuff, Simone M.; Yong, Audrey A.; Wang, Eddie C.Y.

    2012-01-01

    Tumor necrosis factor receptor superfamily (TNFRSF) members were initially identified as immunological mediators, and are still commonly perceived as immunological molecules. However, our understanding of the diversity of TNFRSF members’ roles in mammalian physiology has grown significantly since the first discovery of TNFRp55 (TNFRSF1) in 1975. In particular, the last decade has provided evidence for important roles in brain development, function and the emergent field of neuronal homeostasis. Recent evidence suggests that TNFRSF members are expressed in an overlapping regulated pattern during neuronal development, participating in the regulation of neuronal expansion, growth, differentiation and regional pattern development. This review examines evidence for non-immunological roles of TNFRSF members in brain development, function and maintenance under normal physiological conditions. In addition, several aspects of brain function during inflammation will also be described, when illuminating and relevant to the non-immunological role of TNFRSF members. Finally, key questions in the field will be outlined. PMID:21861782

  1. 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.

  2. Stable Escherichia coli-Clostridium acetobutylicum shuttle vector for secretion of murine tumor necrosis factor alpha.

    PubMed

    Theys, J; Nuyts, S; Landuyt, W; Van Mellaert, L; Dillen, C; Böhringer, M; Dürre, P; Lambin, P; Anné, J

    1999-10-01

    Recombinant plasmids were constructed to secrete mouse tumor necrosis factor alpha (mTNF-alpha) from Clostridium acetobutylicum. The shuttle plasmids contained the clostridial endo-beta1, 4-glucanase (eglA) promoter and signal sequence that was fused in frame to the mTNF-alpha cDNA. The construction was first tested in Escherichia coli and then introduced in C. acetobutylicum DSM792 by electroporation. Controls confirmed the presence and stability of the recombinant plasmids in this organism. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and an in vitro cytotoxic assay were used to monitor expression and secretion of mTNF-alpha during growth. Significant levels of biologically active mTNF-alpha were measured in both lysates and supernatants. The present report deals with investigations on the elaboration of a gene transfer system for cancer treatment using anaerobic bacteria.

  3. Role of Eosinophils and Tumor Necrosis Factor Alpha in Interleukin-25-Mediated Protection from Amebic Colitis

    PubMed Central

    Noor, Zannatun; Watanabe, Koji; Abhyankar, Mayuresh M.; Burgess, Stacey L.; Buonomo, Erica L.

    2017-01-01

    ABSTRACT The parasite Entamoeba histolytica is a cause of diarrhea in infants in low-income countries. Previously, it was shown that tumor necrosis factor alpha (TNF-α) production was associated with increased risk of E. histolytica diarrhea in children. Interleukin-25 (IL-25) is a cytokine that is produced by intestinal epithelial cells that has a role in maintenance of gut barrier function and inhibition of TNF-α production. IL-25 expression was decreased in humans and in the mouse model of amebic colitis. Repletion of IL-25 blocked E. histolytica infection and barrier disruption in mice, increased gut eosinophils, and suppressed colonic TNF-α. Depletion of eosinophils with anti-Siglec-F antibody prevented IL-25-mediated protection. In contrast, depletion of TNF-α resulted in resistance to amebic infection. We concluded that IL-25 provides protection from amebiasis, which is dependent upon intestinal eosinophils and suppression of TNF-α. PMID:28246365

  4. Absence of tumour necrosis factor facilitates primary and recurrent herpes simplex virus-1 infections.

    PubMed

    Minagawa, Hiroko; Hashimoto, Koji; Yanagi, Yusuke

    2004-02-01

    Tumour necrosis factor (TNF) is an important cytokine in the innate immune response against various infections, including herpes simplex virus (HSV) infection. It has recently become a molecular target of anti-cytokine treatment in certain inflammatory diseases. TNF depletion resulted in a more rapid emergence of infectious HSV-1 in the explant cultures of latently infected trigeminal ganglia (TG), compared with controls. To further evaluate the importance of TNF in the host's defence responses against HSV-1, TNF-knockout mice were challenged via scarified cornea. These mice were more susceptible to primary acute corneal HSV-1 infection than controls, as manifested by an increased mortality rate and higher infectious virus titres in the eyes and TG, indicating that TNF is critical for defence during acute HSV infection. These results imply that the administration of anti-inflammatory TNF antagonists might facilitate the propagation of infectious HSV, resulting in an exacerbation of primary and recurrent acute lesions.

  5. Formation of Ion-Permeable Channels by Tumor Necrosis Factor

    NASA Astrophysics Data System (ADS)

    Kagan, Bruce L.; Baldwin, Rae Lynn; Munoz, David; Wisnieski, Bernadine J.

    1992-03-01

    Tumor necrosis factor-α (TNF, cachectin), a protein secreted by activated macrophages, participates in inflammatory responses and in infectious and neoplastic disease states. The mechanisms by which TNF exerts cytotoxic, hormonal, and other specific effects are obscure. Structural studies of the TNF trimer have revealed a central pore-like region. Although several amino acid side chains appear to preclude an open channel, the ability of TNF to insert into lipid vesicles raised the possibility that opening might occur in a bilayer milieu. Acidification of TNF promoted conformational changes concordant with increased surface hydrophobicity and membrane insertion. Furthermore, TNF formed pH-dependent, voltage-dependent, ion-permeable channels in planar lipid bilayer membranes and increased the sodium permeability of human U937 histiocytic lymphoma cells. Thus, some of the physiological effects of TNF may be elicited through its intrinsic ion channel-forming activity.

  6. Passive Immunization against Cachectin/Tumor Necrosis Factor Protects Mice from Lethal Effect of Endotoxin

    NASA Astrophysics Data System (ADS)

    Beutler, B.; Milsark, I. W.; Cerami, A. C.

    1985-08-01

    A highly specific polyclonal rabbit antiserum directed against murine cachectin/tumor necrosis factor (TNF) was prepared. When BALB/c mice were passively immunized with the antiserum or with purified immune globulin, they were protected against the lethal effect of the endotoxin lipopolysaccharide produced by Escherichia coli. The prophylactic effect was dose-dependent and was most effective when the antiserum was administered prior to the injection of the endotoxin. Antiserum to cachectin/TNF did not mitigate the febrile response of endotoxin-treated animals, and very high doses of endotoxin could overcome the protective effect. The median lethal dose of endotoxin in mice pretreated with 50 microliters of the specific antiserum was approximately 2.5 times greater the median lethal dose for controls given nonimmune serum. The data suggest that cachectin/TNF is one of the principal mediators of the lethal effect of endotoxin.

  7. Tumor necrosis factor alpha promoter polymorphism in posttransplantation diabetes mellitus of renal transplant recipients.

    PubMed

    Kao, C-C; Lian, J-D; Chou, M-C; Chang, H-R; Yang, S-F

    2010-11-01

    Posttransplantation diabetes mellitus (PTDM) is a major complication in renal transplant recipients. Some studies have demonstrated that tumor necrosis factor alpha (TNF-α) expression and its genetic polymorphism are associated with diabetes mellitus. We investigated this association in Asian renal transplant recipients. Polymerase chain reaction-restriction-fragment length polymorphism was used to measure TNF-α G-238A and G-308A gene polymorphisms among 241 nonposttransplantation diabetic subjects and 73 PTDM patients. PTDM patients showed higher values of body weight and body mass index (BMI) than the non-PTDM group. However, no significant association was observed between TNF-α G-238A and TNF-α G-308A polymorphisms with PTDM incidence, gender, age at transplantation, follow-up duration, BMI, or type of immunosuppression. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. 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.

  9. Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas.

    PubMed Central

    Picarella, D E; Kratz, A; Li, C B; Ruddle, N H; Flavell, R A

    1992-01-01

    Tumor necrosis factor beta (TNF-beta) (lymphotoxin) may play an important role in the immune response and pathologic inflammatory diseases. Insulitis is an important early step in the development of insulin-dependent diabetes mellitus. To understand better the role of TNF-beta in the regulation of inflammation and type 1 diabetes, we produced transgenic mice in which the murine TNF-beta gene was regulated by the rat insulin II promoter. The transgene was expressed in the pancreas, kidney, and skin of transgenic mice. The expression of TNF-beta in the pancreas of transgenic mice resulted in a leukocytic inflammatory infiltrate consisting primarily of B220+ IgM+ B cells and CD4+ and CD8+ T cells. The insulitis is reminiscent of the early stages of diabetes, though the mice did not progress to diabetes. Images PMID:1279667

  10. 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

  11. The role of tumor necrosis factor receptor superfamily members in mammalian brain development, function and homeostasis.

    PubMed

    Twohig, Jason P; Cuff, Simone M; Yong, Audrey A; Wang, Eddie C Y

    2011-01-01

    Tumor necrosis factor receptor superfamily (TNFRSF) members were initially identified as immunological mediators, and are still commonly perceived as immunological molecules. However, our understanding of the diversity of TNFRSF members' roles in mammalian physiology has grown significantly since the first discovery of TNFRp55 (TNFRSF1) in 1975. In particular, the last decade has provided evidence for important roles in brain development, function and the emergent field of neuronal homeostasis. Recent evidence suggests that TNFRSF members are expressed in an overlapping regulated pattern during neuronal development, participating in the regulation of neuronal expansion, growth, differentiation and regional pattern development. This review examines evidence for non-immunological roles of TNFRSF members in brain development, function and maintenance under normal physiological conditions. In addition, several aspects of brain function during inflammation will also be described, when illuminating and relevant to the non-immunological role of TNFRSF members. Finally, key questions in the field will be outlined.

  12. Mechanism of inhibition of HSV-1 replication by tumor necrosis factor and interferon gamma.

    PubMed

    Feduchi, E; Carrasco, L

    1991-02-01

    Tumor necrosis factor (TNF) synergizes with interferon (IFN gamma) in the blockade of HSV-1 replication. Antibodies against IFN beta block this synergism, implying a role of IFN beta in the antiviral activity of TNF plus IFN gamma. IFN beta 1 added exogenously to Hep-2 cells shows antiviral activity against HSV-1 only at high concentrations, whereas IFN beta 2 (also known as IL-6) alone has no effect on the replication of VSV or HSV-1 even when 1,000 U/ml are present. Our results are in accordance with the idea that TNF induces IFN beta 1 and that both cytokines must be present in the culture medium to synergize with IFN gamma in order to inhibit HSV-1 replication.

  13. Alopecia secondary to anti-tumor necrosis factor-alpha therapy*

    PubMed Central

    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

  14. [Tumor necrosis factor alfa in cardiovascular diseases: molecular biology and genetics].

    PubMed

    Fragoso Lona, José Manuel; Sierra Martínez, Mónica; Vargas Alarcón, Gilberto; Barrios Rodas, Angélica; Ramírez Bello, Julián

    2013-01-01

    Cardiovascular diseases are a major public health problem globally. In 1997, cardiovascular disease caused 41% of deaths in the United States. It has been reported that about 60 million people in the United States have some form of cardiovascular disease. These entities are chronic conditions initiated by a dysregulation of the immune response. One gene and its protein product -tumor necrosis factor a (TNF-α)- a powerful pleiotropic cytokine with multiple cellular functions, plays a role in the inflammation, initiation, development, susceptibility, severity, and response to treatment, etc. of coronary artery disease (CAD). The focus of the present review is to summarize recent evidence showing the biological role of TNF-α in the initiation and progression of endothelial dysfunction and complications of atherosclerosis, and as a genetic variation of TNF-α confer susceptibility, severity, and treatment response in CAD: ST-segment elevation myocardial infarction and non-ST segment elevation myocardial infarction, unstable angina, and coronary restenosis.

  15. Flare and change of psoriasis morphology during the course of treatment with tumour necrosis factor blockers.

    PubMed

    Goiriz, R; Daudén, E; Pérez-Gala, S; Guhl, G; García-Díez, A

    2007-03-01

    Tumour necrosis factor (TNF) blockers represent an exciting advance in the management of psoriasis. However, the safety profile of these drugs is not completely established. We present a review of the literature, and report on eight patients: two with the unexpected appearance of psoriasis, and the remaining six with exacerbation and change in morphology of their existing psoriasis, all of which occurred during treatment with the TNF blockers adalimumab, etanercept and infliximab. The two new cases, neither of whom had any personal or family history of psoriasis, developed pustular psoriasis on the palms and/or soles. The other six patients, previously diagnosed with severe chronic plaque psoriasis (four patients), generalized pustular psoriasis (one) and erythrodermic psoriasis (one), developed eruptive guttate psoriasis between 15 days and 18 months after the beginning of therapy. These patients had never before presented guttate-type psoriatic lesions, and the lesions appeared in areas of the body that were free of psoriatic plaques at baseline.

