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Sample records for necrosis factor therapy

  1. 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

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

    PubMed Central

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

    2012-01-01

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

  3. Potentiated antibodies to tumor necrosis factor-alpha in the therapy of patients with rheumatoid arthritis.

    PubMed

    Kozlovskaya, L V; Mukhin, N A; Rameev, V V; Sarkisova, I A; Epstein, O I

    2003-01-01

    We studied the efficiency and safety of a new homeopathic preparation Artrofoon containing affinely purified antibodies to tumor necrosis factor-alpha in the therapy of patients with rheumatoid arthritis. Artrofoon produced a positive antiinflammatory effect on the course of rheumatoid arthritis. This preparation reduced the severity of arthralgia (indexes of Li and Ritchie) and morning stiffness and decreased the erythrocyte sedimentation rate and contents of rheumatoid factor and C-reactive protein. One-month therapy improved the state of patients. Artrofoon was well tolerable. The preparation did not cause the ulcerogenic and nephrotoxic effects. Artrofoon holds much promise for combination therapy of patients with rheumatoid arthritis (including severe articular-and-visceral forms) and complications after treatment with nonsteroid antiinflammatory preparations.

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

    PubMed

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

    2013-06-01

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

  5. Withdrawal of anti-tumour necrosis factor α therapy in inflammatory bowel disease.

    PubMed

    Papamichael, Konstantinos; Vermeire, Severine

    2015-04-28

    Anti-tumour necrosis factor α (anti-TNFα) therapy is an established treatment in inflammatory bowel disease. However, this treatment is associated with high costs and the possibility of severe adverse events representing a true challenge for patients, clinicians and health care systems. Consequently, a crucial question is raised namely if therapy can be stopped once remission is achieved and if so, how and in whom. Additionally, in a real-life clinical setting, discontinuation may also be considered for other reasons such as the patient's preference, pregnancy, social reasons as moving to countries or continents with less access, or different local policy or reimbursement. In contrast to initiation of anti-TNFα therapy guidelines regarding stopping of this treatment are missing. As a result, the decision of discontinuation is still a challenging aspect in the use of anti-TNFα therapy. Currently this is typically based on an estimated, case-by-case, benefit-risk ratio. This editorial is intended to provide an overview of recent data on this topic and shed light on the proposed drug withdrawal strategies. PMID:25944990

  6. Withdrawal of anti-tumour necrosis factor α therapy in inflammatory bowel disease

    PubMed Central

    Papamichael, Konstantinos; Vermeire, Severine

    2015-01-01

    Anti-tumour necrosis factor α (anti-TNFα) therapy is an established treatment in inflammatory bowel disease. However, this treatment is associated with high costs and the possibility of severe adverse events representing a true challenge for patients, clinicians and health care systems. Consequently, a crucial question is raised namely if therapy can be stopped once remission is achieved and if so, how and in whom. Additionally, in a real-life clinical setting, discontinuation may also be considered for other reasons such as the patient’s preference, pregnancy, social reasons as moving to countries or continents with less access, or different local policy or reimbursement. In contrast to initiation of anti-TNFα therapy guidelines regarding stopping of this treatment are missing. As a result, the decision of discontinuation is still a challenging aspect in the use of anti-TNFα therapy. Currently this is typically based on an estimated, case-by-case, benefit-risk ratio. This editorial is intended to provide an overview of recent data on this topic and shed light on the proposed drug withdrawal strategies. PMID:25944990

  7. Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis

    PubMed Central

    Zampeli, Evanthia; Gizis, Michalis; Siakavellas, Spyros I; Bamias, Giorgos

    2014-01-01

    Ulcerative colitis (UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor (anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve (primary non-response) or lose response after a period of improvement (secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters that may predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular (immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy. PMID:25133030

  8. Anti-tumour necrosis factor α therapy for ankylosing spondylitis: international experience

    PubMed Central

    Braun, J; Sieper, J; Breban, M; Collantes-Estevez, E; Davis, J; Inman, R; Marzo-Ortega, H; Mielants, H

    2002-01-01

    The conventional approach to treatment of patients with spondyloarthritis (SpA), particularly ankylosing spondylitis (AS), has serious limitations, adding a sense of urgency to the evaluation of new treatments for these rheumatic disorders. Tumour necrosis factor α (TNFα) is a cytokine that has been shown to mediate inflammatory and regulatory activities in SpA and other immune mediated diseases, including other arthritides and inflammatory bowel disease. Positive results have been reported in several international open label and randomised controlled trials of infliximab and etanercept, the two main biological agents targeting TNFα, which have included approximately 300 patients with SpA. Specifically, TNFα-directed therapy resulted in significant improvements in disease activity, function, and quality of life in these patients, most of whom had AS and received infliximab. Preliminary evidence from open label, long term extension trials suggests clinical benefit with continued use. Serious side effects were rare and consistent with experience from patient groups receiving infliximab or etanercept treatment for inflammatory bowel disease or rheumatoid arthritis. Together, these findings herald an age of more effective treatment of patients with AS with anti-TNFα and other emerging biological agents. PMID:12381511

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

    PubMed

    Baird, Timothy; Putt, Michael; Dettrick, Andrew

    2016-09-01

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

  10. 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

  11. Pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis: efficacy of anti-tumor necrosis factor α therapy.

    PubMed

    Bruzzese, Vincenzo

    2012-12-01

    We report the case of a patient with a simultaneous presence of pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis. This condition differs from both the PASH (pyoderma gangrenosum, acne, and suppurative hidradenitis) syndrome, in which arthritis is absent, and the PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, in which suppurative hidradenitis is lacking. Our patient failed to respond to etanercept therapy, whereas all dermatologic and rheumatic manifestations completely regressed following infliximab infusion. We therefore propose that simultaneous presence of pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis might represent a distinct syndrome that could be termed the PASS syndrome. Tumor necrosis factor α therapies seem to play selective roles.

  12. 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

  13. A threshold hazard model for estimating serious infection risk following anti-tumor necrosis factor therapy in rheumatoid arthritis patients.

    PubMed

    Fu, Bo; Lunt, Mark; Galloway, James; Dixon, Will; Hyrich, Kimme; Symmons, Deborah

    2013-03-11

    Over recent years novel biologic agents have been developed for the treatment of rheumatoid arthritis. The most common type of biologic agent in use in the United Kingdom is the anti-tumor necrosis factor inhibitor class. To fully appreciate the potential risks of anti-tumor necrosis factor therapy in patients, knowledge about the baseline hazard (risk pattern) and the characteristics of patients associated with serious infection is important. We propose a nonproportional hazard model for estimating the infection risk, by including the drug exposure history information into the baseline hazard. We found that the infection risk reaches a peak within 1 month after drug exposure starts and then declines steadily for nearly 2 years before stabilizing out.

  14. Q Fever Risk in Patients Treated with Chronic Antitumor Necrosis Factor-Alpha Therapy

    PubMed Central

    Astrahan, Anna; Odeh, Majed; Elias, Nizar; Rosner, Itzhak; Rimar, Doron; Kaly, Lisa; Rozenbaum, Michael; Boulman, Nina; Slobodin, Gleb

    2016-01-01

    Q fever is a zoonotic bacterial disease caused by Coxiella burnetii. Tumor necrosis factor-alpha (TNF-α) plays a pivotal role in the defense against infection with this Gram-negative coccobacillus. Theoretically, patients who are treated with anti-TNF-α medications are at risk for developing chronic Q fever. We present two patients who developed Q fever while being treated with anti-TNF-α agents and discuss the significance of timely diagnosis of C. burnetii infection in these patients. PMID:27656302

  15. Q Fever Risk in Patients Treated with Chronic Antitumor Necrosis Factor-Alpha Therapy

    PubMed Central

    Astrahan, Anna; Odeh, Majed; Elias, Nizar; Rosner, Itzhak; Rimar, Doron; Kaly, Lisa; Rozenbaum, Michael; Boulman, Nina; Slobodin, Gleb

    2016-01-01

    Q fever is a zoonotic bacterial disease caused by Coxiella burnetii. Tumor necrosis factor-alpha (TNF-α) plays a pivotal role in the defense against infection with this Gram-negative coccobacillus. Theoretically, patients who are treated with anti-TNF-α medications are at risk for developing chronic Q fever. We present two patients who developed Q fever while being treated with anti-TNF-α agents and discuss the significance of timely diagnosis of C. burnetii infection in these patients.

  16. Update on intravitreal anti-tumor necrosis factor alpha therapies for ocular disorders

    PubMed Central

    2014-01-01

    Tumor necrosis factor alpha (TNF-?) is an important pro-inflammatory cytokine associated with a variety of ocular diseases. The currently available TNF-? inhibitors are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Experimental and clinical studies on the intravitreal use of these agents have been reported with etanercept, infliximab, and adalimumab: etanercept has shown limited efficacy in scarce reports; infliximab has been associated with local safety concerns but appears to benefit certain cases; adalimumab has shown no efficacy in cases of age-related macular degeneration (AMD) or diabetic macular edema (DME), but the combination with bevacizumab may be effective in refractory cases of macular diseases. Further preclinical and clinical studies are warranted in order to be able to obtain a more robust conclusion on the use of intravitreal TNF-? inhibitors. PMID:25825604

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

    PubMed Central

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

    2013-01-01

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

  18. Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: a French national survey

    PubMed Central

    De Bandt, Michel; Sibilia, Jean; Le Loët, Xavier; Prouzeau, Sebastian; Fautrel, Bruno; Marcelli, Christian; Boucquillard, Eric; Siame, Jean Louis; Mariette, Xavier

    2005-01-01

    The development of drug-induced lupus remains a matter of concern in patients treated with anti-tumour necrosis factor (TNF) alpha. The incidence of such adverse effects is unknown. We undertook a retrospective national study to analyse such patients. Between June and October 2003, 866 rheumatology and internal medicine practitioners from all French hospital centres prescribing anti-TNF in rheumatic diseases registered on the website of the 'Club Rhumatismes et Inflammation' were contacted by email to obtain the files of patients with TNF-induced systemic lupus erythematosus. Twenty-two cases were collected, revealing two aspects of these manifestations. Ten patients (six patients receiving infliximab, four patients receiving etanercept) only had anti-DNA antibodies and skin manifestations one could classify as 'limited skin lupus' or 'toxidermia' in a context of autoimmunity, whereas 12 patients (nine patients receiving infliximab, three patients receiving etanercept) had more complete drug-induced lupus with systemic manifestations and at least four American Congress of Rheumatology criteria. One patient had central nervous system manifestations. No patients had lupus nephritis. The signs of lupus occurred within a mean of 9 months (range 3–16 months) in patients treated with infliximab and within a mean of 4 months (range 2–5 months) in patients treated with etanercept. In all cases after diagnosis was determined, anti-TNF was stopped and specific treatment introduced in eight patients: two patients received intravenous methylprednisolone, four patients received oral steroids (15–35 mg/day), and two patients received topical steroids. Lupus manifestations abated within a few weeks (median 8 weeks, standard deviation 3–16) in all patients except one with longer-lasting evolution (6 months). At that time, cautious estimations (unpublished data from Schering Plough Inc. and Wyeth Inc.) indicated that about 7700 patients had been exposed to infliximab and

  19. Infliximab therapy balances regulatory T cells, tumour necrosis factor receptor 2 (TNFR2) expression and soluble TNFR2 in sarcoidosis.