  16. Use of anti tumor necrosis factor-alpha monoclonal antibody for ulcerative jejunoileitis

    PubMed Central

    Seven, Gulseren; Assaad, Adel; Biehl, Thomas; Kozarek, Richard A

    2012-01-01

    Ulcerative jejunoileitis is an uncommon clinical syndrome consisting of abdominal pain, weight loss associated with diarrhea, and multiple inflammatory ulcerations and strictures of the small bowel. Ulcerative jejunoileitis can complicate established celiac disease or develop in patients de novo. Increased levels of tumor necrosis factor-alpha (TNF-α) in the small intestine of patients with untreated celiac disease are associated with a role in the immune pathogenesis of this disorder. No specific therapy has been shown to change the course of ulcerative jejunoileitis. We report a case of severe ulcerative jejunoileitis previously unresponsive to traditional therapies, including high dose corticosteroids and cyclosporine. The patient had a dramatic resolution of symptoms and a complete normalization of endoscopic findings after anti-TNF-α monoclonal antibody, infliximab (Remicade®). PMID:23049226

  17. Inherited variability of tumor necrosis factor production and susceptibility to infectious disease.

    PubMed

    Knight, J C; Kwiatkowski, D

    1999-01-01

    Tumor necrosis factor (TNF) is a critical mediator of host defense against infection but may cause severe pathology when produced in excess. Individuals vary in the amount of TNF produced when their peripheral blood mononuclear cells are stimulated in vitro, and family studies indicate that much of this variability is genetically determined. Since the TNF response to infection is partly regulated at the transcriptional level, TNF promoter polymorphisms have been the subject of intense interest as potential determinants of disease susceptibility. A single nucleotide polymorphism at nucleotide -308 relative to the transcriptional start site has been associated with susceptibility to severe malaria, leishmaniasis, scarring trachoma, and lepromatous leprosy. Some experimental data indicate that this polymorphism acts to upregulate TNF transcription, but this remains controversial. Detailed analysis of multiple genetic markers at this locus and more sophisticated investigations of TNF transcriptional regulation, in different cell types and with a wide range of stimuli, are required to understand the molecular basis of these disease associations.

  18. Tumor necrosis factor alpha selectively sensitizes human immunodeficiency virus-infected cells to heat and radiation

    SciTech Connect

    Wong, G.H.; McHugh, T.; Weber, R.; Goeddel, D.V. )

    1991-05-15

    We report here that infection of the human T-cell line HUT-78 with human immunodeficiency virus (HIV) increases its sensitivity to heat and radiation toxicity. A possible explanation for this result may be the reduced expression of manganous superoxide dismutase (MnSOD) in HIV-infected cells compared to uninfected cells. Tumor necrosis factor alpha (TNF-alpha) further sensitizes HIV-infected cells but not uninfected cells to heat and radiation. This is consistent with the ability of TNF-alpha to induce the expression of MnSOD in uninfected but not in HIV-infected cells. HIV-infected HUT-78 cell lines engineered to overexpress MnSOD are more resistant to heat and radiation than HIV-infected cells that do not overexpress MnSOD. However, treatment with TNF-alpha still sensitizes these cells to heat and radiation.

  19. Psoriasiform lesions induced by tumour necrosis factor antagonists: a skin-deep medical conundrum.

    PubMed

    Carter, J D; Gerard, H C; Hudson, A P

    2008-08-01

    Rarely, tumour necrosis factor (TNF)alpha antagonist therapy has been associated with de novo psoriasiform eruptions. This is unusual in that these same drugs are used to treat psoriasis. Most of these cases involve the palms and soles, yet palmoplantar pustular psoriasis represents only 1.7% of all cases of psoriasis. Keratoderma blenorrhagicum is a psoriasiform rash that occurs primarily on the palms and soles of some patients with reactive arthritis. It is grossly and histologically indistinguishable from pustular psoriasis. Chlamydia trachomatis is a common aetiological agent for reactive arthritis, and in vitro studies have shown that chlamydial replication is inversely proportional to TNFalpha levels. Three patients taking TNFalpha antagonists are presented who developed such lesions and who were found to be positive for C trachomatis DNA in the affected skin. It is proposed that these psoriasiform lesions may not be psoriasis, but rather keratoderma blenorrhagicum.

  20. Tumor necrosis factor-α: regulation of renal function and blood pressure

    PubMed Central

    Garvin, Jeffrey L.

    2013-01-01

    Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that becomes elevated in chronic inflammatory states such as hypertension and diabetes and has been found to mediate both increases and decreases in blood pressure. High levels of TNF-α decrease blood pressure, whereas moderate increases in TNF-α have been associated with increased NaCl retention and hypertension. The explanation for these disparate effects is not clear but could simply be due to different concentrations of TNF-α within the kidney, the physiological status of the subject, or the type of stimulus initiating the inflammatory response. TNF-α alters renal hemodynamics and nephron transport, affecting both activity and expression of transporters. It also mediates organ damage by stimulating immune cell infiltration and cell death. Here we will summarize the available findings and attempt to provide plausible explanations for such discrepancies. PMID:23515717

  1. Paradoxical Roles of Tumour Necrosis Factor-Alpha in Prostate Cancer Biology

    PubMed Central

    Tse, Brian W. C.; Scott, Kieran F.; Russell, Pamela J.

    2012-01-01

    Tumour necrosis factor (TNF) is a pleiotropic cytokine with dual roles in cancer biology including prostate cancer (PCa). On the one hand, there is evidence that it stimulates tumour angiogenesis, is involved in the initiation of PCa from an androgen-dependent to a castrate resistant state, plays a role in epithelial to mesenchymal plasticity, and may contribute to the aberrant regulation of eicosanoid pathways. On the other hand, TNF has also been reported to inhibit neovascularisation, induce apoptosis of PCa cells, and stimulate antitumour immunity. Much of the confusion surrounding its seemingly paradoxical roles in cancer biology stems from the dependence of its effects on the biological model within which TNF is investigated. This paper will address some of these issues and also discuss the therapeutic implications. PMID:23326670

  2. Binding and regulation of cellular functions by monoclonal antibodies against human tumor necrosis factor receptors

    PubMed Central

    1990-01-01

    The present study was undertaken to further characterize the interaction of monoclonal antibodies (mAbs) against tumor necrosis factor (TNF) receptors with different targets, and to assess their ability to influence TNF effects on U937 and human endothelial cell (HEC) functions. Actions of recombinant TNF-alpha on U937 and HEC were effectively inhibited by Htr-5 and Utr-1, and to a greater extent by a combination of both mAbs. These observations indicate that TNF interaction with antigenically different components of membrane receptors (p55 and p75) represents a crucial step in transduction of signals for TNF toxicity against U937 and TNF activation of HEC functions. PMID:2172437

  3. Modulation of the transcripts for tumor necrosis factor-alpha and its receptors in vivo.

    PubMed

    de Kossodo, S; Critico, B; Grau, G E

    1994-03-01

    We investigated the effects of a single bacterial lipopolysaccharide (LPS) injection in vivo on the gene expression of tumor necrosis factor-alpha (TNF) and its receptors: TNF receptor type I (TNF-R 55 kDa or TNF-R1) and TNF receptor type II (TNF-R 75 kDa or TNF-R2) in various tissues and white blood cells. While TNF mRNA rapidly accumulated in most tissues, TNF-R1 and TNF-R2 mRNA levels were found to be differentially regulated in lung, spleen, lymph nodes and white blood cells. In most cases, TNF-R mRNA levels did not parallel TNF mRNA levels. These observations indicate that TNF-R of both types of capable of modulating the host response to LPS, not only by shedding of their extracellular domains, but also by strict regulation of their gene expression.

  4. Importance of tuberculosis screening before inhibiting tumour necrosis factor-alpha therapy.

    PubMed

    García-López, A; Burgueño-Montañés, C

    2013-01-01

    There has been an increase in the incidence of tuberculosis infection in recent years, due to the increasing use of drugs inhibiting tumour necrosis factor-alpha (anti-TNFα) in the treatment of inflammatory diseases. We report the case of a male patient being treated with infliximab (anti-TNFα) who developed disseminated tuberculosis with ocular involvement. It is very important to conduct a proper screening to detect patients at risk for tuberculosis before starting treatment with these drugs. For this purpose, the QuantiFERON®-TB Gold in Tube (Interferon Gamma Release Assay, IGRA) is presented as an alternative screening test with high sensitivity and specificity. Copyright © 2011 Sociedad Española de Oftalmología. Published by Elsevier España, S.L. All rights reserved.

  5. 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.

  6. Proteinase Inhibitor-inducing Factor in Plant Leaves

    PubMed Central

    McFarland, Douglas; Ryan, Clarence A.

    1974-01-01

    Thirty-nine plant species representing 20 families from the four major divisions of plants were surveyed for the presence of proteinase inhibitor-inducing factor activity in leaves or other tissues. Tissue juices were assayed for their capacity to induce accumulation of proteinase inhibitor I in excised tomato (Lycopersico esculentum) leaves. In tissues of only 2 of the 39 species was proteinase inhibitor-inducing factor-like activity not found. The activity was absent in cabbage leaves and celery stalks. Fruiting bodies from one of three fungi genera assayed contained exceptionally large quantities of proteinase inhibitor-inducing factor-like activity. Extracts from Agraricus campestris fruiting bodies contained over 20 times more activity than tomato leaf juice. The survey confirms that substances with proteinase inhibitor-inducing factor-like activity are widespread in the plant kingdom. PMID:16658956

  7. Chronic heart failure-induced skeletal muscle atrophy, necrosis, and changes in myogenic regulatory factors.

    PubMed

    Martinez, Paula F; Okoshi, Katashi; Zornoff, Leonardo A M; Carvalho, Robson F; Oliveira Junior, Silvio A; Lima, Aline R R; Campos, Dijon H S; Damatto, Ricardo L; Padovani, Carlos R; Nogueira, Celia R; Dal Pai-Silva, Maeli; Okoshi, Marina P

    2010-12-01

    Although intrinsic skeletal muscle abnormalities can influence exercise intolerance during heart failure (HF), the factors responsible for muscle changes have not been elucidated. In this study we evaluated the expression of myogenic regulatory factors (MRF), myosin heavy chain (MyHC) isoforms, and fiber trophism in the soleus muscle of rats with myocardial infarction-induced heart failure. Six months after surgery, 2 groups of rats were studied: sham, and infarcted rats with HF (MI/HF+, MI size: 41.1±6.3% of total left ventricular area). In the infarcted group, microscopic evaluation revealed scattered foci of fiber necrosis in combination with inflammatory cells, phagocytosis, and increased fibrous tissue. The frequency of necrotic fibers was significantly higher in the MI/HF+ group than in the sham. The MI/HF+ group had atrophy of type I, IC/IIC, and IIA fibers compared to the sham group (P<0.05). MyoD gene expression was higher in the MI/HF+ group (sham: 1.00±0.49; MI/HF+: 2.53±0.71 arbitrary units; P<0.001). Myogenin and MRF4 gene expression was similar in both groups. Myogenin protein levels were reduced in the MI/HF+ group (sham: 1.00±0.21; MI/HF+: 0.74±0.21 arbitrary units; P=0.026). MyoD and MRF4 protein levels, as well as the MyHC distribution, were not different between groups. The MI/HF+ group had higher TNF-α and IL-6 serum concentrations than the sham group. Heart failure-induced skeletal muscle atrophy is combined with fiber necrosis, increased MyoD gene expression and decreased myogenin protein levels.

  8. 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

  9. Biodentine Reduces Tumor Necrosis Factor Alpha-induced TRPA1 Expression in Odontoblastlike Cells.

    PubMed

    El Karim, Ikhlas A; McCrudden, Maelíosa T C; McGahon, Mary K; Curtis, Tim M; Jeanneau, Charlotte; Giraud, Thomas; Irwin, Chris R; Linden, Gerard J; Lundy, Fionnuala T; About, Imad

    2016-04-01

    The transient receptor potential (TRP) ion channels have emerged as important cellular sensors in both neuronal and non-neuronal cells, with TRPA1 playing a central role in nociception and neurogenic inflammation. The functionality of TRP channels has been shown to be modulated by inflammatory cytokines. The aim of this study was to investigate the effect of inflammation on odontoblast TRPA1 expression and to determine the effect of Biodentine (Septodent, Paris, France) on inflammatory-induced TRPA1 expression. Immunohistochemistry was used to study TRPA1 expression in pulp tissue from healthy and carious human teeth. Pulp cells were differentiated to odontoblastlike cells in the presence of 2 mmol/L beta-glycerophosphate, and these cells were used in quantitative polymerase chain reaction, Western blotting, calcium imaging, and patch clamp studies. Immunofluorescent staining revealed TRPA1 expression in odontoblast cell bodies and odontoblast processes, which was more intense in carious versus healthy teeth. TRPA1 gene expression was induced in cultured odontoblastlike cells by tumor necrosis factor alpha, and this expression was significantly reduced in the presence of Biodentine. The functionality of the TRPA1 channel was shown by calcium microfluorimetry and patch clamp recording, and our results showed a significant reduction in tumor necrosis factor alpha-induced TRPA1 responses after Biodentine treatment. In conclusion, this study showed TRPA1 to be modulated by caries-induced inflammation and that Biodentine reduced TRPA1 expression and functional responses. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  10. p53 and tumor necrosis factor alpha regulate the expression of a mitochondrial chloride channel protein.

    PubMed

    Fernández-Salas, E; Sagar, M; Cheng, C; Yuspa, S H; Weinberg, W C

    1999-12-17

    A novel chloride intracellular channel (CLIC) gene, clone mc3s5/mtCLIC, has been identified from differential display analysis of differentiating mouse keratinocytes from p53+/+ and p53-/- mice. The 4.2-kilobase pair cDNA contains an open reading frame of 762 base pairs encoding a 253-amino acid protein with two putative transmembrane domains. mc3s5/mtCLIC protein shares extensive homology with a family of intracellular organelle chloride channels but is the first shown to be differentially regulated. mc3s5/mtCLIC mRNA is expressed to the greatest extent in vivo in heart, lung, liver, kidney, and skin, with reduced levels in some organs from p53-/- mice. mc3s5/mtCLIC mRNA and protein are higher in p53+/+ compared with p53-/- basal keratinocytes in culture, and both increase in differentiating keratinocytes independent of genotype. Overexpression of p53 in keratinocytes induces mc3s5/mtCLIC mRNA and protein. Exogenous human recombinant tumor necrosis factor alpha also up-regulates mc3s5/mtCLIC mRNA and protein in keratinocytes. Subcellular fractionation of keratinocytes indicates that both the green fluorescent protein-mc3s5 fusion protein and the endogenous mc3s5/mtCLIC are localized to the cytoplasm and mitochondria. Similarly, mc3s5/mtCLIC was localized to mitochondria and cytoplasmic fractions of rat liver homogenates. Furthermore, mc3s5/mtCLIC colocalized with cytochrome oxidase in keratinocyte mitochondria by immunofluorescence and was also detected in the cytoplasmic compartment. Sucrose gradient-purified mitochondria from rat liver confirmed this mitochondrial localization. This represents the first report of localization of a CLIC type chloride channel in mitochondria and the first indication that expression of an organellular chloride channel can be regulated by p53 and tumor necrosis factor alpha.

  11. 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

  12. Piceatannol inhibits MMP-9-dependent invasion of tumor necrosis factor-α-stimulated DU145 cells by suppressing the Akt-mediated nuclear factor-κB pathway

    PubMed Central

    JAYASOORIYA, RAJAPAKSHA GENDARA PRASAD THARANGA; LEE, YONG-GAB; KANG, CHANG-HEE; LEE, KYOUNG-TAE; CHOI, YUNG HYUN; PARK, SUNG-YONG; HWANG, JAE-KWAN; KIM, GI-YOUNG

    2013-01-01

    Piceatannol has potent anti-inflammatory, immunomodulatory, anticancer and antiproliferative effects. However, little is known about the mechanism by which piceatannol inhibits invasion and metastasis. The aim of the current study was to investigate the effects of piceatannol on the expression of matrix metalloproteinase-9 (MMP-9) in DU145 human prostate cancer cells. The results revealed that MMP-9 activity was significantly increased in response to tumor necrosis factor-α (TNF-α). However, treatment with piceatannol reversed TNF-α- and MMP-9-induced gelatin zymography and its gene expression. In addition, a Matrigel invasion assay determined that piceatannol reduces the TNF-α-induced invasion of DU145 cells. Nuclear factor-κ B (NF-κB) is a significant transcription factor that regulates numerous genes involved in tumor cell invasion and metastasis. Therefore, whether piceatannol acts on NF-κB to regulate MMP-9 gene expression was analyzed. The results revealed that piceatannol attenuates MMP-9 gene expression via the suppression of NF-κB activity. Using a specific NF-κB inhibitor, pyrrolidine dithiocarbamate, it was confirmed that TNF-α-induced MMP-9 gene expression is primarily regulated by NF-κB activation. Piceatannol inhibited NF-κB activity by suppressing nuclear translocation of the NF-κB p65 and p50 subunits. Furthermore, TNF-α-induced Akt phosphorylation was significantly downregulated in the presence of piceatannol. The Akt inhibitor LY294002 caused a significant decrease in TNF-α-induced NF-κB activity and MMP-9 gene expression. Overall, these data suggest that piceatannol inhibits TNF-α-induced invasion by suppression of MMP-9 activation via the Akt-mediated NF-κB pathway in DU145 prostate cancer cells. PMID:23255946

  13. Interleukin 10 and Tumor Necrosis Factor-Alpha in Pregnancy: Aspects of Interest in Clinical Obstetrics

    PubMed Central

    Brogin Moreli, Jusciele; Cirino Ruocco, Ana Maria; Vernini, Joice Monaliza; Rudge, Marilza Vieira Cunha; Calderon, Iracema Mattos Paranhos

    2012-01-01

    The purpose of this study was to review the literature regarding the action of the cytokines interleukin 10 (IL-10) and tumor necrosis factor-alpha (TNF-α) in pregnancy and to emphasize the factors that are of interest to clinical obstetrics. The literature highlights several actions of IL-10 and TNF-α during pregnancy. The actions of these cytokines seem to be antagonistic and dependent on the balance between them, which is orchestrated by the specific immunosuppressive action of IL-10. TNF-α has a characteristic inflammatory action, and it is an additional diabetogenic factor in pregnancy. The loss of the control of the production of these cytokines, with increase of TNF-α, is related to the risk for developing obstetric complications, particularly recurrent fetal loss, gestational diabetes mellitus, hypertensive syndromes, and fetal growth restriction. However, study results are controversial and are not clearly defined. These issues are attributed to the heterogeneity of the studies, particularly regarding their sample sizes and sources, the evaluation methods, and the multiplicity of factors and conditions that influence cytokine production. These questions are fundamental and should be addressed in future investigations to obtain more consistent results that can be applied to obstetric practice. PMID:22462002

  14. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease.

    PubMed

    Rickert, Robert C; Jellusova, Julia; Miletic, Ana V

    2011-11-01

    Members of the tumor necrosis factor receptor superfamily (TNFRSF) participate prominently in B-cell maturation and function. In particular, B-cell activating factor belonging to the TNF family receptor (BAFF-R), B-cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) play critical roles in promoting B-cell survival at distinct stages of development by engaging a proliferation-inducing ligand (APRIL) and/or BAFF. CD40 is also essential for directing the humoral response to T-cell-dependent antigens. Signaling by the TNFRSF is mediated primarily, albeit not exclusively, via the TNFR-associated factor (TRAF) proteins and activation of the canonical and/or non-canonical nuclear factor-κB (NF-κB) pathways. Dysregulated signaling by TNFRSF members can promote B-cell survival and proliferation, causing autoimmunity and neoplasia. In this review, we present a current understanding of the functions of and distinctions between APRIL/BAFF signaling by their respective receptors expressed on particular B-cell subsets. These findings are compared and contrasted with CD40 signaling, which employs similar signaling conduits to achieve distinct cellular outcomes in the context of the germinal center response. We also underscore how new findings and conceptual insights into TNFRSF signaling are facilitating the understanding of B-cell malignancies and autoimmune diseases.

  15. 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

  16. Systemic Preconditioning by a Prolyl Hydroxylase Inhibitor Promotes Prevention of Skin Flap Necrosis via HIF-1-Induced Bone Marrow-Derived Cells

    PubMed Central

    Takaku, Mitsuru; Tomita, Shuhei; Kurobe, Hirotsugu; Kihira, Yoshitaka; Morimoto, Atsushi; Higashida, Mayuko; Ikeda, Yasumasa; Ushiyama, Akira; Hashimoto, Ichiro; Nakanishi, Hideki; Tamaki, Toshiaki

    2012-01-01

    Background Local skin flaps often present with flap necrosis caused by critical disruption of the blood supply. Although animal studies demonstrate enhanced angiogenesis in ischemic tissue, no strategy for clinical application of this phenomenon has yet been defined. Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in ischemic vascular responses, and its expression is induced by the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). We assessed whether preoperative stabilization of HIF-1 by systemic introduction of DMOG improves skin flap survival. Methods and Results Mice with ischemic skin flaps on the dorsum were treated intraperitoneally with DMOG 48 hr prior to surgery. The surviving area with neovascularization of the ischemic flaps was significantly greater in the DMOG-treated mice. Significantly fewer apoptotic cells were present in the ischemic flaps of DMOG-treated mice. Interestingly, marked increases in circulating endothelial progenitor cells (EPCs) and bone marrow proliferative progenitor cells were observed within 48 hr after DMOG treatment. Furthermore, heterozygous HIF-1α-deficient mice exhibited smaller surviving flap areas, fewer circulating EPCs, and larger numbers of apoptotic cells than did wild-type mice, while DMOG pretreatment of the mutant mice completely restored these parameters. Finally, reconstitution of wild-type mice with the heterozygous deficient bone marrow cells significantly decreased skin flap survival. Conclusion We demonstrated that transient activation of the HIF signaling pathway by a single systemic DMOG treatment upregulates not only anti-apoptotic pathways but also enhances neovascularization with concomitant increase in the numbers of bone marrow-derived progenitor cells. PMID:22880134

  17. Tumor necrosis factor alpha derived from classically activated "M1" macrophages reduces interstitial cell of Cajal numbers.

    PubMed

    Eisenman, S T; Gibbons, S J; Verhulst, P-J; Cipriani, G; Saur, D; Farrugia, G

    2017-04-01

    Delayed gastric emptying in diabetic mice and humans is associated with changes in macrophage phenotype and loss of interstitial cells of Cajal (ICC) in the gastric muscle layers. In diabetic mice, classically activated M1 macrophages are associated with delayed gastric emptying, whereas alternatively activated M2 macrophages are associated with normal gastric emptying. This study aimed to determine if secreted factors from M1 macrophages could injure mouse ICC in primary culture. Cultures of gastric ICC were treated with conditioned medium (CM) from activated bone marrow-derived macrophages (BMDMs) and the effect of CM was quantified by counting ICC per high-powered field. Bone marrow-derived macrophages were activated to a M1 or M2 phenotype confirmed by qRT-PCR. Conditioned medium from M1 macrophages reduced ICC numbers by 41.1%, whereas M2-CM had no effect as compared to unconditioned, control media. Immunoblot analysis of 40 chemokines/cytokines found 12 that were significantly increased in M1-CM, including tumor necrosis factor alpha (TNF-α). ELISA detected 0.697±0.03 ng mL(-1) TNF-α in M1-CM. Recombinant mouse TNF-α reduced Kit expression and ICC numbers in a concentration-dependent manner (EC50 = 0.817 ng mL(-1) ). Blocking M1-CM TNF-α with a neutralizing antibody preserved ICC numbers. The caspase inhibitor Z-VAD.fmk partly preserved ICC numbers (cells/field; 6.63±1.04, 9.82±1.80 w/Z-VAD.fmk, n=6, P<.05). This work demonstrates that TNF-α secreted from M1 macrophages can result in Kit loss and directly injure ICC in vitro partly through caspase-dependent apoptosis and may play an important role in ICC depletion in diabetic gastroparesis. © 2016 John Wiley & Sons Ltd.

  18. Tumor necrosis factor-alpha regulation of the Id gene family in astrocytes and microglia during CNS inflammatory injury.

    PubMed

    Tzeng, S F; Kahn, M; Liva, S; De Vellis, J

    1999-04-01

    The inhibitors of DNA binding (Id) gene family is highly expressed during embryogenesis and throughout adulthood in the rat central nervous system (CNS). In vitro studies suggest that the Id gene family is involved in the regulation of cell proliferation and differentiation. Recently, Id gene expression was shown to be expressed in immature and mature astrocytes during development and upregulated in reactive astrocytes after spinal cord injury. These results suggest that the Id gene family may play an important role in regulating astrocyte development and reactivity; however, the factors regulating Id expression in astrocytes remain undefined. Tumor necrosis factor-alpha (TNF alpha), a proinflammatory cytokine, is thought to play a crucial role in astrocyte/microglia activation after injury to the CNS. To determine if TNF alpha plays a role in Id gene expression, we exogenously administered TNF alpha into developing postnatal rats. We report that TNF alpha injections resulted in a rapid and transient increase in both cell number and mRNA expression for Id2 and Id3 when compared to levels observed in noninjected or control-injected animals. Id1 mRNA levels were also upregulated after TNF alpha treatment, but to a lesser degree. Significant increases in TNF alpha-induced Id2 and Id3 mRNA were observed in the ventricular/subventricular zone, cingulum and corpus callosum. TNF alpha also increased Id2 mRNA expression in the caudate putamen and hippocampus at the injection site. Id2 and Id3 mRNA+ cells were identified as GFAP+ and S100 alpha + astrocytes as well as ED1+ microglia. This is the first report to show TNF-alpha-induced modulation of the Id gene family and suggests that Id may be involved in the formation of reactive astrocytes and activated microglia in the rodent brain. These results suggest a putative role for the Id family in the molecular mechanisms regulating cellular responsiveness to TNF alpha and CNS inflammation.

  19. Blockade of the tumor necrosis factor-related apoptosis inducing ligand death receptor DR5 prevents beta-amyloid neurotoxicity.

    PubMed

    Uberti, Daniela; Ferrari-Toninelli, Giulia; Bonini, Sara Anna; Sarnico, Ilenia; Benarese, Marina; Pizzi, Marina; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Spano, PierFranco; Facchetti, Fabio; Memo, Maurizio

    2007-04-01

    We originally suggested that inhibition of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) death pathway could be taken into consideration as a potential therapeutic strategy for Alzheimer's disease (AD). However, because the critical role of TRAIL in immune surveillance, the neutralization of TRAIL protein by an antibody to prevent its binding to death receptors is definitely a risky approach. Here, we demonstrated that the blockade of the TRAIL death receptor DR5 with a specific antibody completely prevented amyloid beta peptide (A beta) neurotoxicity in both neuronal cell line and primary cortical neurons. DR5 was demonstrated to be a key factor in TRAIL death pathway. In fact, whereas TRAIL expression was enhanced dose-dependently by concentrations of beta amyloid ranging from 10 nM to 1 microM, only the highest toxic dose of A beta (25 microM) induced the increased expression of DR5 and neuronal cell death. In addition, the increased expression of DR5 receptor after beta amyloid treatment was sustained by p53 transcriptional activity, as demonstrated by the data showing that the p53 inhibitor Pifithrin alpha prevented both beta amyloid-induced DR5 induction and cell death. These data suggest a sequential activation of p53 and DR5 upon beta amyloid exposure. Further insight into the key role of DR5 in AD was suggested by data showing a significant increase of DR5 receptor in cortical slices of AD brain. Thus, these findings may give intracellular TRAIL pathway a role in AD pathophysiology, making DR5 receptor a possible candidate as a pharmacological target.