    PubMed

    Verwoerd, A; Hijdra, D; Vorselaars, A D M; Crommelin, H A; van Moorsel, C H M; Grutters, J C; Claessen, A M E

    2016-08-01

    Sarcoidosis is a systemic granulomatous disease of unknown aetiology that most commonly affects the lungs. Although elevated levels of regulatory T cells (Tregs ) have been reported, the extent to which they play a role in sarcoidosis pathogenesis remains unclear. Tumour necrosis factor (TNF) is thought to be one of the driving forces behind granuloma formation, illustrated by the efficacy of infliximab in severe sarcoidosis. Tregs express TNF receptor 2 (TNFR2) highly. Here, we examined the influence of infliximab therapy on Tregs and (soluble) TNFR2 levels in sarcoidosis, and correlated these with response to therapy. We observed that relative frequencies of Tregs were significantly higher in patients (n = 54) compared to healthy controls (n = 26; median 6·73 versus 4·36%; P < 0·001) and decreased following therapy (4·95; P < 0·001). Baseline TNFR2 expression on Tregs was increased significantly in patients versus controls (99·4 versus 96·2%; P = 0·031), and also in responders to therapy versus non-responders (99·6 versus 97·3%; P = 0·012). Furthermore, baseline soluble TNFR2 (sTNFR2) was higher in responders than in non-responders (mean 174 versus 107 pg/ml; P = 0·015). After treatment, responders showed a significant reduction in sTNFR2 levels in peripheral blood (-44·7 pg/ml; P < 0·001), in contrast to non-responders (+3·59 pg/ml). Our results demonstrated that Treg frequencies and TNFR2 expression on Tregs are increased in sarcoidosis, followed by a decline during infliximab therapy, suggesting a pathophysiological role of this T cell subset. Interestingly, sTNFR2 levels at baseline differed significantly between responders and non-responders, making it a potential marker in predicting which patients might benefit from infliximab.

  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 factor-α inhibitor 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 factor-α inhibitor 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 factor-α inhibitor therapy to validate in a larger cohort of patients. PMID:26061065

  1. Influence of antimicrobial therapy on kinetics of tumor necrosis factor levels in experimental endocarditis caused by Klebsiella pneumoniae.

    PubMed

    Mohler, J; Fantin, B; Mainardi, J L; Carbon, C

    1994-05-01

    The kinetics of tumor necrosis factor (TNF) levels in serum during therapy with cell wall-active agents (ceftriaxone, imipenem) and gentamicin were investigated in rabbits with experimental endocarditis caused by an isogenic pair of Klebsiella pneumoniae strains: a TEM-3 beta-lactamase-producing strain (KpR) or its susceptible variant (KpS). In vitro, KpR was resistant to ceftriaxone and was susceptible to gentamicin and imipenem, while KpS was susceptible to all three antibiotics. Serum TNF levels were determined in control rabbits hourly after bacterial inoculation and then daily; they were determined in treated animals hourly after the first antibiotic injection and then daily during a 4-day therapy with either imipenem (60 mg/kg of body weight four times daily), ceftriaxone (75 mg/kg once daily), or gentamicin (4 mg/kg once daily) alone or in combination with ceftriaxone. After a transient peak (10.2 +/- 3.1 ng/ml) at 90 min following bacterial challenge, serum TNF levels remained low and stable in control animals. The peak in the serum TNF levels occurred 4 h after the first antibiotic injection and with ceftriaxone was significantly higher (P < 0.05) against KpS (1.99 +/- 0.52 ng/ml) than against KpR (1.40 +/- 0.17 ng/ml). Against the KpR strain, the levels observed with ceftriaxone were significantly higher (P < 0.05) than those obtained with the other therapeutic regimens (0.70 to 0.80 ng/ml). On the day of sacrifice, effective regimens were associated with low TNF levels. We concluded that TNF production depends on (i) the antiobiotic's mechanism of action and the susceptibility of the strain at the early phase of therapy, without any effect of the rapidity of bacterial killing, and (ii) the final reduction of the bacterial count at a later stage of therapy.

  2. Influence of antimicrobial therapy on kinetics of tumor necrosis factor levels in experimental endocarditis caused by Klebsiella pneumoniae.

    PubMed Central

    Mohler, J; Fantin, B; Mainardi, J L; Carbon, C

    1994-01-01

    The kinetics of tumor necrosis factor (TNF) levels in serum during therapy with cell wall-active agents (ceftriaxone, imipenem) and gentamicin were investigated in rabbits with experimental endocarditis caused by an isogenic pair of Klebsiella pneumoniae strains: a TEM-3 beta-lactamase-producing strain (KpR) or its susceptible variant (KpS). In vitro, KpR was resistant to ceftriaxone and was susceptible to gentamicin and imipenem, while KpS was susceptible to all three antibiotics. Serum TNF levels were determined in control rabbits hourly after bacterial inoculation and then daily; they were determined in treated animals hourly after the first antibiotic injection and then daily during a 4-day therapy with either imipenem (60 mg/kg of body weight four times daily), ceftriaxone (75 mg/kg once daily), or gentamicin (4 mg/kg once daily) alone or in combination with ceftriaxone. After a transient peak (10.2 +/- 3.1 ng/ml) at 90 min following bacterial challenge, serum TNF levels remained low and stable in control animals. The peak in the serum TNF levels occurred 4 h after the first antibiotic injection and with ceftriaxone was significantly higher (P < 0.05) against KpS (1.99 +/- 0.52 ng/ml) than against KpR (1.40 +/- 0.17 ng/ml). Against the KpR strain, the levels observed with ceftriaxone were significantly higher (P < 0.05) than those obtained with the other therapeutic regimens (0.70 to 0.80 ng/ml). On the day of sacrifice, effective regimens were associated with low TNF levels. We concluded that TNF production depends on (i) the antiobiotic's mechanism of action and the susceptibility of the strain at the early phase of therapy, without any effect of the rapidity of bacterial killing, and (ii) the final reduction of the bacterial count at a later stage of therapy. PMID:8067731

  3. Adenoviral Delivery of Tumor Necrosis Factor-α and Interleukin-2 Enables Successful Adoptive Cell Therapy of Immunosuppressive Melanoma.

    PubMed

    Siurala, Mikko; Havunen, Riikka; Saha, Dipongkor; Lumen, Dave; Airaksinen, Anu J; Tähtinen, Siri; Cervera-Carrascon, Víctor; Bramante, Simona; Parviainen, Suvi; Vähä-Koskela, Markus; Kanerva, Anna; Hemminki, Akseli

    2016-08-01

    Adoptive T-cell transfer is a promising treatment approach for metastatic cancer, but efficacy in solid tumors has only been achieved with toxic pre- and postconditioning regimens. Thus, adoptive T-cell therapies would benefit from complementary modalities that enable their full potential without excessive toxicity. We aimed to improve the efficacy and safety of adoptive T-cell transfer by using adenoviral vectors for direct delivery of immunomodulatory murine cytokines into B16.OVA melanoma tumors with concomitant T-cell receptor transgenic OT-I T-cell transfer. Armed adenoviruses expressed high local and low systemic levels of cytokine when injected into B16.OVA tumors, suggesting safety of virus-mediated cytokine delivery. Antitumor efficacy was significantly enhanced with adenoviruses coding for murine interleukin-2 (mIL-2) and tumor necrosis factor-α (mTNFα) when compared with T-cell transfer alone or viruses alone. Further improvement in efficacy was achieved with a triple combination of mIL-2, mTNFα, and OT-I T-cells. Mechanistic studies suggest that mIL-2 has an important role in activating T-cells at the tumor, while mTNFα induces chemokine expression. Furthermore, adenovirus treatments enhanced tumor-infiltration of OT-I T-cells as demonstrated by SPECT/CT imaging of (111)In-labeled cells. Our results suggest the utility of cytokine-coding adenoviruses for improving the efficacy of adoptive T-cell therapies.

  4. Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy

    PubMed Central

    Cui, Jing; Saevarsdottir, Saedis; Thomson, Brian; Padyukov, Leonid; van der Helm-van Mil, Annette H. M.; Nititham, Joanne; Hughes, Laura B.; de Vries, Niek; Raychaudhuri, Soumya; Alfredsson, Lars; Askling, Johan; Wedrén, Sara; Ding, Bo; Guiducci, Candace; Wolbink, Gert Jan; Crusius, J. Bart A.; van der Horst-Bruinsma, Irene E.; Herenius, Marieke; Weinblatt, Michael E.; Shadick, Nancy A.; Worthington, Jane; Batliwalla, Franak; Kern, Marlena; Morgan, Ann W.; Wilson, Anthony G.; Isaacs, John D.; Hyrich, Kimme; Seldin, Michael F.; Moreland, Larry W.; Behrens, Timothy W.; Allaart, Cornelia F.; Criswell, Lindsey A.; Huizinga, Tom W. J.; Tak, Paul P.; Bridges, S. Louis; Toes, Rene E. M.; Barton, Anne; Klareskog, Lars; Gregersen, Peter K.; Karlson, Elizabeth W.; Plenge, Robert M.

    2013-01-01

    Objective Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. Methods A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. Results Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99). Conclusion Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections

  5. 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

  6. Fundamental principals of tumor necrosis factor-alpha gene therapy approach and implications for patients with lung carcinoma.