  20. Increased Tumor Necrosis Factor (TNF)-α and Its Promoter Polymorphisms Correlate with Disease Progression and Higher Susceptibility towards Vitiligo

    PubMed Central

    Laddha, Naresh C.; Dwivedi, Mitesh; Begum, Rasheedunnisa

    2012-01-01

    Abstract Tumor Necrosis Factor (TNF)-α, is a paracrine inhibitor of melanocytes, which plays a critical role in the pathogenesis of several autoimmune diseases including vitiligo, as abnormal immune responses have frequently been observed in vitiligo patients. Moreover, vitiligo patients show higher lesion levels of TNF-α. Genetic polymorphisms in the promoter region of TNF-α are involved in the regulation of its expression. The present study explores TNF-α promoter polymorphisms and correlates them with TNF-α transcript and protein levels in vitiligo patients and controls of Gujarat along with its effect on disease onset and progression. PCR-RFLP technique was used for genotyping of these polymorphisms in 977 vitiligo patients and 990 controls. TNF-α transcript and protein levels were measured by Real time PCR and ELISA respectively. The genotype and allele frequencies for the investigated polymorphisms were significantly associated with vitiligo patients. The study revealed significant increase in TNF-α transcript and protein levels in vitiligo patients compared to controls. In particular, haplotypes: AATCC, AACCT, AGTCT, GATCT, GATCC and AGCCT were found to increase the TNF-α levels in vitiligo patients. Analysis of TNF-α levels based on the gender and disease progression suggests that female patients and patients with active vitiligo had higher levels of TNF-α. Also, the TNF-α levels were high in patients with generalized vitiligo as compared to localized vitiligo. Age of onset analysis of the disease suggests that the haplotypes: AACAT, AACCT, AATCC and AATCT had a profound effect in the early onset of the disease. Moreover, the analysis suggests that female patients had an early onset of vitiligo. Overall, our results suggest that TNF-α promoter polymorphisms may be genetic risk factors for susceptibility and progression of the disease. The up-regulation of TNF-α transcript and protein levels in individuals with susceptible haplotypes advocates

  1. Differences and Similarities in TRAIL- and Tumor Necrosis Factor-Mediated Necroptotic Signaling in Cancer Cells

    PubMed Central

    Philipp, Stephan; Fuchslocher Chico, Johaiber; Saggau, Carina; Fritsch, Jürgen; Föll, Alexandra; Plenge, Johannes; Arenz, Christoph; Pinkert, Thomas; Kalthoff, Holger; Trauzold, Anna; Schmitz, Ingo; Schütze, Stefan; Adam, Dieter

    2016-01-01

    Recently, a type of regulated necrosis (RN) called necroptosis was identified to be involved in many pathophysiological processes and emerged as an alternative method to eliminate cancer cells. However, only a few studies have elucidated components of TRAIL-mediated necroptosis useful for anticancer therapy. Therefore, we have compared this type of cell death to tumor necrosis factor (TNF)-mediated necroptosis and found similar signaling through acid and neutral sphingomyelinases, the mitochondrial serine protease HtrA2/Omi, Atg5, and vacuolar H+-ATPase. Notably, executive mechanisms of both TRAIL- and TNF-mediated necroptosis are independent of poly(ADP-ribose) polymerase 1 (PARP-1), and depletion of p38α increases the levels of both types of cell death. Moreover, we found differences in signaling between TNF- and TRAIL-mediated necroptosis, e.g., a lack of involvement of ubiquitin carboxyl hydrolase L1 (UCH-L1) and Atg16L1 in executive mechanisms of TRAIL-mediated necroptosis. Furthermore, we discovered indications of an altered involvement of mitochondrial components, since overexpression of the mitochondrial protein Bcl-2 protected Jurkat cells from TRAIL- and TNF-mediated necroptosis, and overexpression of Bcl-XL diminished only TRAIL-induced necroptosis in Colo357 cells. Furthermore, TRAIL does not require receptor internalization and endosome-lysosome acidification to mediate necroptosis. Taken together, pathways described for TRAIL-mediated necroptosis and differences from those for TNF-mediated necroptosis might be unique targets to increase or modify necroptotic signaling and eliminate tumor cells more specifically in future anticancer approaches. PMID:27528614

  2. 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.

  3. Genetic markers of tumour necrosis factor alpha in aggressive and chronic periodontitis.

    PubMed

    Schulz, Susanne; Machulla, Helmut K G; Altermann, Wolfgang; Klapproth, Jana; Zimmermann, Uta; Gläser, Christiane; Kluttig, Alexander; Stein, Jamal; Schaller, Hans-Günter; Reichert, Stefan

    2008-06-01

    Tumour necrosis factor alpha (TNFalpha) plays an important role in the pathogenesis of periodontitis. TNFalpha production is influenced by gene polymorphisms. The aim of this study was to evaluate links between genetic variants and chronic/aggressive periodontitis in a multivariate model. One hundred and twenty-three periodontitis patients (chronic: n=54, aggressive: n=69) and 52 healthy controls without periodontitis were included in the study. Single nucleotide polymorphisms (SNPs) c.-308G>A, c.-238G>A and haplotypes were analysed by a polymerase chain reaction with sequence-specific primers (PCR-SSP). The clinical investigation included smoking status, plaque and bleeding indexes, pocket depth and attachment loss. Prevotella intermedia occurred more frequently in individuals positive for the -308GG/-238GG haplotype combination (Odds Ratio=2, 95% Confidence interval: 1.1-3.7, p=0.037, 1-beta=61%). In binary logistic regression analyses, this TNFalpha haplotype could not be shown to be associated with periodontitis considering smoking, age, gender and approximal plaque index or subgingival bacterial colonization as confounding factors. Although the genetic background of TNFalpha could be shown to be associated with subgingival colonization with P. Intermedia, there is no evidence that it is an independent risk factor for periodontitis in multivariate models.

  4. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Prognostic significance of ligands belonging to tumour necrosis factor superfamily in acute lymphoblastic leukaemia.

    PubMed

    Bolkun, L; Lemancewicz, D; Jablonska, E; Szumowska, A; Bolkun-Skornicka, U; Moniuszko, M; Dzieciol, J; Kloczko, J

    2015-03-01

    Altered activities of ligands belonging to tumour necrosis factor (TNF) superfamily, namely B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL) and apoptosis inducing ligand (TRAIL) were demonstrated in several haematological diseases including acute lymphoblastic leukaemia (ALL). BAFF, APRIL and TRAIL provide crucial survival signals to immature, naive and activated B cells. These ligands are capable of activating a broad spectrum of intracellular signalling cascades that can either induce apoptosis or protect from programmed cell death. BAFF and APRIL, which can directly activate the NF-κB pathway, have been identified as crucial survival factors for ALL cells. Here, we have analyzed serum BAFF, APRIL and TRAIL concentrations in 48 patients with newly diagnosed ALL and 44 healthy volunteers. The levels of APRIL and BAFF were significantly higher in ALL patients as compared to healthy volunteers. In contrast, concentrations of TRAIL were significantly lower in ALL patients. Moreover, following induction, the levels of APRIL, but not BAFF or TRAIL, were significantly lower in a group of patients with complete remission (CR) as compared to non-respondent (NR) ALL patients. Furthermore, we demonstrated statistically significant differences in concentrations of APRIL between CR MRD-negative and CR, MRD-positive ALL patients. Notably detection of higher concentrations of APRIL was associated with shorter leukaemia-free survival and overall survival. Altogether, our data indicate that APRIL can play an important role in the pathogenesis of ALL and the measurement of APRIL levels can improve prognostication in ALL patients.

  6. Activated microglia provide a neuroprotective role by balancing glial cell-line derived neurotrophic factor and tumor necrosis factor-α secretion after subacute cerebral ischemia.

    PubMed

    Wang, Jianping; Yang, Zhitang; Liu, Cong; Zhao, Yuanzheng; Chen, Yibing

    2013-01-01

    Microglia are the major immune cells in the central nervous system and play a key role in brain injury pathology. However, the role of activated microglia after subacute cerebral ischemia (SCI) remains unknown. To address this issue, we established a permanent middle cerebral artery occlusion (pMCAO) rat model and treated pMCAO rats with N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide (PJ34) (an inhibitor of microglial activation), or with vehicle alone. Finally, we determined the differences between the PJ34-and vehicle-treated rats with respect to neurological deficits, infarct volume, neuronal loss and the expression of CD11b (a marker of microglial activation), glial cell line-derived neurotrophic factor (GDNF) and tumor necrosis factor-α (TNF-α) at 1, 3 and 7 days after treatment. We found that the PJ34-treated rats had more severe neurological deficits and a larger infarct volume and exhibited a decreased CD11b expression, more neuronal loss, decreased expression of GDNF mRNA and protein but increased expression of TNF-α mRNA and protein compared with the vehicle-treated rats at 3 and 7 days after treatment. These results indicate that activated microglia provide a neuroprotective role through balancing GDNF and TNF-α expression following SCI.

  7. Chrysin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells via suppression of nuclear factor-kappaB.

    PubMed

    Li, Xin; Huang, Qing; Ong, Choon-Nam; Yang, Xing-Fen; Shen, Han-Ming

    2010-07-01

    Chrysin (5,7-dihydroxyflavone) is a natural flavonoid commonly found in many plants. The anti-cancer property of chrysin has been demonstrated although the molecular mechanisms remain to be further elucidated. In the present study, we found that, pretreatment with chrysin greatly sensitized various human cancer cells to tumor necrosis factor-alpha (TNFalpha)-induced apoptosis. In the search of the molecular mechanisms responsible for the sensitization effect of chrysin, we discovered that such sensitization is closely associated with the inhibitory effect of chrysin on TNFalpha-mediated nuclear transcription factor-kappaB (NF-kappaB) activation. Pretreatment with chrysin inhibited TNFalpha-induced degradation of Inhibitor of kappaB (IkappaB) protein and subsequent nuclear translocation of p65. As a result, chrysin suppressed the expression of NF-kappaB-targeted anti-apoptotic gene, c-FLIP-L. The role of c-FLIP-L was further confirmed by its ectopic expression, which significantly protected cell death induced by combined treatment with chrysin and TNFalpha. Data from this study thus reveal a novel function of chrysin and enhance the value of chrysin as an anti-cancer agent.

  8. Water extract isolated from Chelidonium majus enhances nitric oxide and tumour necrosis factor-alpha production via nuclear factor-kappaB activation in mouse peritoneal macrophages.

    PubMed

    Chung, Hwan-Suck; An, Hyo-Jin; Jeong, Hyun-Ja; Won, Jin-Hee; Hong, Seung-Heon; Kim, Hyung-Min

    2004-01-01

    Chelidonium majus is used to treat several inflammatory diseases and tumours. We have examined the effect of C. majus on nitric oxide (NO) production using mouse peritoneal macrophages. When C. majus was used in combination with recombinant interferon-gamma (rIFN-gamma, 10 U mL(-1)), there was a marked cooperative induction of NO production. Treatment of rIFN-gamma plus C. majus (1 mgmL(-1)) in macrophages caused a significant increase in tumour necrosis factor-alpha (TNF-alpha) production. The increased production of NO and TNF-alpha from rIFN-gamma plus C. majus-stimulated cells was almost completely inhibited by nuclear factor-kappaB (NF-kappaB) inhibitor, pyrrolidine dithiocarbamate (100 microM). These findings demonstrated that C. majus increased the production of NO and TNF-alpha by rIFN-gamma-primed macrophages and suggested that NF-kappaB played a critical role in mediating the effects of C. majus.

  9. Histoplasmosis in Patients With Cell-Mediated Immunodeficiency: Human Immunodeficiency Virus Infection, Organ Transplantation, and Tumor Necrosis Factor-α Inhibition.

    PubMed

    Luckett, Keith; Dummer, J Stephen; Miller, Geraldine; Hester, Sydney; Thomas, Lora

    2015-01-01

    Background.  Histoplasmosis causes severe disease in patients with defects of cell-mediated immunity. It is not known whether outcomes vary related to the type of immunodeficiency or class of antifungal treatment. Methods.  We reviewed cases of active histoplasmosis that occurred at Vanderbilt University Medical Center from July 1999 to June 2012 in patients with human immunodeficiency virus (HIV) infection, a history of transplantation, or tumor necrosis factor (TNF)-α inhibitor use. These groups were compared for differences in clinical presentation and outcomes. In addition, outcomes were related to the initial choice of treatment. Results.  Ninety cases were identified (56 HIV, 23 transplant, 11 TNF-α inhibitor). Tumor necrosis factor-α patients had milder disease, shorter courses of therapy, and fewer relapses than HIV patients. Histoplasma antigenuria was highly prevalent in all groups (HIV 88%, transplant 95%, TNF-α 91%). Organ transplant recipients received amphotericin B formulation as initial therapy less often than other groups (22% vs 57% HIV vs 55% TNF-α; P = .006). Treatment failures only occurred in patients with severe disease. The failure rate was similar whether patients received initial amphotericin or triazole therapy. Ninety-day histoplasmosis-related mortality was 9% for all groups and did not vary significantly with choice of initial treatment. Conclusions.  Histoplasmosis caused milder disease in patients receiving TNF-α inhibitors than patients with HIV or solid organ transplantation. Treatment failures and mortality only occurred in patients with severe disease and did not vary based on type of immunosuppression or choice of initial therapy.