    PubMed

    Sanlioglu, Ahter D; Aydin, Cigdem; Bozcuk, Hakan; Terzioglu, Ender; Sanlioglu, Salih

    2004-05-01

    Apoptosis, known as programmed cell death, is defined as a cell's preferred form of death under hectic conditions through genetically conserved and complex pathways. There is a decisive balance between stimulatory and inhibitory signaling pathways to maintain homeostasis in cells. In order to shift the balance towards apoptosis, the modulation of both apoptotic and anti-apoptotic pathways represents an attractive target for cancer therapeutics. Currently, chemotherapy and radiotherapy are among the most commonly used treatment modalities against lung cancer. Tumor suppressor gene, p53, is required in order for both of these treatment methods to work as anti-tumor agents. As a result, tumors lacking p53 display resistance to both chemotherapy and radiotherapy. However, death ligands induce apoptosis regardless of p53 status of cells. Thus, these methods constitute a complementary therapeutic approach to currently employed conventional treatment modalities. At present, death ligands are being evaluated as potential cancer therapeutic agents. Since resistance to tumor necrosis factor (TNF)-alpha-mediated apoptosis represented an obstacle for the treatment of patients with lung carcinoma in the earlier attempts, an extensive research was recently initiated to understand molecular mechanism of TNF-alpha signaling. NF-kappaB transcription factors have been demonstrated to modulate the apoptotic program, mostly as blockers of apoptosis in different cell types. In this review, we concentrate on the current progress in the understanding of TNF-alpha-mediated apoptosis for lung carcinoma. Representative models of NF-kappaB-inhibiting gene therapy strategies from various labs including ours are also provided as examples of up-to-date approaches to defeat TNF resistance. In order to give the reader better understanding and appreciation of such approaches, previously unpublished in vivo assays are also incorporated into this review. Current progress in clinical trials using

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

    PubMed

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

    2009-07-15

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

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

    PubMed

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

    2009-07-15

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

  9. Diagnosis of delayed cerebral radiation necrosis following proton beam therapy

    SciTech Connect

    Kaufman, M.; Swartz, B.E.; Mandelkern, M.; Ropchan, J.; Gee, M.; Blahd, W.H. )

    1990-04-01

    A 27-year-old man developed delayed cerebral radiation necrosis following proton beam therapy to an arteriovenous malformation. Neuroimaging with technetium 99m diethylenetriamine penta-acetic acid and positron emission tomographic scanning with fludeoxyglucose F 18 aided in his evaluation. Significant improvement of his neurologic deficits resulted from corticosteroid therapy. Clinical resolution was corroborated by serial computed tomographic scans demonstrating regression of the abnormality (a mass lesion). Various facets of radiation injury are discussed, including pathogenesis, risk factors, diagnosis, and therapy.

  10. Changes of energy metabolism, nutritional status and serum cytokine levels in patients with Crohn’s disease after anti-tumor necrosis factortherapy

    PubMed Central

    Nishida, Nao; Sasaki, Masaya; Kurihara, Mika; Ichimaru, Satomi; Wakita, Maki; Bamba, Shigeki; Andoh, Akira; Fujiyama, Yoshihide; Amagai, Teruyoshi

    2013-01-01

    We investigated the effects of treatment with antibodies against tumor necrosis factor (TNF)-α on energy metabolism, nutritional status, serum cytokine levels in patients with Crohn’s disease (CD). Twelve patients were enrolled. Resting energy expenditure (REE) levels were measured by indirect calorimetry. Crohn’s disease activity index (CDAI) significantly decreased after treatment with anti-TNF-α therapy. Anti-TNF-α therapy did not affect REE, but respiratory quotient (RQ) significantly increased after treatment. Serum interleukin-6 levels were significantly decreased and RQ were significantly increased in high REE (≥25 kcal/kg/day) group as compared to low REE (<25 kcal/kg/day) group. In conclusion, high REE value on admission is a predictive factor for good response to treatment with anti-TNF-α antibodies in active CD patients. PMID:24062610

  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. Tumor necrosis factor alpha and toxicology.

    PubMed

    Luster, M I; Simeonova, P P; Gallucci, R; Matheson, J

    1999-09-01

    The molecular cloning of a group of proteins, collectively referred to as cytokines, and including interleukins, chemokines, growth factors, colony stimulating factors, and tumor necrosis factors, has allowed for the increased understanding of the mechanisms for many disease processes as well as provided strategies for the development of novel therapies. Conceptually similar to hormones and peptides, this group of phylogenetically related molecules are also involved in various toxicological processes, including apoptosis, cell repair, and in particular inflammation. In this review, we offer a description of what many believe represents the primary regulatory cytokine, tumor necrosis factor (TNF)alpha and its role in toxicological processes. For over a decade it has been suspected that this molecule helps mediate the shock state induced by bacterial endotoxin and the wasting diathesis that typifies chronic diseases. Advances in molecular biology that have provided tools to modulate TNFalpha regulation and synthesis have allowed for the identification of additional roles for TNFalpha in homeostasis, cellular damage, and repair. This review provides a brief summary of our understanding of TNFalpha biology followed by a discussion of its role in toxicological responses. This is followed by specific examples of organ-specific and tissue-specific responses to chemical damage where TNFalpha has been implicated. The review concludes with a review of its implication in human risk assessment, particularly as it relates to genetic polymorphisms of TNFalpha expression and disease susceptibility.

  13. How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

    PubMed

    Ward, Mark G; Irving, Peter M; Sparrow, Miles P

    2015-10-28

    In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients.

  14. How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

    PubMed Central

    Ward, Mark G; Irving, Peter M; Sparrow, Miles P

    2015-01-01

    In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients. PMID:26525434

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

    PubMed

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

    2008-01-01

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

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

    PubMed

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

    2008-01-01

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

  17. Intestinal microsporidiosis: a hidden risk in rheumatic disease patients undergoing anti-tumor necrosis factor therapy combined with disease-modifying anti-rheumatic drugs?

    PubMed Central

    Aikawa, Nadia Emi; de Oliveira Twardowsky, Aline; de Carvalho, Jozélio Freire; Silva, Clovis A; Silva, Ivan Leonardo Avelino França e; de Medeiros Ribeiro, Ana Cristina; Saad, Carla Gonçalves Schain; Moraes, Julio César Bertacini; de Toledo, Roberto Acayaba; Bonfá, Eloísa

    2011-01-01

    OBJECTIVE: Immunosuppressed patients are at risk of microsporidiosis, and this parasitosis has an increased rate of dissemination in this population. Our objective was to evaluate the presence of microsporidiosis and other intestinal parasites in rheumatic disease patients undergoing anti-tumor necrosis factor/disease-modifying anti-rheumatic drug treatment. METHODS: Ninety-eight patients (47 with rheumatoid arthritis, 31 with ankylosing spondylitis and 11 with psoriatic arthritis) and 92 healthy control patients were enrolled in the study. Three stool samples and cultures were collected from each subject. RESULTS: The frequency of microsporidia was significantly higher in rheumatic disease patients than in control subjects (36 vs. 4%, respectively; p<0.0001), as well as in those with rheumatic diseases (32 vs. 4%, respectively; p<0.0001), ankylosing spondylitis (45 vs. 4%, respectively; p<0.0001) and psoriatic arthritis (40 vs. 4%, respectively; p<0.0001), despite a similar social-economic class distribution in both the patient and control groups (p = 0.1153). Of note, concomitant fecal leukocytes were observed in the majority of the microsporidia-positive patients (79.5%). Approximately 80% of the patients had gastrointestinal symptoms, such as diarrhea (26%), abdominal pain (31%) and weight loss (5%), although the frequencies of these symptoms were comparable in patients with and without this infection (p>0.05). Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis disease activity parameters were comparable in both groups (p>0.05). The duration of anti-tumor necrosis factor/disease-modifying anti-rheumatic drugs and glucocorticoid use were also similar in both groups. CONCLUSION: We have documented that microsporidiosis with intestinal mucosa disruption is frequent in patients undergoing concomitant anti-tumor necrosis factor/disease-modifying anti-rheumatic drug therapy. Impaired host defenses due to the combination of the underlying disease

  18. Impact of thiopurines and anti-tumour necrosis factor therapy on hospitalisation and long-term surgical outcomes in ulcerative colitis

    PubMed Central

    Alexakis, Christopher; Pollok, Richard CG

    2015-01-01

    Ulcerative colitis (UC) is a chronic inflammatory condition affecting the large bowel and is associated with a significant risk of both requirement for surgery and the need for hospitalisation. Thiopurines, and more recently, anti-tumour necrosis factor (aTNF) therapy have been used successfully to induce clinical remission. However, there is less data available on whether these agents prevent long-term colectomy rates or the need for hospitalisation. The focus of this article is to review the recent and pertinent literature on the long-term impact of thiopurines and aTNF on long-term surgical and hospitalisation rates in UC. Data from population based longitudinal research indicates that thiopurine therapy probably has a protective role against colectomy, if used in appropriate patients for a sufficient duration. aTNF agents appear to have a short term protective effect against colectomy, but data is limited for longer periods. Whereas there is insufficient evidence that thiopurines affect hospitalisation, evidence favours that aTNF therapy probably reduces the risk of hospitalisation within the first year of use, but it is less clear on whether this effect continues beyond this period. More structured research needs to be conducted to answer these clinically important questions. PMID:26730281

  19. Anti-Tumor Necrosis Factor-α Antibody Therapy Management Before and After Intestinal Surgery for Inflammatory Bowel Disease: A CCFA Position Paper.

    PubMed

    Holubar, Stefan D; Holder-Murray, Jennifer; Flasar, Mark; Lazarev, Mark

    2015-11-01

    Biologic therapy with anti-tumor necrosis factor (TNF)-α antibody medications has become part of the standard of care for medical therapy for patients with inflammatory bowel disease and may help to avoid surgery in some. However, many of these patients will still require surgical intervention in the form of bowel resection and anastomosis or ostomy formation for the treatment of their disease. Postsurgical studies suggest up to 30% of patients with inflammatory bowel disease may be on or have used anti-TNF-α antibody medications for disease management preoperatively. Significant controversy exists regarding the potential deleterious impact of these medications on the outcomes of surgery, specifically overall and/or infectious complications. In this position statement, we systematically reviewed the literature regarding the potential risk of anti-TNF-α antibody use in the perioperative period, offer recommendations based both on the best-available evidence and expert opinion on the use and timing of anti-TNF-α antibody therapy in the perioperative period, and discuss whether or not the presence of these medications should lead to an alteration in surgical technique such as temporary stoma formation. PMID:26422516

  20. Anti–Tumor Necrosis Factor-α Antibody Therapy Management Before and After Intestinal Surgery for Inflammatory Bowel Disease: A CCFA Position Paper

    PubMed Central

    Holder-Murray, Jennifer; Flasar, Mark; Lazarev, Mark

    2015-01-01

    Abstract: Biologic therapy with anti–tumor necrosis factor (TNF)-α antibody medications has become part of the standard of care for medical therapy for patients with inflammatory bowel disease and may help to avoid surgery in some. However, many of these patients will still require surgical intervention in the form of bowel resection and anastomosis or ostomy formation for the treatment of their disease. Postsurgical studies suggest up to 30% of patients with inflammatory bowel disease may be on or have used anti–TNF-α antibody medications for disease management preoperatively. Significant controversy exists regarding the potential deleterious impact of these medications on the outcomes of surgery, specifically overall and/or infectious complications. In this position statement, we systematically reviewed the literature regarding the potential risk of anti–TNF-α antibody use in the perioperative period, offer recommendations based both on the best-available evidence and expert opinion on the use and timing of anti–TNF-α antibody therapy in the perioperative period, and discuss whether or not the presence of these medications should lead to an alteration in surgical technique such as temporary stoma formation. PMID:26422516

  1. Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia.