  10. Factors responsible for the development of avascular necrosis secondary to the treatment of congenital dislocation of the hip.

    PubMed

    Burgos-Flores, J; Ocete-Guzman, G; Gonzalez-Herranz, P; Hevia-Sierra, E; Amaya-Alarcon, S

    1993-11-01

    We present 104 cases of unilateral congenital dislocation of the hip treated with the same regime between 1977 and 1988. The patients had an average age of 12 months (range 4-24). The average age at follow-up was 6 years (range 3-13). The incidence of avascular necrosis was 37%. Avascular necrosis presented most frequently in babies of 7 months at the start of treatment, in Tonnis type IV when an adductor tenotomy was not performed, and after open reductions. The most influential factor was the absence of the femoral head descent at the end of the period of traction. The "effective" prereduction traction and the performance of an adductor tenotomy when necessary were the principle factors in avoiding avascular necrosis.

  11. Astrocyte Mitogen Inhibitor Related to Epidermal Growth Factor Receptor

    NASA Astrophysics Data System (ADS)

    Nieto-Sampedro, Manuel

    1988-06-01

    Epidermal growth factor (EGF) is a well-characterized polypeptide hormone with diverse biological activities, including stimulation of astrocyte division. A soluble astrocyte mitogen inhibitor, immunologically related to the EGF receptor, is present in rat brain. Injury to the brain causes a time-dependent reduction in the levels of this inhibitor and the concomitant appearance of EGF receptor on the astrocyte surface. Intracerebral injection of antibody capable of binding the inhibitor caused the appearance of numerous reactive astrocytes. EGF receptor-related inhibitors may play a key role in the control of glial cell division in both normal and injured brain.

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

    PubMed

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

    2012-04-01

    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. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

  13. Effect of homologous interleukin-1, interleukin-6 and tumor necrosis factor-alpha on the core body temperature of mice.

    PubMed

    Wang, J; Ando, T; Dunn, A J

    1997-01-01

    Lipopolysaccharide (LPS) and homologous cytokines were tested for their effect on core temperature in mice using battery-operated telemetric devices placed in the peritoneal cavity. One microgram LPS injected intraperitoneally (i.p.) induced a biphasic effect on core body temperature (Tc), a rapid decrease in Tc with a peak around 30-45 min followed by a prolonged rise around 150-300 min. When a higher dose of LPS (5 microg) was used, the hypothermia was increased in magnitude and lasted much longer, and no fever was observed. Both the decrease and the increase in Tc caused by LPS were prevented by pretreating the mice with indomethacin, a cyclooxygenase inhibitor, but not by a nitric oxide synthase inhibitor. Mouse interleukin-1beta (mIL-1beta, 100 ng, i.p.) induced changes resembling those to LPS, a short-lived decrease in Tc, followed by a small increase. When 1 microg mIL-1beta was injected a profound hypothermia lasting more than 3 h was observed. Mouse IL-6 (1 microg) failed to alter core temperature after either intravenous (i.v.) or i.p. administration. Human IL-6 was also ineffective. Recombinant mouse tumor necrosis factor-alpha (mTNFalpha) also failed to alter the core temperature of mice when injected at a dose of 1 microg (i.p. or i.v.). However, a higher dose of mTNFalpha (5 microg i.p.) caused a short-lived decrease in Tc, followed by a small increase. Similar results were obtained with LPS and the cytokines in C57Bl/6J mice, except that mIL-1beta was ineffective in this strain. These results indicate that the endocrine, neurochemical and behavioral responses to IL-1, IL-6 and TNFalpha administration cannot be explained by changes in Tc, although they may contribute to them. They also suggest that IL-1beta may account for the fever observed following LPS, but that these cytokines are probably not the only factors involved in LPS-induced changes in Tc.

  14. Human Tumour Necrosis Factor: Physiological and Pathological Roles in Placenta and Endometrium

    PubMed Central

    Haider, S.; Knöfler, M.

    2010-01-01

    The cytokine tumour necrosis factor α (TNF) is a well known member of the TNF superfamily consisting of at least 18 ligands and 29 different receptors involved in numerous cellular processes. TNF signals through two distinct receptors TNFR1 and TNFR2 thereby controlling expression of cytokines, immune receptors, proteases, growth factors and cell cycle genes which in turn regulate inflammation, survival, apoptosis, cell migration, proliferation and differentiation. Since expression of TNF was discovered in amnion and placenta many studies demonstrated the presence of the cytokine and its receptors in the diverse human reproductive tissues. Whereas TNF has been implicated in ovulation, corpus luteum formation and luteolysis, this review focuses on the functions of TNF in human placental, endometrial and decidual cell types of normal tissues and also discusses its role in endometrial and gestational diseases. Physiological levels of the cytokine could be important for balancing cell fusion and apoptotic shedding of villous trophoblasts and to limit trophoblast invasion into maternal decidua. Regulation of the TNF/TNFR system by steroid hormones also suggests a role in uterine function including menstrual cycle-dependent destruction and regeneration of endometrial tissue. Aberrant levels of TNF, however, are associated with diverse reproductive diseases such as amniotic infections, recurrent spontaneous abortions, preeclampsia, preterm labour or endometriosis. Hence, concentrations, receptor distribution and length of stimulation determine whether TNF has beneficial or adverse effects on female reproduction and pregnancy. PMID:19027157

  15. Inhibition of human erythroid colony-forming units by tumor necrosis factor requires beta interferon.

    PubMed Central

    Means, R T; Krantz, S B

    1993-01-01

    We have previously reported that inhibition of human CFU-erythroid (E) colony formation by tumor necrosis factor (TNF) is an indirect effect mediated by a soluble factor released from a fraction of marrow accessory cells which are predominantly stromal elements (Means, R. T., Jr., E. N. Dessypris, and S. B. Krantz. 1990. J. Clin. Invest. 86:538-541). Further studies reported here identify a mediator of this effect. The inhibitory effect of recombinant TNF on marrow CFU-E is ablated by neutralizing antibodies to human beta IFN, but not by antibodies to gamma IFN or IL-1. Anti-beta IFN also neutralizes the inhibitory effect of conditioned medium prepared from marrow cells exposed to TNF. Human beta IFN inhibits colony formation by unpurified marrow CFU-E as well as highly purified CFU-E generated from peripheral blood progenitors, and limiting dilution analysis shows that this is a direct inhibitory effect. TNF has been implicated in the pathogenesis of the anemia of chronic diseases since blood TNF levels are elevated in many patients with this syndrome, and since exposure to TNF produces a similar anemia in either humans or mice. The present study demonstrates that beta IFN is a required mediator of this inhibitory effect on erythropoiesis. PMID:8432849

  16. Tumour-necrosis factor from the rabbit. I. Mode of action, specificity and physicochemical properties.

    PubMed

    Matthews, N; Watkins, J F

    1978-08-01

    Sera from rabbits injected with BCG and then with endotoxin contain a factor (tumour-necrosis factor TNF) which, even at high dilutions, is cytotoxic in vitro for mouse L cells and some other cell lines. Using a 51Cr-release assay, cytotoxicity was detected as early as 7-8 h after addition of TNF serum to L cells and cell death was evident microscopically by 24 h. TNF was cytotoxic at 37 degrees C but not at 21 degrees C or 4 degrees C, and acted on both dividing and non-dividing cells. The antimetabolites sodium azide and dinitrophenol partially protected L cells from TNF, suggesting that actively metabolizing cells are the most sensitive. Treatment of L cells with trypsin did not delay cytotoxicity nor was cytotoxicity inhibited in the presence of various saccharide derivatives of cell-surface glycoproteins. Rabbit TNF was remarkably stable with a mol. wt. of 40-50,000. It was eluted with the more acidic serum proteins on ion-exchange chromatography, but precipitated in 50%-saturated ammonium sulphate. Sensitivity to TNF could not be correlated with tumourigenicity of several animal and human lines tested nor with the production of C-type viruses.

  17. 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

  18. Tumor necrosis factor gene polymorphisms in patients with cirrhosis from chronic hepatitis C virus infection.

    PubMed

    Yee, L J; Tang, J; Herrera, J; Kaslow, R A; van Leeuwen, D J

    2000-08-01

    Pro-inflammatory cytokines including tumour necrosis factor (TNF) mediate the pathogenesis of hepatitis C virus (HCV) infection. The distribution of TNF gene polymorphisms was examined among cirrhotic and non-cirrhotic patients infected with HCV. Thirty Caucasians with cirrhosis due to chronic HCV infection and 114 HCV-infected patients histopathologically free of cirrhosis were genotyped for genetic variants in TNF, lymphotoxin alpha and TNF-receptor type I using PCR-based techniques. Variability in the progression of HCV-related cirrhosis was assessed in a multivariate model including genetic and non-genetic factors such as gender, estimated duration of infection, alcohol consumption, and viral genotype. Viral genotype and non-genetic host features were not independently related to the occurrence or rate of development of cirrhosis in the patient population. In contrast, the TNF promoter variants TNF2 (-238A) and TNF3 (-308A) conferred a 3.2-fold and 5.1-fold risk of cirrhosis respectively (P = 0.03 for both). Reciprocal effects were observed with several TNF alleles and haplotypes defined by the -238G/A and -308G/A dimorphic sequences. Polymorphisms in the TNF alpha promoter appear to be associated with variability in the histological severity of chronic hepatitis C infection.

  19. PPARγ regulates the mitochondrial dysfunction in human neural stem cells with tumor necrosis factor alpha.

    PubMed

    Chiang, M-C; Cheng, Y-C; Lin, K-H; Yen, C-H

    2013-01-15

    Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated transcription factors, and its ligands are known to control many physiological and pathological conditions. The hypothesis of our study was that the PPARγ agonist (rosiglitazone) could mediate tumor necrosis factor alpha (TNFα) related to the regulation of human neural stem cells (hNSCs), by which TNFα possibly fulfills important roles in neuronal impairment. The results show that PPARγ mediates the cell viability of hNSCs via the downregulation of the activity of caspase 3, indicating that this rescue effect of PPARγ could improve the reduced levels of two mitochondrial regulators, adenosine monophosphate-activated protein kinase (AMPK) and Sirtuin 1 (SIRT1) in the hNSCs with TNFα. The stimulation of mitochondrial function by PPARγ was associated with activation of the PPAR coactivator1 alpha (PGC1α) pathway by up-regulation of oxidative defense and mitochondrial systems. The above protective effects appeared to be exerted by a direct activation of the rosiglitazone, because it protected hNSCs from TNFα-evoked oxidative stress and mitochondrial deficiency. Here we show that the rosiglitazone protects hNSCs against Aβ-induced apoptosis and promotes cell survival. These findings extend our understanding of the central role of PPARγ in TNFα-related neuronal impairment, which probably increases risks of neurodegenerative diseases. The anti-inflammatory effects of PPARγ in the hNSCs with TNFα, and the involved mechanisms were also characterized.

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

    PubMed Central

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

    2015-01-01

    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

  1. Involvement of tumor necrosis factor-alpha in the pathogenesis of autoimmune orchitis in rats.

    PubMed

    Suescun, María O; Rival, Claudia; Theas, María S; Calandra, Ricardo S; Lustig, Livia

    2003-06-01

    We studied the testicular macrophages of rats with experimental autoimmune orchitis (EAO) and analyzed whether the tumor necrosis factor-alpha (TNFalpha) is involved in germ cell apoptosis and in Leydig cell steroidogenesis. The EAO was induced in adult male Sprague-Dawley rats by active immunization with testicular homogenate and adjuvants. In the experimental group, a severe orchitis was observed 80 days after the first immunization. ED1- and ED2-positive macrophages were quantified by immunohistochemistry. The TNFalpha concentration of conditioned media from testicular macrophages (TMCM) was determined by ELISA. The number of apoptotic TNF receptor 1 (TNFR1)-positive germ cells was identified by combining in situ end labeling of apoptotic DNA and immunohistochemical techniques. The effect of TNFalpha on Leydig cell testosterone production was determined by RIA. In rats with EAO, we observed a significant increase in the number of TNFalpha-positive testicular macrophages, the TNFalpha concentration in TMCM, and the number of TNFR1-positive germ cells. Sixty percent of TNFR1-positive germ cells were apoptotic. These results suggest that TNFalpha could be involved in the pathogenesis of EAO. Acting together with other local factors such as Fas-FasL, TNFalpha could trigger germ cell apoptosis. We also demonstrated that TNFalpha inhibited in vitro testosterone production in basal and hCG-stimulated Leydig cells from rats with orchitis.