    PubMed

    Madsen, Pernille M; Clausen, Bettina H; Degn, Matilda; Thyssen, Stine; Kristensen, Lotte K; Svensson, Martina; Ditzel, Nicholas; Finsen, Bente; Deierborg, Tomas; Brambilla, Roberta; Lambertsen, Kate L

    2016-09-01

    Microglia respond to focal cerebral ischemia by increasing their production of the neuromodulatory cytokine tumor necrosis factor, which exists both as membrane-anchored tumor necrosis factor and as cleaved soluble tumor necrosis factor forms. We previously demonstrated that tumor necrosis factor knockout mice display increased lesion volume after focal cerebral ischemia, suggesting that tumor necrosis factor is neuroprotective in experimental stroke. Here, we extend our studies to show that mice with intact membrane-anchored tumor necrosis factor, but no soluble tumor necrosis factor, display reduced infarct volumes at one and five days after stroke. This was associated with improved functional outcome after experimental stroke. No changes were found in the mRNA levels of tumor necrosis factor and tumor necrosis factor-related genes (TNFR1, TNFR2, TACE), pro-inflammatory cytokines (IL-1β, IL-6) or chemokines (CXCL1, CXCL10, CCL2); however, protein expression of TNF, IL-1β, IL-6 and CXCL1 was reduced in membrane-anchored tumor necrosis factor(Δ/Δ) compared to membrane-anchored tumor necrosis factor(wt/wt) mice one day after experimental stroke. This was paralleled by reduced MHCII expression and a reduction in macrophage infiltration in the ipsilateral cortex of membrane-anchored tumor necrosis factor(Δ/Δ) mice. Collectively, these findings indicate that membrane-anchored tumor necrosis factor mediates the protective effects of tumor necrosis factor signaling in experimental stroke, and therapeutic strategies specifically targeting soluble tumor necrosis factor could be beneficial in clinical stroke therapy. PMID:26661199

  2. Effects of Antitumor Necrosis Factor Therapy on Osteoprotegerin, Neopterin, and sRANKL Concentrations in Patients with Rheumatoid Arthritis

    PubMed Central

    Kurz, Katharina; Herold, Manfred; Russe, Elisabeth; Klotz, Werner; Weiss, Guenter; Fuchs, Dietmar

    2015-01-01

    Background. Rheumatoid arthritis is a systemic autoimmune disease characterized by joint erosions, progressive focal bone loss, and chronic inflammation. Methods. 20 female patients with moderate-to-severe rheumatoid arthritis were treated with anti-TNF-antibody adalimumab in addition to concomitant antirheumatic therapies. Patients were assessed for overall disease activity using the DAS28 score, and neopterin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) concentrations as well as osteoprotegerin (OPG) and soluble receptor activator of NF-κB ligand (sRANKL) concentrations were determined before therapy and at week 12. Neopterin as well as OPG and sRANKL were determined by commercial ELISAs. Results. Before anti-TNF therapy patients presented with high disease activity and elevated concentrations of circulating inflammatory markers. OPG concentrations correlated with neopterin (rs = 0.494, p = 0.027), but not with DAS28. OPG concentrations and disease activity scores declined during anti-TNF-treatment (both p < 0.02). Patients who achieved remission (n = 7) or showed a good response according to EULAR criteria (n = 13) presented with initially higher baseline OPG levels, which subsequently decreased significantly during treatment (p = 0.018 for remission, p = 0.011 for good response). Conclusions. Adalimumab therapy was effective in modifying disease activity and reducing proinflammatory and bone remodelling cascades. PMID:26576067

  3. Effect of Dosimetric Factors on Occurrence and Volume of Temporal Lobe Necrosis Following Intensity Modulated Radiation Therapy for Nasopharyngeal Carcinoma: A Case-Control Study

    SciTech Connect

    Zhou, Xin; Ou, Xiaomin; Xu, Tingting; Wang, Xiaosheng; Shen, Chunying; Ding, Jianhui; Hu, Chaosu

    2014-10-01

    Purpose: To determine dosimetric risk factors for the occurrence of temporal lobe necrosis (TLN) among nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiation therapy (IMRT) and to investigate the impact of dose-volume histogram (DVH) parameters on the volume of TLN lesions (V-N). Methods and Materials: Forty-three NPC patients who had developed TLN following IMRT and 43 control subjects free of TLN were retrospectively assessed. DVH parameters included maximum dose (Dmax), minimum dose (Dmin), mean dose (Dmean), absolute volumes receiving specific dose (Vds) from 20 to 76 Gy (V20-V76), and doses covering certain volumes (Dvs) from 0.25 to 6.0 cm{sup 3} (D0.25-D6.0). V-Ns were quantified with axial magnetic resonance images. Results: DVH parameters were ubiquitously higher in temporal lobes with necrosis than in healthy temporal lobes. Increased Vds and Dvs were significantly associated with higher risk of TLN occurrence (P<.05). In particular, Vds at a dose of ≥70 Gy were found with the highest odds ratios. A common increasing trend was detected between V-N and DVH parameters through trend tests (P for trend of <.05). Linear regression analysis showed that V45 had the strongest predictive power for V-N (adjusted R{sup 2} = 0.305, P<.0001). V45 of <15.1 cm{sup 3} was relatively safe as the dose constraint for preventing large TLN lesions with V-N of >5 cm{sup 3}. Conclusions: Dosimetric parameters are significantly associated with TLN occurrence and the extent of temporal lobe injury. To better manage TLN, it would be important to avoid both focal high dose and moderate dose delivered to a large area in TLs.

  4. Avascular necrosis of bone complicating corticosteroid replacement therapy.

    PubMed Central

    Williams, P L; Corbett, M

    1983-01-01

    Two patients who developed widespread severe avascular necrosis of bone while on steroid replacement therapy are described. One, a diabetic, underwent yttrium-90 pituitary ablation for retinopathy and developed avascular necrosis within 18 months of starting prednisolone. The other, who had Addison's disease, developed avascular necrosis within 14 months of starting cortisol replacement therapy. Both cases came to bilateral total hip replacement. Images PMID:6859959

  5. 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

  6. COMPARISON OF TOPICAL INTERLEUKIN-1 VS TUMOR NECROSIS FACTOR-ALPHA BLOCKADE WITH CORTICOSTEROID THERAPY ON MURINE CORNEAL INFLAMMATION, NEOVASCULARIZATION, AND TRANSPLANT SURVIVAL (AN AMERICAN OPHTHALMOLOGICAL SOCIETY THESIS)

    PubMed Central

    Dana, Reza

    2007-01-01

    Purpose: Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) play critical roles in mediating corneal inflammation. In this study, topical blockade of IL-1 and TNF-α, alone or in combination, was compared to conventional corticosteroid anti-inflammatory therapy in suppressing infiltration of the cornea by antigen-presenting Langerhans cells (LCs) and in promoting corneal transplant survival in a mouse model of keratoplasty. Methods: Study drugs included topical 2% IL-1 receptor antagonist (IL-1Ra), 1.5% soluble TNF-α receptor (sTNFR), and 1% prednisolone phosphate (Pred), all formulated in hyaluronic acid vehicle. Fifty eyes of BALB/c mice were used for LC studies where the numbers of LCs were determined 1 week after electrocautery to the corneal surface or transplantation of C57BL/6 corneas. Additionally, 65 BALB/c mice received corneal allografts and were randomized to receive one of the following for 8 weeks: (1) IL-1Ra, (2) sTNFR, (3) Pred, (4) combined IL-1Ra and Pred, or (5) vehicle alone. Results: Mean suppression of LC infiltration after electrocautery or transplantation was 67% and 71%, respectively, for IL-1Ra, 40% and 62% for sTNFR, 70% and 72% for sTNFR+IL-1Ra, and 77% and 78% for Pred alone. Rejection rates were 15% for IL-1Ra (P = .01), 38% for sTNFR (P = .1), 17% for Pred (P = .02), and 7% for combined IL-1Ra+Pred (P = .002) as compared to 69% for the vehicle-treated group. IL-1Ra and Pred, but not sTNFR, significantly inhibited post-transplantation neovascularization. Conclusions: Topical IL-1Ra and prednisolone are comparable in their capacity to promote graft survival. sTNFR therapy, though effective, has much lower efficacy as compared to IL-1Ra or Pred. Combination IL-1Ra and steroid therapy offers only minimal added efficacy over either agent used alone. PMID:18427620

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

    PubMed

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

    2015-04-01

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

  8. T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells.

    PubMed

    Marigo, Ilaria; Zilio, Serena; Desantis, Giacomo; Mlecnik, Bernhard; Agnellini, Andrielly H R; Ugel, Stefano; Sasso, Maria Stella; Qualls, Joseph E; Kratochvill, Franz; Zanovello, Paola; Molon, Barbara; Ries, Carola H; Runza, Valeria; Hoves, Sabine; Bilocq, Amélie M; Bindea, Gabriela; Mazza, Emilia M C; Bicciato, Silvio; Galon, Jérôme; Murray, Peter J; Bronte, Vincenzo

    2016-09-12

    Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies.

  9. T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells.

    PubMed

    Marigo, Ilaria; Zilio, Serena; Desantis, Giacomo; Mlecnik, Bernhard; Agnellini, Andrielly H R; Ugel, Stefano; Sasso, Maria Stella; Qualls, Joseph E; Kratochvill, Franz; Zanovello, Paola; Molon, Barbara; Ries, Carola H; Runza, Valeria; Hoves, Sabine; Bilocq, Amélie M; Bindea, Gabriela; Mazza, Emilia M C; Bicciato, Silvio; Galon, Jérôme; Murray, Peter J; Bronte, Vincenzo

    2016-09-12

    Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies. PMID:27622331

  10. 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.

  11. Bevacizumab as Therapy for Radiation Necrosis in Four Children With Pontine Gliomas

    SciTech Connect

    Liu, Arthur K.; Macy, Margaret E.; Foreman, Nicholas K.

    2009-11-15

    Purpose: Diffuse pontine gliomas are a pediatric brain tumor that is fatal in nearly all patients. Given the poor prognosis for patients with this tumor, their quality of life is very important. Radiation therapy provides some palliation, but can result in radiation necrosis and associated neurologic decline. The typical treatment for this necrosis is steroid therapy. Although the steroids are effective, they have numerous side effects that can often significantly compromise quality of life. Bevacizumab, an antibody against vascular endothelial growth factor, has been suggested as a treatment for radiation necrosis. We report on our initial experience with bevacizumab therapy for radiation necrosis in pediatric pontine gliomas. Materials and Methods: Four children with pontine gliomas treated at the Children's Hospital in Denver and the University of Colorado Denver developed evidence of radiation necrosis both clinically and on imaging. Those 4 children then received bevacizumab as a treatment for the radiation necrosis. We reviewed the clinical outcome and imaging findings. Results: After bevacizumab therapy, 3 children had significant clinical improvement and were able to discontinue steroid use. One child continued to decline, and, in retrospect, had disease progression, not radiation necrosis. In all cases, bevacizumab was well tolerated. Conclusions: In children with pontine gliomas, bevacizumab may provide both therapeutic benefit and diagnostic information. More formal evaluation of bevacizumab in these children is needed.