  2. Harnessing tumor necrosis factor receptors to enhance antitumor activities of drugs.

    PubMed

    Muntané, Jordi

    2011-10-17

    Cancer is the second-leading cause of death in the U.S. behind heart disease and over stroke. The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The inhibition of cell death pathways is one of these tumor characteristics which also include sustained proliferative signaling, evading growth suppressor signaling, replicative immortality, angiogenesis, and promotion of invasion and metastasis. Cell death is mediated through death receptor (DR) stimulation initiated by specific ligands that transmit signaling to the cell death machinery or through the participation of mitochondria. Cell death involving DR is mediated by the superfamily of tumor necrosis factor receptor (TNF-R) which includes TNF-R type I, CD95, DR3, TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 (TRAIL-R1) and -2 (TRAIL-R2), DR6, ectodysplasin A (EDA) receptor (EDAR), and the nerve growth factor (NGF) receptor (NGFR). The expression of these receptors in healthy and tumor cells induces treatment side effects that limit the systemic administration of cell death-inducing therapies. The present review is focused on the different therapeutic strategies such as targeted antibodies or small molecules addressed to selective stimulated DR-mediated apoptosis or reduce cell proliferation in cancer cells.

  3. 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

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

    2016-01-28

    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. Population based cohort study. Nationwide data from Sweden. 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. Hazard ratio of first in situ or invasive squamous cell skin cancer (1998-2012) and first basal cell cancer (2004-12). 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. 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. Vigilance regarding skin malignancies may be advisable in rheumatoid arthritis

  4. Comparative evaluation of HMG CoA reductase inhibitors in experimentally-induced myocardial necrosis: Biochemical, morphological and histological studies.

    PubMed

    Variya, Bhavesh C; Patel, Snehal S; Trivedi, Jinal I; Gandhi, Hardik P; Rathod, S P

    2015-10-05

    The present study was carried out to evaluate the protective effect of different statins on isoproterenol (ISO) induced myocardial necrosis. Atorvastatin, rosuvastatin, fluvastatin, simvastatin and pravastatin (10 mg/kg/day) were administered for 12 weeks. After pretreatment of 12 weeks myocardial necrosis was induced by subsequent injection of ISO (85 mg/kg/day, s.c.) to wistar rats. Serum biochemical parameters like glucose, lipid profile, cardiac markers and transaminases were evaluated. Animals were killed and heart was excised for histopathology and antioxidant study. Statins pretreated rats showed significant protection against ISO induced elevation in serum biochemical parameters and serum level of cardiac marker enzymes and transaminase level as compared to ISO control group. Mild to moderate protection was observed in different statins treated heart in histopathology and TTC stained sections. Result from our study also revealed that statins could efficiently protect against ISO intoxicated myocardial necrosis by impairing membrane bound enzyme integrity and endogenous antioxidant enzyme levels. Amongst all statins used, rosuvastatin and pravastatin were found to have maximum cardio-protective activity against ISO induced myocardial necrosis as compared to other statins. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. The proinflammatory cytokine tumor necrosis factor-α excites subfornical organ neurons.

    PubMed

    Simpson, Nick J; Ferguson, Alastair V

    2017-09-01

    Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine implicated in cardiovascular and autonomic regulation via actions in the central nervous system. TNF-α(-/-) mice do not develop angiotensin II (ANG II)-induced hypertension, and administration of TNF-α into the bloodstream of rats increases blood pressure and sympathetic tone. Recent studies have shown that lesion of the subfornical organ (SFO) attenuates the hypertensive and autonomic effects of TNF-α, while direct administration of TNF-α into the SFO increases blood pressure, suggesting the SFO to be a key site for the actions of TNF-α. Therefore, we used patch-clamp techniques to examine both acute and long-term effects of TNF-α on the excitability of Sprague-Dawley rat SFO neurons. It was observed that acute bath application of TNF-α depolarized SFO neurons and subsequently increased action potential firing rate. Furthermore, the magnitude of depolarization and the proportion of depolarized SFO neurons were concentration dependent. Interestingly, following 24-h incubation with TNF-α, the basal firing rate of the SFO neurons was increased and the rheobase was decreased, suggesting that TNF-α elevates SFO neuron excitability. This effect was likely mediated by the transient sodium current, as TNF-α increased the magnitude of the current and lowered its threshold of activation. In contrast, TNF-α did not appear to modulate either the delayed rectifier potassium current or the transient potassium current. These data suggest that acute and long-term TNF-α exposure elevates SFO neuron activity, providing a basis for TNF-α hypertensive and sympathetic effects.NEW & NOTEWORTHY Considerable recent evidence has suggested important links between inflammation and the pathological mechanisms underlying hypertension. The present study describes cellular mechanisms through which acute and long-term exposure of tumor necrosis factor-α (TNF-α) influences the activity of subfornical organ neurons by

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

    USDA-ARS?s Scientific Manuscript database

    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...

  7. Reliability of Tuberculosis Screening Test in Patients Receiving Tumor Necrosis Factor Antagonist Therapy in a United States Rheumatology Clinic

    DTIC Science & Technology

    2013-05-06

    necrosis factor (TNF) in United States military rheumatology clinic. Method: QTB-G blood testing became available 18 months after the study initiation and...Candida and/or Tetanus Patient with (+) TST and/or (+) QTB-G and those with CXR finding concerning for LTBI were referred to Infectious Disease for evaluation

  8. Platelet-activating factor, tumor necrosis factor, hypoxia and necrotizing enterocolitis.

    PubMed

    Hsueh, W; Caplan, M S; Sun, X; Tan, X; MacKendrick, W; Gonzalez-Crussi, F

    1994-01-01

    The pathogenesis of necrotizing enterocolitis (NEC) is poorly understood. We have established several animal models of NEC by using a combination of various stimuli and stress, including endotoxin, PAF, TNF, and hypoxia. We discuss the mechanism of their actions and the possible roles of these factors in the pathogenesis of human NEC.

  9. Comparative proteome analysis of Tumor necrosis factor α-stimulated human Vascular Smooth Muscle Cells in response to melittin

    PubMed Central

    2013-01-01

    Background Bee venom has been used to relieve pain and to treat inflammatory diseases, including rheumatoid arthritis, in humans. To better understand the mechanisms of the anti-inflammatory and anti-atherosclerosis effect of bee venom, gel electrophoresis and mass spectrometry were used to identify proteins whose expression was altered in human Vascular Smooth Muscle Cells (hVSMCs) stimulated by tumor necrosis factor alpha after 12 h in the presence of melittin. Results To obtain valuable insights into the anti-inflammatory and anti-atherosclerosis mechanisms of melittin, two-dimensional (2-D) gel electrophoresis and MALDI-TOF/TOF were used. The proteome study, we showed 33 significant proteins that were differentially expressed in the cells treated with tumor necrosis factor alpha and melittin. Thirteen proteins were significantly increased in the cells treated with tumor necrosis factor alpha, and those proteins were reduced in the cells treated with melittin. Five of the proteins that showed increased expression in the cells treated with tumor necrosis factor alpha are involved in cell migration, including calreticulin, an essential factor of development that plays a role in transcription regulation. The proteins involved in cell migration were reduced in the melittin treated cells. The observed changes in the expression of GRP75, prohibitin, and a select group of other proteins were validated with reverse transcribed-PCR. It was confirmed that the observed change in the protein levels reflected a change in the genes level. In addition, the phosphorylation of EGFR and ERK was validated by analyzing the protein pathway. Conclusion Taken together, these data established that the expression of some proteins was significantly changed by melittin treatment in tumor necrosis factor alpha stimulated the cells and provided insights into the mechanism of the melittin function for its potential use as an anti-inflammatory agent. PMID:23651618

  10. Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present.

    PubMed

    Li, Jianrong; Ramenaden, E Radhika; Peng, Jie; Koito, Hisami; Volpe, Joseph J; Rosenberg, Paul A

    2008-05-14

    Reactive microglia and astrocytes are present in lesions of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, it is not clear whether they are actively involved in the pathogenesis of these disorders. Previous studies demonstrated that microglia, but not astrocytes, are required for lipopolysaccharide (LPS)-induced selective killing of developing oligodendrocytes (preOLs) and that the toxicity is mediated by microglia-derived peroxynitrite. Here we report that, when astrocytes are present, the LPS-induced, microglia-dependent toxicity to preOLs is no longer mediated by peroxynitrite but instead by a mechanism dependent on tumor necrosis factor-alpha (TNFalpha) signaling. Blocking peroxynitrite formation with nitric oxide synthase (NOS) inhibitors or a decomposition catalyst did not prevent LPS-induced loss of preOLs in mixed glial cultures. PreOLs were highly vulnerable to peroxynitrite; however, the presence of astrocytes prevented the toxicity. Whereas LPS failed to kill preOLs in cocultures of microglia and preOLs deficient in inducible NOS (iNOS) or gp91(phox), the catalytic subunit of the superoxide-generating NADPH oxidase, LPS caused a similar degree of preOL death in mixed glial cultures of wild-type, iNOS-/-, and gp91(phox-/-) mice. TNFalpha neutralizing antibody inhibited LPS toxicity, and addition of TNFalpha induced selective preOL injury in mixed glial cultures. Furthermore, disrupting the genes encoding TNFalpha or its receptors TNFR1/2 completely abolished the deleterious effect of LPS. Our results reveal that TNFalpha signaling, rather than peroxynitrite, is essential in LPS-triggered preOL death in an environment containing all major glial cell types and underscore the importance of intercellular communication in determining the mechanism underlying inflammatory preOL death.

  11. In vivo regulation of replicative Legionella pneumophila lung infection by endogenous tumor necrosis factor alpha and nitric oxide.

    PubMed Central

    Brieland, J K; Remick, D G; Freeman, P T; Hurley, M C; Fantone, J C; Engleberg, N C

    1995-01-01

    The in vivo role of endogenous tumor necrosis factor alpha (TNF-alpha) and reactive nitrogen intermediates (RNIs) in modulation of growth of Legionella pneumophila in the lung was assessed using a murine model of replicative L. pneumophila lung infection. Intratracheal inoculation of mice with L. pneumophila resulted in induction of endogenous TNF-alpha, which preceded clearance of L. pneumophila from the lung. Inhibition of endogenous TNF-alpha activity, via in vivo administration of TNF-alpha neutralizing antibody, or inhibition of endogenous RNIs, via administration of the nitric oxide (NO) synthetase inhibitor N-monomethyl-L-arginine (NMMA), resulted in enhanced growth of L. pneumophila in the lung at > or = 3 days postinfection (when compared with untreated L. pneumophila-infected mice). Because of the similar kinetics of enhanced pulmonary growth of L. pneumophila in mice treated in vivo with either anti-TNF-alpha antibody or NMMA, the immunomodulatory effect of NO on endogenous TNF-alpha activity in the lung was assessed. Administration of NMMA to L. pneumophila-infected mice resulted in a significant decrease in endogenous TNF-alpha activity in the lung during replicative L. pneumophila infections in vivo. However, administration of exogenous TNF-alpha to NMMA-treated mice failed to significantly enhance clearance of L. pneumophila from the lung. Results of these studies indicate that both endogenous NO and TNF-alpha facilitate resolution of replicative L. pneumophila lung infections and that regulation of L. pneumophila replication by TNF-alpha is mediated, at least in part, by NO. PMID:7642253

  12. Freshwater clam extract supplementation improves wound healing by decreasing the tumor necrosis factor α level in blood.

    PubMed

    Peng, Yi-Chi; Fwu-LinYang; Subeq, Yi-Maun; Tien, Chin-Chieh; Lee, Ru-Ping

    2017-03-01

    The freshwater clam (Corbicula fluminea) is a widely consumed functional food in Asia and is traditionally used to improve health and either prevent or treat inflammation-related diseases. Numerous studies have proposed that freshwater clams act to prevent and attenuate inflammatory responses, and also serve as a possible inhibitor to systemic inflammation. However, there is limited information available about the effects of freshwater clams on wound healing. The present study investigated the influence of freshwater clam extract (FCE) on wound healing and inflammatory responses in a cutaneous incision model. Sixteen rats were used and divided into two groups: the FCE group and the normal saline (NS) group. The rats underwent dorsal full-thickness skin excisional wounds (diameter 20 × 10 mm). FCE or NS was administered for oral feeding twice daily for 14 days after wounding. Blood samples were taken and analyzed, and wound areas were measured at several time points during the 2 weeks after excision. On day 14 after wounding, skin biopsies from the wound sites were sent for histological examination. Treatment with FCE (71.63 ± 9.51 pg mL(-1) ) decreased tumor necrosis factor-α levels compared to the NS group (109.86 ± 12.55 pg mL(-1) ) after wounding at 3 h (P < 0.05). There were no significant differences in the levels of white blood cells, interleukin (IL)-6, or IL-10. The wound areas of the NS group (23.9%) were larger than those in the FCE group (8.26%) on day 14 (P < 0.05). Numerous fibroblasts and collagen fiber organization were observed in the FCE group. FCE supplementation improves the wound healing process. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

  13. Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response.

    PubMed

    Powell, Timothy R; Schalkwyk, Leonard C; Heffernan, Andrew L; Breen, Gerome; Lawrence, Timothy; Price, Tom; Farmer, Anne E; Aitchison, Katherine J; Craig, Ian W; Danese, Andrea; Lewis, Cathryn; McGuffin, Peter; Uher, Rudolf; Tansey, Katherine E; D'Souza, Ursula M

    2013-09-01

    Converging evidence suggests that the activation of the inflammatory cytokine pathway is important in the pathophysiology of unipolar depression. Antidepressants have anti-inflammatory properties and evidence suggests that inter-individual variability in response to antidepressants may reflect genetic differences in the inflammatory cytokine pathway. In particular, protein levels of Tumor Necrosis Factor (TNF) and the SNPs rs1126757 in interleukin-11 (IL11), and rs7801617 in interleukin-6 (IL6), have previously been implicated in the clinical response to the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram. This study investigated the transcription of TNF, IL11 and IL6 as well as genes in the wider inflammatory cytokine pathway both at baseline and after escitalopram treatment in depressed patients who were either clinical "responders" (n=25) or "non-responders" (n=21). Samples were obtained as a subset of the Genome-Based Therapeutic Drugs for Depression (GENDEP) project and response status is based on changes in the Montgomery-Asberg Depression Rating Scores over a 12 wk treatment period. Binary logistic regressions revealed significant expression differences at baseline between responders and non-responders in TNF, and after escitalopram treatment in TNF and IL11. Differences in IL11 after treatment were found to be driven by drug-induced allele-specific expression differences relating to rs1126757. Top hits in the wider inflammatory cytokine pathway at both baseline and after escitalopram treatment were found to be targets of TNF. The current study adds substantial support for the role of the inflammatory cytokine pathway in mediating response to the SSRI escitalopram, and is the first to identify TNF and its targets as putative transcriptomic predictors of clinical response.

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

    PubMed

    Pires, Paulo W; Girgla, Saavia S; Moreno, Guillermo; McClain, Jonathon L; Dorrance, Anne M

    2014-09-01

    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.

  15. Transmembrane tumor necrosis factor is a potent inducer of colitis even in the absence of its secreted form.

    PubMed

    Corazza, Nadia; Brunner, Thomas; Buri, Caroline; Rihs, Silvia; Imboden, Martin A; Seibold, Inge; Mueller, Christoph

    2004-09-01

    Tumor necrosis factor (TNF) is cleaved proteolytically from a 26-kilodalton transmembrane precursor protein into secreted 17-kilodalton monomers. Transmembrane (tm) and secreted trimeric TNF are biologically active and may mediate distinct activities. We assessed the consequences of a complete inhibition of TNF processing on the course of colitis in recombination activating gene (RAG)2 -/- mice on transfer of CD4 CD45RB hi T cells. TNF -/- mice, transgenic for a noncleavable mutant TNF gene, were used as donors of CD4 T cells, and, on a RAG2 -/- background, also as recipients. Kinetics of disease development were compared in the absence of TNF, in the absence of secreted TNF, and in the presence of secreted and tmTNF. The analysis at the end of the observation period included the histopathologic assessment of the intestine and the localization of TNF and interferon gamma (IFNgamma)-expressing cells. The complete prevention of TNF secretion in tmTNF transgenic RAG2 -/- mice neither prevented nor delayed disease induction by transferred transgenic for a noncleavable transmembrane mutant of mouse TNF (tmTNF tg) CD4 CD45RB hi T cells. tmTNF expression by transferred CD4 T cells, however, was not required for disease induction because severe colitis and weight loss also were observed in tmTNF RAG2 -/- recipients of TNF -/- CD4 CD45RB hi T cells. In the presence of tmTNF, the absence of secreted TNF did not affect frequency and distribution of TNF and interferon-gamma messenger RNA (mRNA)-expressing cells. These results indicate that specific inhibitors of TNF processing are not appropriate for modulating the pro-inflammatory and disease-inducing effects of TNF in chronic inflammatory disorders of the intestine.

  16. Halocynthiaxanthin and peridinin sensitize colon cancer cell lines to tumor necrosis factor-related apoptosis-inducing ligand.

    PubMed

    Yoshida, Tatsushi; Maoka, Takashi; Das, Swadesh K; Kanazawa, Kazuki; Horinaka, Mano; Wakada, Miki; Satomi, Yoshiko; Nishino, Hoyoku; Sakai, Toshiyuki

    2007-06-01

    Carotenoids are compounds contained in foods and possess anticarcinogenic activity. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapeutics due to its ability to induce apoptosis selectively in cancer cells. However, some tumors remain tolerant to TRAIL-induced apoptosis. Therefore, it is important to develop agents that overcome this resistance. We show, for the first time, that certain carotenoids sensitize cancer cells to TRAIL-induced apoptosis. Combined treatment with halocynthiaxanthin, a dietary carotenoid contained in oysters and sea squirts, and TRAIL drastically induced apoptosis in colon cancer DLD-1 cells, whereas each agent alone only slightly induced apoptosis. The combination induced nuclear condensation and poly(ADP-ribose) polymerase cleavage, which are major features of apoptosis. Various caspase inhibitors could attenuate the apoptosis induced by this combination. Furthermore, the dominant-negative form of a TRAIL receptor could block the apoptosis, suggesting that halocynthiaxanthin specifically facilitated the TRAIL signaling pathway. To examine the molecular mechanism of the synergistic effect of the combined treatment, we did an RNase protection assay. Halocynthiaxanthin markedly up-regulated a TRAIL receptor, death receptor 5 (DR5), among the death receptor-related genes, suggesting a possible mechanism for the combined effects. Moreover, we examined whether other carotenoids also possess the same effects. Peridinin, but not alloxanthin, diadinochrome, and pyrrhoxanthin, induced DR5 expression and sensitized DLD-1 cells to TRAIL-induced apoptosis. These results indicate that the combination of certain carotenoids and TRAIL is a new strategy to overcome TRAIL resistance in cancer cells.

  17. Inhibition of Inflammation Mediated Through the Tumor Necrosis Factor α Biochemical Pathway Can Lead to Favorable Outcomes in Alzheimer Disease

    PubMed Central

    Shamim, Daniah; Laskowski, Michael

    2017-01-01

    Tumor necrosis factor α (TNF-α) inhibitors have long been used as disease-modifying agents in immune disorders. Recently, research has shown a role of chronic neuroinflammation in the pathophysiology of neurodegenerative diseases such as Alzheimer disease, and interest has been generated in the use of anti-TNF agents and TNF-modulating agents for prevention and treatment. This article extensively reviewed literature on animal studies testing these agents. The results showed a role for direct and indirect TNF-α inhibition through agents such as thalidomide, 3,6-dithiothalidomide, etanercept, infliximab, exendin-4, sodium hydrosulfide, minocycline, imipramine, and atorvastatin. Studies were performed on mice, rats, and monkeys, with induction of neurodegenerative physiology either through the use of chemical agents or through the use of transgenic animals. Most of these agents showed an improvement in cognitive function as tested with the Morris water maze, and immunohistochemical and histopathological staining studies consistently showed better outcomes with these agents. Brains of treated animals showed significant reduction in pro-inflammatory TNF-α and reduced the burden of neurofibrillary tangles, amyloid precursor protein, and β-amyloid plaques. Also, recruitment of microglial cells in the central nervous system was significantly reduced through these drugs. These studies provide a clearer mechanistic understanding of the role of TNF-α modulation in Alzheimer disease. All studies in this review explored the use of these drugs as prophylactic agents to prevent Alzheimer disease through immune modulation of the TNF inflammatory pathway, and their success highlights the need for further research of these drugs as therapeutic agents. PMID:28811745

  18. Protein kinase Cmu downregulation of tumor-necrosis-factor-induced apoptosis correlates with enhanced expression of nuclear-factor-kappaB-dependent protective genes.

    PubMed

    Johannes, F J; Horn, J; Link, G; Haas, E; Siemienski, K; Wajant, H; Pfizenmaier, K

    1998-10-01

    Protein kinase Cmu (PKCmu) represents a new subtype of the PKC family characterized by the presence of a pleckstrin homology (PH) domain and an amino-terminal hydrophobic region. In order to analyse the potential role of PKCmu in signal-transduction pathways, stable PKCmu transfectants were established with human and murine cell lines. All transfectants showed a reduced sensitivity to tumor-necrosis-factor (TNF)-induced apoptosis, which correlated with the amount of transgene expressed and with an enhanced basal transcription rate of NF-kappaB-driven genes including the inhibitor of apoptosis protein 2 (cIAP2) and TNF-receptor-associated protein 1 (TRAF1). Sensitivity to apoptosis induced by the lipid mediator ceramide was unchanged in PKCmu transfectants. In support of a PKCmu action on NF-kappaB, we show enhancement and downregulation of TNF-induced expression of a NF-kappaB-dependent reporter gene by transient overexpression of wild-type and kinase-negative mutants of PKCmu, respectively. Interestingly, no significant changes were found in an electrophoretic mobility shift assay, indicative of PKCmu action downstream of IkappaB degradation, probably by modulation of the transactivation capacity of NF-kappaB. The dominant negative action of the kinase-negative mutant further suggest a regulatory role of PKCmu for NF-kappaB-dependent gene expression.

  19. 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

  20. 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

  1. Expression of tumour necrosis factor alpha and accumulation of fibronectin in coronary artery restenotic lesions retrieved by atherectomy.

    PubMed Central

    Clausell, N.; de Lima, V. C.; Molossi, S.; Liu, P.; Turley, E.; Gotlieb, A. I.; Adelman, A. G.; Rabinovitch, M.

    1995-01-01

    BACKGROUND--The formation of coronary artery neointima experimentally induced in piglets after cardiac transplantation is related to an immune-inflammatory reaction associated with increased expression of T cells and inflammatory mediators (tumour necrosis factor alpha and interleukin 1 beta) and upregulation of fibronectin. In vivo blockade of tumour necrosis factor alpha in rabbits after cardiac transplantation results in reduced neointimal formation. The objective of this study was to investigate the hypothesis that coronary restenosis after atherectomy or percutaneous balloon angioplasty is associated with a similar inflammatory cascade initiated by mechanical injury. METHODS--Specimens taken at coronary atherectomy were analysed from 16 patients. Nine had had the procedure performed twice, firstly, to remove a primary lesion, and secondly, to remove a restenotic lesion. Seven had percutaneous balloon angioplasty after removal of restenotic tissue. Coronary atherectomy specimens were analysed by immunohistochemistry for the presence of T cells, macrophages, major histocompatibility complex II, interleukin 1 beta, tumour necrosis factor alpha, fibronectin, and the receptor for hyaluronan mediated motility. RESULTS--The groups were clinically and angiographically similar with equivalent lumens before and after atherectomy. Restenotic lesions had increased expression of tumour necrosis factor alpha and fibronectin compared with the primary lesions (P < 0.05 for both). There was also a trend towards a greater number of T cells and increased expression of interleukin 1 beta. CONCLUSIONS--Restenosis is associated with increased expression of tumour necrosis factor alpha and fibronectin, suggesting that an immune-inflammatory reaction probably contributes to neointimal formation and may represent a form of wound healing and repair secondary to mechanical injury. Images PMID:7626352

  2. Symptomatic Avascular Necrosis: An Understudied Risk Factor for Acute Care Utilization by Patients with SCD.

    PubMed

    Yu, Tiffany; Campbell, Timothy; Ciuffetelli, Isabella; Haywood, Carlton; Carroll, Christopher Patrick; Resar, Linda; Strouse, John J; Lanzkron, Sophie

    2016-09-01

    Sickle cell disease (SCD) is associated with high healthcare utilization rates and poor outcomes in a subset of patients, although the underlying factors that predict this phenotype are poorly understood. Prior studies suggest that comorbid avascular necrosis (AVN) contributes to high healthcare utilization. We sought to clarify whether AVN independently predicts acute care utilization in adults with SCD and to identify characteristics of those with AVN that predict higher utilization. We reviewed the medical records of 87 patients with SCD with symptomatic AVN and compared acute care utilization and clinical characteristics with 87 sex- and age-matched patients with SCD without symptomatic AVN. Patients with ≥2 years of follow-up were included. Outcomes were compared using bivariate analysis and multivariate regression. Our study included 1381 follow-up years, with a median of 7 years per patient. The AVN cohort had greater median rates of urgent care visits (3.2/year vs 1.3/year; P = 0.0155), admissions (1.3/year vs 0.4/year; P = 0.0002), and admission days (5.1 days/year vs 1.8 days/year; P = 0.0007). History of high utilization (odds ratio [OR] 4.28; P = 0.001), acute chest syndrome (OR 3.12; P = 0.005), pneumonia (OR 3.20; P = 0.023), hydroxyurea therapy (OR 2.23; P = 0.0136), and long-term transfusion (OR 2.33; P = 0.014) were associated with AVN. In a median regression model, AVN, acute chest syndrome, and pneumonia were independently associated with greater urgent care visits and admissions. Symptomatic AVN was found to be an independent risk factor for acute care utilization in patients with SCD. Because this is a potentially modifiable factor, further studies are urgently needed to determine whether AVN prevention/early treatment interventions will alter utilization and improve outcomes for patients with SCD.

  3. 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.

  4. 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

  5. Recurrent abdominal pain as the presentation of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in an Asian girl: a case report and review of the literature.

    PubMed

    Chen, Yun-Ju; Yu, Hsin-Hui; Yang, Yao-Hsu; Lau, Yu-Lung; Lee, Wen-I; Chiang, Bor-Luen

    2014-12-01

    Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is characterized by periodic fever, cutaneous rash, conjunctivitis, lymphadenopathy, abdominal pain, myalgia, and arthralgia. It is a rare autosomal dominant disease and strongly associated with heterozygous mutations in the tumor necrosis factor (TNF) receptor super family 1A (TNFRSF1A) gene. It is believed to be more common in Western countries than in Asian countries. Here, we present the case of a 14-year-old girl with periodic fever and abdominal pain with elevation of inflammatory markers for 2 years. After extensive work-up of infectious etiology with negative results, the diagnosis of TRAPS was made although no gene mutations were identified in the TNFRSF1A gene, MVK gene, and NALP3/CIAS1 gene. She had partial clinical response to corticosteroids and immunomodulatory agents. However, the treatment response to TNF-α inhibitor etanercept was dramatic. She has remained symptom free under regular weekly to biweekly etanercept treatment for 2 years. We also reviewed the related literature and summarized the data of 10 Asian cases of TRAPS.