  12. Tumour necrosis factor in synovial exudates.

    PubMed Central

    Di Giovine, F S; Nuki, G; Duff, G W

    1988-01-01

    The actions of tumour necrosis factor (TNF) include resorption of bone and cartilage, suggesting a potential role in the pathogenesis of arthritis. TNF activity was looked for in synovial fluids from 137 patients with different rheumatic diseases. Unfractionated samples were tested in the L929 bioassay. Significant TNF activity that was neutralised by monoclonal antibody to TNF alpha occurred in 13 (30%) of 44 samples. Raised TNF levels were not associated with any particular disease type or routine laboratory markers of inflammation but were related to disease duration in osteoarthritis. The finding of biologically active TNF in symptomatic joints of arthritic patients supports the idea that it may contribute to the pathogenesis of joint damage in chronic rheumatic diseases. PMID:3263088

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

    PubMed

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

    2016-05-01

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

  14. The effects of calcitriol therapy on serum interleukin-1, interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis.

    PubMed

    Inanir, A; Ozoran, K; Tutkak, H; Mermerci, B

    2004-01-01

    Seventy post-menopausal women with osteoporosis were randomized into two groups: 40 patients received calcitriol (0.5 microg/day) and calcium (1000 mg/day); and 30 control patients received calcium (1000 mg/day) alone. Thirty healthy women formed the healthy control group. Bone mineral density (BMD) and serum interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha (TNF-alpha) concentrations were measured at baseline and after 6 months of treatment. Calcitriol treatment for 6 months significantly increased BMD and reduced serum IL-1 and TNF-alpha concentrations compared with no significant changes in patients treated with calcium alone. Both treatments increased serum calcium and decreased parathyroid hormone concentrations. The healthy control group had a significantly lower IL-6 concentration than the post-menopausal women with osteoporosis. We have shown that calcitriol was an effective treatment for osteoporosis. Significant reductions in serum IL-1 and TNF-alpha concentrations suggest that, in addition to increasing the absorption of calcium, calcitriol may directly affect bone metabolism via cytokines.

  15. TRAF1/C5 but Not PTPRC Variants Are Potential Predictors of Rheumatoid Arthritis Response to Anti-Tumor Necrosis Factor Therapy

    PubMed Central

    Rodrigues, Ana Maria; Santos, Maria José; Bettencourt, Bruno F.; Cui, Jing; Rocha, Fabiana L.; Canas Silva, José; Polido-Pereira, Joaquim; Pereira Silva, José Alberto; Costa, José António; Araujo, Domingos; Silva, Cândida; Santos, Helena; Duarte, Cátia; Cáliz, Rafael; Filipescu, Ileana; Pimentel-Santos, Fernando; Branco, Jaime; Sainz, Juan; Plenge, Robert M.; Solomon, Daniel H.; Bruges-Armas, Jácome; Da Silva, José António P.; Fonseca, João Eurico; Karlson, Elizabeth W.

    2015-01-01

    Background. The aim of our work was to replicate, in a Southern European population, the association reported in Northern populations between PTPRC locus and response to anti-tumor necrosis factor (anti-TNF) treatment in rheumatoid arthritis (RA). We also looked at associations between five RA risk alleles and treatment response. Methods. We evaluated associations between anti-TNF treatment responses assessed by DAS28 change and by EULAR response at six months in 383 Portuguese patients. Univariate and multivariate linear and logistic regression analyses were performed. In a second step to confirm our findings, we pooled our population with 265 Spanish patients. Results. No association was found between PTPRC rs10919563 allele and anti-TNF treatment response, neither in Portuguese modeling for several clinical variables nor in the overall population combining Portuguese and Spanish patients. The minor allele for RA susceptibility, rs3761847 SNP in TRAF1/C5 region, was associated with a poor response in linear and logistic univariate and multivariate regression analyses. No association was observed with the other allellic variants. Results were confirmed in the pooled analysis. Conclusion. This study did not replicate the association between PTPRC and the response to anti-TNF treatment in our Southern European population. We found that TRAF1/C5 risk RA variants potentially influence anti-TNF treatment response. PMID:25834819

  16. Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy.

    PubMed

    Schaer, David A; Hirschhorn-Cymerman, Daniel; Wolchok, Jedd D

    2014-01-01

    With the success of ipilimumab and promise of programmed death-1 pathway-targeted agents, the field of tumor immunotherapy is expanding rapidly. Newer targets for clinical development include select members of the tumor necrosis factor receptor (TNFR) family. Agonist antibodies to these co-stimulatory molecules target both T and B cells, modulating T-cell activation and enhancing immune responses. In vitro and in vivo preclinical data have provided the basis for continued development of 4-1BB, OX40, glucocorticoid-induced TNFR-related gene, herpes virus entry mediator, and CD27 as potential therapies for patients with cancer. In this review, we summarize the immune response to tumors, consider preclinical and early clinical data on select TNFR family members, discuss potential translational challenges and suggest possible combination therapies with the aim of inducing durable antitumor responses. PMID:24855562

  17. 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.

  18. Evaluation of Th9 lymphocytes in peripheral blood of rheumatoid arthritis patients and correlation with anti-tumor necrosis factor therapy: results from an in vitro pivotal study.

    PubMed

    Talotta, R; Berzi, A; Atzeni, F; Dell'Acqua, D; Sarzi Puttini, P; Trabattoni, D

    2016-01-01

    The aim of this study was to determine the prevalence of T helper 9 (Th9) lymphocytes in rheumatoid arthritis (RA) patients and to identify a possible association between the percentage of Th9 and the discontinuation of a biological treatment with an anti-tumor necrosis factor (TNF) (infliximab). We collected peripheral blood mononuclear cells (PBMCs) from 55 consecutive RA outpatients and 10 healthy controls. Among RA patients, 15 were not receiving any immunosuppressive drug, 20 were successfully treated with infliximab and 20 discontinued infliximab because of adverse events or inefficacy and were treated with other biological agents. PBMCs were cultured with/without infliximab 50 mg/L for 18 h, and the percentage of Th9 cells was assessed by means of flow cytometry. Th9 lymphocytes were identified as interferon gamma, interleukin (IL)4-, IL17-, IL9-secreting cluster of differentiation 4 (CD4)+ T cells. Cytometric analysis revealed no significant decrease in the percentage of Th9 cells after infliximab exposure in any of the groups, although it was lower in healthy controls than RA patients either before and after the infliximab stimulation assay. Th9 cells are IL-9-secreting T helper lymphocytes whose role in RA is still poorly known. IL-9 levels are increased in RA patients, in whom this cytokine plays a crucial role. Th9 cells are the major producers of IL-9, and their prevalence is higher in RA patients than in healthy subjects; however our experiment in vitro does not demonstrate an association between Th9 lymphocytes and the response to infliximab. Further studies are required to evaluate the real involvement of Th9 population in the immunogenicity of anti-TNF agents. PMID:27608796

  19. 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

  20. Tumour necrosis factors in childhood asthma.

    PubMed

    Najam, F I; Giasuddin, A S; Shembesh, A H

    2001-03-01

    Tumour necrosis factor-alpha (TNF alpha) and TNF beta levels in serum were measured by enzyme immunoassays in 64 Libyan children (age: 1-12 years, sex: 39 males, 25 females) with mild to moderately severe asthma (Group A). Among these patients, 35 had active disease (AA) and 29 had inactive disease (NA). According to age range, 20, 21 and 23 patients were between 1-3 years (A1), > 3-5 years (A2) and > 5-12 years (A3) respectively. A1 had 9 and 11 patients with active (AA1) and inactive (NA1) disease; A2 had 10 and 11 patients with active (AA2) and inactive (NA2) disease; A3 had 16 and 7 patients with active (AA3) and inactive (NA3) disease respectively. Age-matched comparisons was made with 57 healthy children (age: 1-12 years; sex: 30 males, 27 females) (Group B). Among the controls, 15, 19 and 23 children were between 1-3 years (B1), > 3-5 years (B2) and > 5-12 years (B3) respectively. It was observed that serum mean TNF alpha level was significantly higher in patients, while TNF beta levels was normal (A vs B-TNF alpha P < 0.001, TNF beta: P > 0.1). The TNF alpha level was elevated significantly in active disease, while it was normal in inactive disease (AA, NA, B: P = 0.0001; AA vs NA; P < 0.0001; NA vs B: P > 0.05) and TNF beta levels were normal in both groups (AA, NA, B: P = 0.25). Further, TNF alpha levels were significantly higher in all age ranges but in patients with active disease only (AA1, NA1, B: P = 0.0008; AA2, NA2, B: P = 0.0003; AA3, NA3, B: P = 0.0396). TNF alpha may therefore be involved in the pathophysiology of asthma possibly through various proinflammatory mechanisms.

  1. Induction maintenance with tumour necrosis factor-inhibitor combination therapy with discontinuation versus methotrexate monotherapy in early rheumatoid arthritis: a systematic review and meta-analysis of efficacy in randomised controlled trials

    PubMed Central

    Emamikia, Sharzad; Arkema, Elizabeth V; Györi, Noémi; Detert, Jacqueline; Chatzidionysiou, Katerina; Dougados, Maxime; Burmester, Gerd Rüdiger; van Vollenhoven, Ronald

    2016-01-01

    Objective To determine whether an induction-maintenance strategy of combined therapy (methotrexate (MTX)+tumour necrosis factor (TNF) inhibitor (TNFi)) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy, since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn. Methods We performed a meta-analysis of trials using the initial combination of MTX+TNFi in conventional synthetic disease-modifying antirheumatic drug-naïve patients with early rheumatoid arthritis (RA). A systematic literature search was performed for induction-maintenance randomised controlled trials (RCTs) where initial combination therapy was compared with MTX monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved low disease activity (LDA; Disease Activity Score (DAS)28<3.2) and/or remission (DAS28<2.6) at 12–76 weeks of follow-up. A random-effects model was used to pool the risk ratio (RR) for LDA and remission and heterogeneity was explored by subgroup analyses. Results We identified 6 published RCTs, 4 of them where MTX+adalimumab was given as initial therapy and where adalimumab was withdrawn in a subset of patients after LDA/remission had been achieved. 2 additional trials used MTX+infliximab as combination therapy. The pooled RRs for achieving LDA and clinical remission at follow-up after withdrawal of TNFi were 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively. There was significant heterogeneity between trials due to different treatment strategies, which was a limitation to this study. Conclusions Initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNFi. PMID:27651929

  2. Induction maintenance with tumour necrosis factor-inhibitor combination therapy with discontinuation versus methotrexate monotherapy in early rheumatoid arthritis: a systematic review and meta-analysis of efficacy in randomised controlled trials

    PubMed Central

    Emamikia, Sharzad; Arkema, Elizabeth V; Györi, Noémi; Detert, Jacqueline; Chatzidionysiou, Katerina; Dougados, Maxime; Burmester, Gerd Rüdiger; van Vollenhoven, Ronald

    2016-01-01

    Objective To determine whether an induction-maintenance strategy of combined therapy (methotrexate (MTX)+tumour necrosis factor (TNF) inhibitor (TNFi)) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy, since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn. Methods We performed a meta-analysis of trials using the initial combination of MTX+TNFi in conventional synthetic disease-modifying antirheumatic drug-naïve patients with early rheumatoid arthritis (RA). A systematic literature search was performed for induction-maintenance randomised controlled trials (RCTs) where initial combination therapy was compared with MTX monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved low disease activity (LDA; Disease Activity Score (DAS)28<3.2) and/or remission (DAS28<2.6) at 12–76 weeks of follow-up. A random-effects model was used to pool the risk ratio (RR) for LDA and remission and heterogeneity was explored by subgroup analyses. Results We identified 6 published RCTs, 4 of them where MTX+adalimumab was given as initial therapy and where adalimumab was withdrawn in a subset of patients after LDA/remission had been achieved. 2 additional trials used MTX+infliximab as combination therapy. The pooled RRs for achieving LDA and clinical remission at follow-up after withdrawal of TNFi were 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively. There was significant heterogeneity between trials due to different treatment strategies, which was a limitation to this study. Conclusions Initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNFi.

  3. Anti-tumor necrosis factortherapy and changes of flow-mediated vasodilatation in psoriatic and rheumatoid arthritis patients.

    PubMed

    Mazzoccoli, Gianluigi; Notarsanto, Incoronata; de Pinto, Gennaro Davide; Dagostino, Mariangela Pia; De Cata, Angelo; D'Alessandro, Giuseppe; Tarquini, Roberto; Vendemiale, Gianluigi

    2010-12-01

    For a long time, the endothelial covering of the vessels has been considered an inert surface. On the contrary, the endothelial cells are active and dynamic elements in the interaction between blood and tissues. The control of the vessel basal tone is obtained by the complex balance between the relaxing and contracting endothelial factors. Previous clinical studies show that patients suffering from rheumatoid arthritis and other autoimmune rheumatologic pathologies are at high risk of death being prematurely affected by atherosclerosis and cardiovascular diseases. Blocking tumor necrosis factor (TNF)-α by biological drugs improves the endothelial function. The aim of our study was to evaluate the effects of two anti-TNF-α drugs (infliximab and etanercept) on the endothelial function by evaluating the flow-mediated dilatation (FMD), which was measured in the brachial artery before and after treatment and after 8-12 weeks. We enrolled 36 patients (average age 52 ± 9.8 years, 12 men and 24 women), 25 of them were affected by rheumatoid arthritis (RA) and 11 were affected by psoriatic arthritis (PsA) and they were divided into three groups: 10 patients were treated with etanercept, 13 patients were treated with infliximab, 13 patients were treated with DMARDs. We measured the common carotid intimal-medial thickness (ccIMT) and the endothelial function was evaluated by FMD measurement in the brachial artery, before treatment, 1 h after the beginning of treatment and after 8-12 weeks. No statistically significant difference between the three groups was found for the ultrasonographic evaluation of the carotid IMT. On the contrary, the differences between FMD values before and after the treatment in the patients treated with etanercept (13.1 ± 0.01 vs. 18.8 ± 0.01%, p < 0.01) and in the patients treated with infliximab (11.8 ± 0.09 vs. 16.7 ± 0.09%, p < 0.01) were statistically significant. Long-term evaluation for infliximab and etanercept was

  4. [Cell therapy for aseptic necrosis of femoral head].

    PubMed

    Toguchida, Junya; Aoyama, Tomoki; Goto, Koji; Kakinoki, Ryosuke; Kasai, Yasunari

    2011-12-01

    As the clinical application of mesenchymal stem cell (MSC), we have engaged in the development of cell transplantation therapy for aseptic necrosis of femoral head. Based on the results obtained by in vitro and in vivo preclinical experiments, we established the protocol for the clinical trial combining MSC with vascularized bone grafts. The protocol was approved by IRB on November 25, 2007, and the first case was operated on February 22, 2008. Since then 10 cases have been successfully treated and were followed at least 24 months with satisfactory results.

  5. PDE3A-SLCO1C1 locus is associated with response to anti-tumor necrosis factor therapy in psoriatic arthritis.

    PubMed

    Julià, Antonio; Rodríguez, Jesús; Fernández-Sueiro, José Luis; Gratacós, Jordi; Queiró, Rubén; Montilla, Carlos; Torre-Alonso, Juan Carlos; Pérez-Venegas, José Javier; Manrique-Arija, Sara; Muñoz-Fernández, Santiago; González, Carlos; Roig, Daniel; Zarco, Pedro; Erra, Alba; Castañeda, Santos; García, Alicia; Salvador, Georgina; Díaz-Torne, César; Blanco, Ricardo; Domínguez, Alfredo Willisch; Mosquera, José Antonio; Vela, Paloma; Tornero, Jesús; Sánchez-Fernández, Simón; Corominas, Héctor; Ramírez, Julio; Avila, Gabriela; Alonso, Arnald; Tortosa, Raül; López-Lasanta, María; Cañete, Juan D; Marsal, Sara

    2014-11-01

    Aim: Variation at PDE3A-SLCO1C1 locus has been recently associated with the response to anti-TNF therapy in rheumatoid arthritis. We undertook the present study to determine whether PDE3A-SLCO1C1 is also associated with the response to anti-TNF therapy in psoriatic arthritis. Patients & methods: Genomic DNA was obtained from 81 psoriatic arthritis patients that had been treated with anti-TNF therapy. PDE3A-SLCO1C1 SNP rs3794271 was genotyped using Taqman realt-time PCR. The clinical response to anti-TNF therapy was measured as the change from baseline in the level of disease activity according to the DAS28 score. Results: A significant association between rs3794271 and anti-TNF response in psoriatic arthritis was found (beta = -0.71; p = 0.0036). Conclusion: PDE3A-SLCO1C1 locus is also associated with response to anti-TNF therapy in psoriatic arthritis. Original submitted 12 May 2014; Revision submitted 18 August 2014.

  6. B cells from rheumatoid arthritis patients show important alterations in the expression of CD86 and FcγRIIb, which are modulated by anti-tumor necrosis factor therapy

    PubMed Central

    2010-01-01

    Introduction Several molecules help preserve peripheral B cell tolerance, but when altered, they may predispose to autoimmunity. This work studied the expression of the costimulatory molecule CD86 and the inhibitory receptor for IgG immune complexes FcγRIIb (CD32b), on B cells from rheumatoid arthritis (RA) patients, and the influence of anti-tumor necrosis factor (TNF) therapy. Methods Peripheral B cells from 18 RA patients and 13 healthy donors were characterized using flow cytometry. Eleven patients who underwent a six-month adalimumab therapy were further assessed for phenotypic changes on their B cells. Results RA patients exhibited a high percentage of naïve and memory B cells expressing CD86. In contrast, expression of FcγRIIb was significantly reduced on RA memory B cells and plasmablasts as compared to healthy donors, probably due to downregulation of this receptor when differentiating from naïve to memory cells. These alterations on FcγRIIb were associated with high levels of anti-citrullinated vimentin autoantibodies. In addition, treatment with adalimumab normalized the expression of CD86 on memory B cells and reduced the expression of FcγRIIb, mainly on naïve B cells. Conclusions Our findings show that peripheral B cells from RA patients have an altered expression of key molecules, such as CD86 and FcγRIIb. Because this latter receptor is required for feedback inhibition, a deficient expression might contribute to humoral autoimmune responses. Furthermore, these molecules are likely to be influenced by inflammatory factors, since they were modulated by TNF inhibition. PMID:20398308

  7. Dose–Volume Relationships Associated With Temporal Lobe Radiation Necrosis After Skull Base Proton Beam Therapy

    SciTech Connect

    McDonald, Mark W.; Linton, Okechukwu R.; Calley, Cynthia S.J.

    2015-02-01

    Purpose: We evaluated patient and treatment parameters correlated with development of temporal lobe radiation necrosis. Methods and Materials: This was a retrospective analysis of a cohort of 66 patients treated for skull base chordoma, chondrosarcoma, adenoid cystic carcinoma, or sinonasal malignancies between 2005 and 2012, who had at least 6 months of clinical and radiographic follow-up. The median radiation dose was 75.6 Gy (relative biological effectiveness [RBE]). Analyzed factors included gender, age, hypertension, diabetes, smoking status, use of chemotherapy, and the absolute dose:volume data for both the right and left temporal lobes, considered separately. A generalized estimating equation (GEE) regression analysis evaluated potential predictors of radiation necrosis, and the median effective concentration (EC50) model estimated dose–volume parameters associated with radiation necrosis. Results: Median follow-up time was 31 months (range 6-96 months) and was 34 months in patients who were alive. The Kaplan-Meier estimate of overall survival at 3 years was 84.9%. The 3-year estimate of any grade temporal lobe radiation necrosis was 12.4%, and for grade 2 or higher radiation necrosis was 5.7%. On multivariate GEE, only dose–volume relationships were associated with the risk of radiation necrosis. In the EC50 model, all dose levels from 10 to 70 Gy (RBE) were highly correlated with radiation necrosis, with a 15% 3-year risk of any-grade temporal lobe radiation necrosis when the absolute volume of a temporal lobe receiving 60 Gy (RBE) (aV60) exceeded 5.5 cm{sup 3}, or aV70 > 1.7 cm{sup 3}. Conclusions: Dose–volume parameters are highly correlated with the risk of developing temporal lobe radiation necrosis. In this study the risk of radiation necrosis increased sharply when the temporal lobe aV60 exceeded 5.5 cm{sup 3} or aV70 > 1.7 cm{sup 3}. Treatment planning goals should include constraints on the volume of temporal lobes receiving

  8. Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study

    PubMed Central

    Keystone, E C; Genovese, M C; Klareskog, L; Hsia, E C; Hall, S T; Miranda, P C; Pazdur, J; Bae, S-C; Palmer, W; Zrubek, J; Wiekowski, M; Visvanathan, S; Wu, Z; Rahman, M U

    2009-01-01

    Objective: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy. Methods: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n  =  133), golimumab 100 mg injections plus placebo capsules (group 2, n  =  133), golimumab 50 mg injections plus methotrexate capsules (group 3, n  =  89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n  =  89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24. Results: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively. Conclusion: The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function. PMID:19066176

  9. Necrosis prediction of photodynamic therapy applied to skin disorders

    NASA Astrophysics Data System (ADS)

    Fanjul-Vélez, F.; Romanov, O. G.; López-Escobar, M.; Ortega-Quijano, N.; Arce-Diego, J. L.