  6. Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis.

    PubMed

    Bisoendial, Radjesh; Tabet, Fatiha; Tak, Paul P; Petrides, Francine; Cuesta Torres, Luisa F; Hou, Liming; Cook, Adam; Barter, Philip J; Weninger, Wolfgang; Rye, Kerry-Anne

    2015-11-01

    Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apolipoprotein (apo) A-I, the principal apolipoprotein of high-density lipoproteins, to preserve the normal function of lymphatic endothelial cells treated with TNF. TNF decreased the ability of lymphatic endothelial cells to form tube-like structures. Preincubation of lymphatic endothelial cells with apoA-I attenuated the TNF-mediated inhibition of tube formation in a concentration-dependent manner. In addition, apoA-I reversed the TNF-mediated suppression of lymphatic endothelial cell migration and lymphatic outgrowth in thoracic duct rings. ApoA-I also abrogated the negative effect of TNF on lymphatic neovascularization in an ATP-binding cassette transporter A1-dependent manner. At the molecular level, this involved downregulation of TNF receptor-1 and the conservation of prospero-related homeobox gene-1 expression, a master regulator of lymphangiogenesis. ApoA-I also re-established the normal phenotype of the lymphatic network in the diaphragms of human TNF transgenic mice. ApoA-I restores the neovascularization capacity of the lymphatic system during TNF-mediated inflammation. This study provides a proof-of-concept that high-density lipoprotein-based therapeutic strategies may attenuate chronic inflammation via its action on lymphatic vasculature. © 2015 American Heart Association, Inc.

  7. Human tumor necrosis factor alpha gene regulation by virus and lipopolysaccharide.

    PubMed

    Goldfeld, A E; Doyle, C; Maniatis, T

    1990-12-01

    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.

  8. Downregulation of adenine nucleotide translocator 1 exacerbates tumor necrosis factor-α-mediated cardiac inflammatory responses.

    PubMed

    Pan, Shi; Wang, Nadan; Bisetto, Sara; Yi, Bing; Sheu, Shey-Shing

    2015-01-01

    Inflammation contributes significantly to cardiac dysfunction. Although the initial phase of inflammation is essential for repair and healing, excessive proinflammatory cytokines are detrimental to the heart. We found that adenine nucleotide translocator isoform-1 (ANT1) protein levels were significantly decreased in the inflamed heart of C57BL/6 mice following cecal ligation and puncture. To understand the molecular mechanisms involved, we performed small-interfering RNA-mediated knockdown of ANT1 and studied tumor necrosis factor-α (TNFα)-induced inflammatory responses in myocardium-derived H9c2 cells and cardiomyocytes. ANT1 knockdown significantly increased swollen mitochondria and mitochondrial reactive oxygen species, concomitant with increased TNFα-induced NF-κB reporter gene activity and interleukin-6 and TNFα expression. A mitochondrial-targeted antioxidant mito-TEMPO attenuated TNFα-induced mitochondrial reactive oxygen species, NF-κB reporter gene activity, and cytokine expression in ANT1 knockdown cells. Interestingly, TNFα or lipopolysaccharide (LPS) treatment significantly decreased ANT1 protein levels, suggesting a feed-forward regulation of proinflammatory cytokine expression activated by ANT1 downregulation. These data suggest that ANT1 downregulation contributes to cardiac inflammation post-cecal ligation and puncture. Preventing ANT1 downregulation could provide a novel molecular target to temper cardiac inflammation. Copyright © 2015 the American Physiological Society.

  9. Downregulation of adenine nucleotide translocator 1 exacerbates tumor necrosis factor-α-mediated cardiac inflammatory responses

    PubMed Central

    Pan, Shi; Wang, Nadan; Bisetto, Sara; Yi, Bing

    2014-01-01

    Inflammation contributes significantly to cardiac dysfunction. Although the initial phase of inflammation is essential for repair and healing, excessive proinflammatory cytokines are detrimental to the heart. We found that adenine nucleotide translocator isoform-1 (ANT1) protein levels were significantly decreased in the inflamed heart of C57BL/6 mice following cecal ligation and puncture. To understand the molecular mechanisms involved, we performed small-interfering RNA-mediated knockdown of ANT1 and studied tumor necrosis factor-α (TNFα)-induced inflammatory responses in myocardium-derived H9c2 cells and cardiomyocytes. ANT1 knockdown significantly increased swollen mitochondria and mitochondrial reactive oxygen species, concomitant with increased TNFα-induced NF-κB reporter gene activity and interleukin-6 and TNFα expression. A mitochondrial-targeted antioxidant mito-TEMPO attenuated TNFα-induced mitochondrial reactive oxygen species, NF-κB reporter gene activity, and cytokine expression in ANT1 knockdown cells. Interestingly, TNFα or lipopolysaccharide (LPS) treatment significantly decreased ANT1 protein levels, suggesting a feed-forward regulation of proinflammatory cytokine expression activated by ANT1 downregulation. These data suggest that ANT1 downregulation contributes to cardiac inflammation post-cecal ligation and puncture. Preventing ANT1 downregulation could provide a novel molecular target to temper cardiac inflammation. PMID:25380814

  10. Tumor necrosis factor-α gene polymorphisms in FMF and their association with amyloidosis.

    PubMed

    Bonyadi, Mortaza; Bahrami, Salahadin; Jahanafrooz, Zohreh; Dastgiri, Saeed

    2012-11-01

    Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by periodic provocative attacks of fever with peritonitis, pleuritis, arthritis, or eriseplemya. Tumor necrosis factor-α (TNF-α) plays an important role in the regulation of the immune response as a part of the cytokine network, including activation of macrophages and apoptosis. We investigated the possible association of TNF-α promoter -1031T/C and -308G/A polymorphisms in 86 FMF patients carrying M694 V homozygous mutation and 100 matched healthy controls both from Iranian Azeri Turks. Our data showed that patients with TNF-α -308 GG are more susceptible to the development of amyloidosis and arthritis (P value <.05). These data also showed that the frequency of TNF-α -308 A allele is considerably low among patients with amyloidosis, and it may have protective role among them (odds ratio [OR] = 0.083, χ(2) = 5.46, P value = .003). Further evaluation of this polymorphism may be important and need further studies.

  11. Processing of newly synthesized cachectin/tumor necrosis factor in endotoxin-stimulate macrophages

    SciTech Connect

    Jue, Dae-Myung; Sherry, B.; Luedke, C.; Manogue, K.R.; Cerami, A. )

    1990-09-11

    The biosynthesis and processing of cachetin/tumor necrosis factor (TNF) were examined in the murine macrophage-like cell line RAW 264.7. Lipipolysaccharide-stimulated cells secreted both glycosylated and nonglycosylated 17-kilodalton (kDa) mature cachectin/TNF into the culture medium. Secreted cachectin/TNF was derived from membrane-associated precursors that were precipitated by polyclonal antisera raised against either the mature protein or synthetic peptide fragments of the 79 amino acid cachectin/TNF prohormone sequence. About half of the precursors were N-glycosylated, apparently cotranslationally. The cachectin/TNF precursors were then proteolytically cleaved to release soluble mature cytokine into the medium, while the membrane-bound 14-kDa prosequence remained cell associated. During the period of LPS stimulation, the amount of macrophage cell surface cachectin/TNF remained at a low level, suggesting that both nonglycosylated and glycosylated precursors of cachectin/TNF are efficiently cleaved by these cells. These findings suggest the presence of a unique mechanism for the secretion of cachectin/TNF.

  12. Anti-Tumor Necrosis Factor Ameliorates Joint Disease in Murine Collagen- Induced Arthritis

    NASA Astrophysics Data System (ADS)

    Williams, Richard O.; Feldmann, Marc; Maini, Ravinder N.

    1992-10-01

    There is considerable evidence implicating tumor necrosis factor α (TNF-α) in the pathogenesis of rheumatoid arthritis. This evidence is based not only on the universal presence of TNF-α in arthritic joints accompanied by the upregulation of TNF-α receptors but also on the effects of neutralizing TNF-α in joint cell cultures. Thus, neutralization of TNF-α in vitro results in inhibition of the production of interleukin 1, which like TNF-α, is believed to contribute to joint inflammation and erosion. To determine the validity of this concept in vivo, the effect of administering TNF-neutralizing antibodies to mice with collagen-induced arthritis has been studied. This disease model was chosen because of its many immunological and pathological similarities to human rheumatoid arthritis. TN3-19.12, a hamster IgG1 monoclonal antibody to murine TNF-α/β, was injected i.p. into mice either before the onset of arthritis or after the establishment of clinical disease. Anti-TNF administered prior to disease onset significantly reduced paw swelling and histological severity of arthritis without reducing the incidence of arthritis or the level of circulating anti-type II collagen IgG. More relevant to human disease was the capacity of the antibody to reduce the clinical score, paw swelling, and the histological severity of disease even when injected after the onset of clinical arthritis. These results have implications for possible modes of therapy of human arthritis.

  13. 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.

  14. CrmE, a Novel Soluble Tumor Necrosis Factor Receptor Encoded by Poxviruses

    PubMed Central

    Saraiva, Margarida; Alcami, Antonio

    2001-01-01

    Cytokines and chemokines play a critical role in both the innate and acquired immune responses and constitute prime targets for pathogen sabotage. Molecular mimicry of cytokines and cytokine receptors is a mechanism encoded by large DNA viruses to modulate the host immune response. Three tumor necrosis factor receptors (TNFRs) have been identified in the poxvirus cowpox virus. Here we report the identification and characterization of a fourth distinct soluble TNFR, named cytokine response modifier E (CrmE), encoded by cowpox virus. The crmE gene has been sequenced in strains of the orthopoxviruses cowpox virus, ectromelia virus, and camelpox virus, and was found to be active in cowpox virus. crmE is expressed as a secreted 18-kDa protein with TNF binding activity. CrmE was produced in the baculovirus and vaccinia virus expression systems and was shown to bind human, mouse, and rat TNF, but not human lymphotoxin α, conjugates of lymphotoxins α and β, or seven other ligands of the TNF superfamily. However, CrmE protects cells only from the cytolytic activity of human TNF. CrmE is a new member of the TNFR superfamily which is expressed as a soluble molecule that blocks the binding of TNF to high-affinity TNFRs on the cell surface. The remarkable finding of a fourth poxvirus-encoded TNFR suggests that modulation of TNF activity is complex and represents a novel viral immune evasion mechanism. PMID:11119592

  15. Plasma levels of soluble tumour necrosis factor receptors are increased in coal miners with pneumoconiosis.

    PubMed

    Schins, R P; Borm, P J

    1995-10-01

    Among other cytokines, tumour necrosis factor (TNF)-alpha is considered to play a key role in the development of mineral dust related fibrosis. Previously, we showed that ex-vivo release of TNF by peripheral blood monocytes is a marker for progression of coal workers' pneumoconiosis (CWP). Since soluble TNF receptors (sTNF-Rs) are believed to play an important regulatory role in systemic effects of TNF, we measured plasma levels of sTNF-R55 and sTNF-R75 in coal miners with (n = 28) or without (n = 76) CWP and in nonexposed controls (n = 29). sTNF-R75 levels were significantly increased in miners with CWP (2.09 +/- 0.44 ng.mL-1) versus the nonexposed controls (1.86 +/- 0.23 ng.mL-1). Neither sTNF-R55 nor sTNF-R75 were related to exposure, stage of pneumoconiosis, smoking, or (spontaneous or ex-vivo induced) monocyte TNF-release. sTNF-R55 was increased in subjects with medication (especially those using cardiovascular drugs); upon exclusion of these subjects, sTNF-R55 was found also to be significantly increased in CWP. In conclusion, bearing in mind a confounding effect of medication, soluble TNF receptors are elevated in plasma of retired miners with coal workers' pneumoconiosis. These observations further support the important role of TNF-mediated pathways in the pathogenesis of mineral dust related fibrosis.

  16. Effects of Combined Tristetraprolin/Tumor Necrosis Factor Receptor Deficiency on the Splenic Transcriptome

    PubMed Central

    Patial, Sonika; Stumpo, Deborah J.; Young, W. Scott; Ward, James M.; Flake, Gordon P.

    2016-01-01

    Tristetraprolin (TTP) acts by binding to AU-rich elements in certain mRNAs, such as tumor necrosis factor (TNF) mRNA, and increasing their decay rates. TTP knockout mice exhibit a profound inflammatory syndrome that is largely due to increased TNF levels. Although TTP's effects on gene expression have been well studied in cultured cells, little is known about its functions in intact tissues. We performed deep RNA sequencing on spleens from TTP knockout mice that were also deficient in both TNF receptors (“triple knockout” mice) to remove the secondary effects of excess TNF activity. To help identify posttranscriptionally regulated transcripts, we also compared changes in mature mRNA levels to levels of transiently expressed pre-mRNA. In the triple knockout spleens, levels of 3,014 transcripts were significantly affected by 1.5-fold or more, but only a small fraction exhibited differential mRNA/pre-mRNA changes suggestive of increased mRNA stability. Transferrin receptor mRNA, which contains two highly conserved potential TTP b