    2009-02-01

    The great selectivity and the lack of side effects of Photodynamic Therapy make it more advantageous than radiotherapy or chemotherapy. The application of PDT to skin diseases is particularly appropriate, due to the accessibility of this tissue. Common disorders like nonmelanoma skin cancer, that includes basocelullar or squamous cell carcinomas, can be treated with PDT. Conventional procedures, like surgery or radiotherapy, are not so efficient and do not, in general, obtain the same favourable results. PDT in dermatology medical praxis uses fixed protocols depending on the photosensitizer and the optical source used. These protocols are usually provided by the photosensitizer laboratory, and every lesion is treated with the same parameters. In this work we present a photo-chemical model of PDT applied to skin disorders treated with topical photosensitizers. Optical propagation inside the tissue is calculated by means of a 3D diffusion equation, solved via a finite difference numerical method. The photosensitizer degradation or photobleaching is taken into account, as the drug looses efficiency with the irradiation time. With these data the necrosis area is estimated, so this model could be used as a predictive tool to adjust the optical power and exposition time for the particular disease under treatment.

  10. 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.

  11. Renal papillary necrosis and pyelonephritis accompanying fenoprofen therapy.

    PubMed

    Husserl, F E; Lange, R K; Kantrow, C M

    1979-10-26

    Renal papillary necrosis occurred after fenoprofen calcium administration in a patient with systemic lupus erythematosus and urinary tract infection. Possible mechanisms of renal damage may be hypersensitivity, decreased blood flow, and decreased production of a prostaglandin E-like substance.

  12. 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.

  13. Lichenoid Reactions in Association with Tumor Necrosis Factor Alpha Inhibitors: A Review of the Literature and Addition of a Fourth Lichenoid Reaction.

    PubMed

    McCarty, Morgan; Basile, Amy; Bair, Brooke; Fivenson, David

    2015-06-01

    In this manuscript, a clinical case of a patient treated with adalimumab for Behcet's disease develops lichen planopilaris. A variety of mucocutaneous lichenoid eruptions have recently been described in association with tumor necrosis factor alpha inhibitors. The authors briefly discuss the clinical and pathological presentation of lichen planopilaris as well as a potential pathogenesis of cutaneous adverse effects seen as the result of tumor necrosis factor alpha inhibitor therapy. They review all case reports of lichen planopilaris occurring on tumor necrosis factor alpha inhibitors and suggest its classification as a fourth recognized pattern on this therapy.

  14. Molecular biology and immunology for clinicians 23: autoimmunity and the superfamilies of tumor necrosis factor and tumor necrosis factor receptor.

    PubMed

    Sigal, Leonard H

    2003-04-01

    The parsimony of nature can be stated as "if its not broke don't fix it, just tweak it and reuse it again and again." Nature recycles: once a motif is demonstrably useful it shows up again, often in unexpected places. Tumor necrosis factor and its receptor(s) are examples of this. At least 20 molecules have now been identified as being 25% homologous or more identical with tumor necrosis factor and being involved in a variety of immune and nonimmune functions. Members of the receptor superfamily have shared structural motifs and trigger shared intracellular signaling pathways. Rather than having been implicated in arcane and rare syndromes, some of these activities are pivotal in immune function and, when perturbed, some predispose to known immunodeficiency and autoimmune disease. Not surprisingly, some of these are becoming targets for immunomodulation. New members of these 2 superfamilies are currently being described and the newcomers and the "original stock" will show up in the clinic before you know it! Part of the confusion has always been that each laboratory describing a new biologic principle names the mediating compound. Thus, multiple labs, multiple names for the same protein (recall Ro/SS-A, La/SS-B). Thus, special attention is paid below to acronyms and their synonyms.

  15. Progressive Outer Retinal Necrosis and Immunosuppressive Therapy in Myasthenia Gravis

    PubMed Central

    Coisy, Solène; Ebran, Jean-Marc; Milea, Dan

    2014-01-01

    Introduction Progressive outer retinal necrosis (PORN) is a rare but devastating infectious retinitis associated with varicella zoster virus (VZV) and responsible for severe visual loss. Case Report A 59-year-old man treated for generalized myasthenia with oral azathioprine and prednisone presented with severe unilateral necrotizing retinitis. Polymerase chain reaction of the aqueous and vitreous humors was diagnostic for VZV PORN. Conclusion VZV PORN is a severe potential ocular complication of immunosuppression, prompting urgent diagnosis and appropriate treatment. PMID:24926266

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

    PubMed

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

    2015-09-01

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

  17. 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

  18. Tumor necrosis factor-alpha antagonist-induced sarcoidosis.

    PubMed

    Clementine, Rochelle Robicheaux; Lyman, Justin; Zakem, Jerald; Mallepalli, Jyothi; Lindsey, Stephen; Quinet, Robert

    2010-09-01

    Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Tumor necrosis factor (TNF)-alpha is an important player in granuloma formation, and recent clinical trials have investigated the efficacy of TNF-alpha inhibitors in sarcoidosis. Paradoxically, there are several case reports in the medical literature describing the development of sarcoidosis in patients treated with TNF-alpha inhibitors. We describe 3 cases of TNF-alpha antagonist-induced sarcoidosis: 1 case of pulmonary, ocular and cutaneous sarcoidosis developing in a patient receiving infliximab for erosive rheumatoid arthritis, 1 case of etanercept-induced sarcoidosis in a patient with seronegative rheumatoid arthritis, and 1 case of sarcoidosis developing in a patient receiving etanercept for erosive rheumatoid arthritis. We also provide a brief discussion on the role of TNF alpha in granuloma formation and implications in the use of TNF-alpha antagonists in autoimmune disease.

  19. Malaria: a tumour necrosis factor inhibitor from parasitized erythrocytes.

    PubMed Central

    Sheikh, N A; Caro, H N; Taverne, J; Playfair, J H; Rademacher, T W

    1996-01-01

    The excessive production of tumour necrosis factor (TNF) is associated with the pathology of blood-stage malaria and phosphatidylinositol-containing phospholipid antigens from parasitized erythrocytes stimulate its secretion by macrophages, thus acting as toxins. This brief report describes some properties of an inhibitor present in lysates from erythrocytes infected with malarial parasites that blocked the detection of recombinant TNF in an enzyme-linked immunosorbent assay and diminished or abolished the cytotoxicity of TNF. It was not found in control lysates of normal erythrocytes. Its addition to macrophage cultures stimulated by toxic malarial preparations or by bacterial lipopolysaccharide also blocked the detection of TNF. These findings may explain the contradictory results obtained from different assays for TNF, and emphasize the need for caution when interpreting the results of a single assay system. If released when parasitized erythrocytes rupture in vivo, the inhibitor could help protect both parasite and host from the damaging effects of TNF. PMID:8778034

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

    PubMed

    Vadlamani, Lou; Iyengar, Srinivas

    2004-01-01

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

  1. 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.

  2. Predictive Risk of Radiation Induced Cerebral Necrosis in Pediatric Brain Cancer Patients after VMAT Versus Proton Therapy

    PubMed Central

    Freund, Derek; Zhang, Rui; Sanders, Mary; Newhauser, Wayne

    2015-01-01

    Cancer of the brain and central nervous system (CNS) is the second most common of all pediatric cancers. Treatment of many of these cancers includes radiation therapy of which radiation induced cerebral necrosis (RICN) can be a severe and potentially devastating side effect. Risk factors for RICN include brain volume irradiated, the dose given per fraction and total dose. Thirteen pediatric patients were selected for this study to determine the difference in predicted risk of RICN when treating with volumetric modulated arc therapy (VMAT) compared to passively scattered proton therapy (PSPT) and intensity modulated proton therapy (IMPT). Plans were compared on the basis of dosimetric endpoints in the planned treatment volume (PTV) and brain and a radiobiological endpoint of RICN calculated using the Lyman-Kutcher-Burman probit model. Uncertainty tests were performed to determine if the predicted risk of necrosis was sensitive to positional errors, proton range errors and selection of risk models. Both PSPT and IMPT plans resulted in a significant increase in the maximum dose to the brain, a significant reduction in the total brain volume irradiated to low doses, and a significant lower predicted risk of necrosis compared with the VMAT plans. The findings of this study were upheld by the uncertainty analysis. PMID:25866999

  3. Tumour necrosis factor-alpha induces translocation of protein kinase C in tumour necrosis factor-sensitive cell lines.

    PubMed Central

    Matsubara, N; Fuchimoto, S; Orita, K

    1991-01-01

    In this study we investigated whether the anti-proliferative effect of tumour necrosis factor-alpha (TNF-alpha) was associated with the activation of protein kinase C (PKC), using PANC-1 cells (TNF-alpha sensitive) and LoVo cells (TNF-alpha resistant). In combination with 12-0-tetradecanoylphorbol-13-acetate (TPA), a potent activator of PKC, TNF-alpha caused marked inhibition of the growth of LoVo cells. Inhibition of PANC-1 cell growth by TNF-alpha was blocked by pretreatment with TPA for 24 hr, along with down-regulation of PKC activity. Intracellular translocation of PKC from cytosol to membrane was induced by TNF-alpha treatment in PANC-1 cells but not in LoVo cells. PMID:1916896

  4. Unexpected radiation laryngeal necrosis after carbon ion therapy using conventional dose fractionation for laryngeal cancer.

    PubMed

    Demizu, Yusuke; Fujii, Osamu; Nagano, Fumiko; Terashima, Kazuki; Jin, Dongcun; Mima, Masayuki; Oda, Naoharu; Takeuchi, Kaoru; Takeda, Makiko; Ito, Kazuyuki; Fuwa, Nobukazu; Okimoto, Tomoaki

    2015-11-01

    Carbon ion therapy is a type of radiotherapy that can deliver high-dose radiation to a tumor while minimizing the dose delivered to organs at risk. Moreover, carbon ions are classified as high linear energy transfer radiation and are expected to be effective for even photon-resistant tumors. A 73-year-old man with glottic squamous cell carcinoma, T3N0M0, refused laryngectomy and received carbon ion therapy of 70 Gy (relative biological effectiveness) in 35 fractions. Three months after the therapy, the patient had an upper airway inflammation, and then laryngeal edema and pain occurred. Five months after the therapy, the airway stenosis was severe and computed tomography showed lack of the left arytenoid cartilage and exacerbation of laryngeal necrosis. Despite the treatment, 5 and a half months after the therapy, the laryngeal edema and necrosis had become even worse and the surrounding mucosa was edematous and pale. Six months after the therapy, pharyngolaryngoesophagectomy and reconstruction with free jejunal autograft were performed. The surgical specimen pathologically showed massive necrosis and no residual tumor. Three years after the carbon ion therapy, he is alive without recurrence. The first reported laryngeal squamous cell carcinoma case treated with carbon ion therapy resulted in an unexpected radiation laryngeal necrosis. Tissue damage caused by carbon ion therapy may be difficult to repair even for radioresistant cartilage; therefore, hollow organs reinforced by cartilage, such as the larynx, may be vulnerable to carbon ion therapy. Caution should be exercised when treating tumors in or adjacent to such organs with carbon ion therapy.

  5. Extracorporeal shockwave therapy for avascular necrosis of femoral head.

    PubMed

    Wang, Ching-Jen; Cheng, Jai-Hong; Huang, Chung-Cheng; Yip, Han-Kan; Russo, Sergio

    2015-12-01

    The etiology of osteonecrosis of the femoral head (ONFH) is multifactorial. Treatment of ONFH is disease stage dependent. For early stages, femoral head preservation procedures are preferred including core decompression, muscle pedicle grafting and de-rotational osteotomy. Core decompression with bone grafting is considered the gold standard. However, the results are inconsistence and unpredictable. An effective non-invasive method of treatment is imperative. Recently, extracorporeal shockwave therapy (ESWT) has shown beneficial effects in ONFH. ESWT improves pain and function of the hip and regression of the ONFH lesion. ESWT is more effective than core decompression with or without bone grafting, cocktail therapy that combined HBO, ESWT and oral alendronate is shown effective for patients with early osteonecrosis. The purpose of the article is to review, update and summarize the clinical treatment of ONFH using shockwave therapy.

  6. 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.

  7. 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 factortherapy 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

  8. Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

    PubMed Central

    Torres, David; Janot, Laure; Quesniaux, Valerie F.J.; Grivennikov, Sergei I.; Maillet, Isabelle; Sedgwick, Jonathon D.; Ryffel, Bernhard; Erard, Francois

    2005-01-01

    Tumor necrosis factor (TNF) plays a critical role in the host response to the intracellular pathogen Listeria monocytogenes (LM). TNF exists in soluble and membrane-bound forms and exhibits both unique and overlapping activities. We examined the role of membrane TNF in the absence of secreted TNF for host resistance in knockin mice in which the endogenous TNF was replaced by a regulated, noncleavable allele (mem-TNF). Macrophages expressing mem-TNF produced nitric oxide and displayed normal bactericidal activity. Although mice completely deficient in TNF (TNF−/−) succumbed to LM infection within 4 days, mem-TNF mice controlled LM infection at a low dose (104 CFU) but succumbed at a higher dose of infection (105 CFU). In contrast to complete TNF deficiency, mem-TNF mice developed confined microabscesses that expressed inducible nitric oxide synthase. The transfer of lymphocytes from immunized mem-TNF, but not TNF−/−, mice protected TNF−/− mice from fatal infection. Taken together the data suggest that in the absence of soluble TNF, the presence of membrane-expressed TNF on phagocytes and lymphocytes partially restores host defense to LM infection. PMID:16314479

  9. 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. PMID:7842491

  10. 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

  11. Tumour necrosis factor induction by malaria exoantigens depends upon phospholipid.

    PubMed Central

    Bate, C A; Taverne, J; Román, E; Moreno, C; Playfair, J H

    1992-01-01

    In patients with malaria, the clinical manifestations of the disease are associated with the presence of high concentrations of tumour necrosis factor (TNF) in the serum. Blood-stage parasites of human and rodent malarial parasites release serologically related exoantigens which induce the production of TNF in vitro and in vivo and which can kill mice made hypersensitive to TNF by pretreatment with D-galactosamine. They also elicit the production of T-independent antibody, which blocks these effects. The capacity of the exoantigens to stimulate macrophages to secrete TNF does not require the presence of protein or carbohydrate, but is associated with a lipid whose activity can be abolished by treatment with phospholipase C. Treatments of the exoantigens which destroyed their activity in vitro also abrogated their immunogenicity and their toxicity for mice. No TNF-inducing activity could be detected in preparations of parasitized erythrocytes that was not associated with phospholipid, and the TNF-inducing properties of the malarial phospholipids are quite distinct from those of bacterial lipopolysaccharide. We conclude that release of potentially toxic phospholipids by parasites may be responsible for some of the pathology of malaria. PMID:1537589

  12. Tumor necrosis factor alpha-induced pulmonary vascular endothelial injury.

    PubMed Central

    Goldblum, S E; Hennig, B; Jay, M; Yoneda, K; McClain, C J

    1989-01-01

    Tumor necrosis factor alpha (TNF-alpha) mediates components of the acute-phase response, stimulates granulocyte metabolism, and induces endothelial cell surface changes. We studied whether human recombinant TNF-alpha (rTNF-alpha) could increase pulmonary edema formation and pulmonary vascular permeability. Rabbits preinfused with 125I-albumin were administered rTNF-alpha or saline. Animals were sacrificed, and lung wet/dry weight ratios as well as bronchoalveolar lavage fluid and plasma 125I activities were determined. rTNF-alpha increased lung wet/dry weight ratios by 151% (P less than 0.02) and bronchoalveolar lavage fluid/plasma 125I activity ratios by 376% (P less than 0.01) compared with values for saline controls. Electron microscopy of lung sections demonstrated endothelial injury, perivascular edema, and extravasation of an ultrastructural permeability tracer. To demonstrate that rTNF-alpha could directly increase pulmonary vascular endothelial permeability in vitro, we studied albumin transfer across cultured porcine pulmonary artery endothelial cell monolayers. rTNF-alpha induced time-dependent dose-response increments in transendothelial albumin flux in the absence of granulocyte effector cells. These observations suggest that rTNF-alpha can provoke acute pulmonary vascular endothelial injury in vivo as well as in vitro. Images PMID:2925247

  13. Haplotypes of tumor necrosis factor gene and tracheal aspirate fluid levels of tumor necrosis factor-alpha in preterm infants.

    PubMed

    Kazzi, S Nadya J; Tromp, Gerard; Quasney, Michael W; Buhimschi, Irina A

    2008-08-01

    Individual variability in the production of tumor necrosis factor-alpha (TNF-alpha) has been attributed to genetic factors. We examined whether alleles of TNF gene (lymphotoxin-alpha+250, TNF-alpha-308, and TNF-alpha-238) affect tracheal aspirate fluid (TAF) levels of TNF-alpha among preterm infants at risk of bronchopulmonary dysplasia. TAF samples were collected within 48 h of birth and 7, 14, 21, and 28 d later. Haplotypes [designated using the nucleotide bases in the chromosome order (lymphotoxin-alpha+250, TNF-alpha-308, TNF-alpha-238)] of TNF were correlated with levels of TNF-alpha. Diplotypes of TNF (genotypes of haplotypes) classified as high, intermediate, or low based on their relation to TAF TNF-alpha levels were also correlated with TNF-alpha levels. The most frequent (and reference haplotype) was AGG. The GGG haplotype was associated with the lowest TAF TNF-alpha levels on day 7 among African American infants (p < 0.008). Sequential changes in levels of TNF-alpha correlated with infants' diplotype status [high (HH), intermediate (HL), low (LL)]. Fetal chorioamnionitis but not bronchopulmonary dysplasia was associated with infants' diplotypes (p < 0.005). Haplotypes of the TNF gene influence TAF levels of TNF-alpha. Diplotypes of TNF are associated with fetal chorioamnionitis.

  14. Lack of validation of genetic variants associated with anti–tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis

    PubMed Central

    2014-01-01

    Introduction In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations. Methods The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients. Results None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis. Conclusion Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes. PMID:24612463

  15. Warfarin-induced skin necrosis diagnosed on clinical grounds and treated with maggot debridement therapy.

    PubMed

    Biscoe, Anna Louise; Bedlow, Alison

    2013-01-01

    A patient with a history of deep vein thrombosis presented with painful bruising and blistering on his left leg 7-10 days after warfarin treatment. A complicated 2-month treatment followed, where vasculitis was originally diagnosed from histological findings before the final diagnosis of warfarin-induced skin necrosis (WISN) was made on clinical grounds. Warfarin was stopped, reversed and low molecular weight heparin started but, the lesions had progressed to full thickness necrosis. This was originally treated with conventional surgical debridement before introducing maggot debridement therapy (MDT) in an effort to try to salvage the limb.

  16. 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

  17. Fibrinolytic response to tumor necrosis factor in healthy subjects.

    PubMed

    van der Poll, T; Levi, M; Büller, H R; van Deventer, S J; de Boer, J P; Hack, C E; ten Cate, J W

    1991-09-01

    Tumor necrosis factor (TNF) may be involved in the disturbance of the procoagulant-fibrinolytic balance in septicemia, leading to microvascular thrombosis. To assess the dynamics of the fibrinolytic response to TNF in humans, we performed a crossover saline-controlled study in six healthy men, investigating the effects of a bolus intravenous injection of recombinant human TNF (50 micrograms/m2) on the stimulation and inhibition of plasminogen activation as well as on plasmin activity and inhibition. TNF induced a brief fourfold increase in the overall plasma plasminogen activator (PA) activity peaking after 1 h (p less than 0.0001), which was associated with rises in the antigenic levels of urokinase-type plasminogen activator (p less than 0.0001) and tissue-type plasminogen activator (p less than 0.0001). Plasminogen activator inhibitor type I antigen remained unchanged in the first hour, but showed a rapid eightfold increase thereafter (p less than 0.0001), which coincided with the decrease in PA activity. Generation of plasmin activity in the first hour was signified by an 11-fold rise in D-dimer levels (p less than 0.0001); inhibition of plasmin was reflected by a 36-fold rise in plasmin-alpha 2 antiplasmin complexes (p less than 0.0001), as well as by a transient 16% decrease in alpha 2-antiplasmin activity (p less than 0.01). In conclusion, TNF induced an early activation of the fibrinolytic system becoming maximal in 1 h, with a rapid inhibition thereafter. Earlier observations in the same subjects showed sustained coagulation activation for 6-12 h. The observed disbalance between the procoagulant and fibrinolytic mechanisms after TNF injection confirms the in vivo relevance of the effects of TNF on vascular endothelium in vitro and may explain the tendency towards microvascular thrombosis in septicemia.

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

    PubMed

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

    2015-10-01

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

  19. 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.

  20. Exogenous tumour necrosis factor α induces suppression of autoimmune arthritis

    PubMed Central

    2008-01-01

    Introduction Our previous studies showed that arthritic Lewis (LEW) rats produced the highest levels of tumour necrosis factor (TNF)α in the recovery phase of adjuvant arthritis (AA), suggesting a correlation between high TNFα levels and reduced severity of arthritis. To further explore this correlation, we compared the TNFα secretion profile of the AA-resistant Wistar Kyoto (WKY) rats with that of LEW rats, determined the effect of exogenous TNFα on the course of AA in LEW rats, and examined various mechanisms involved in TNFα-induced disease modulation. Methods A cohort each of LEW and WKY rats was immunised subcutaneously with heat-killed Mycobacterium tuberculosis H37Ra (Mtb). At different time points thereafter, subgroups of rats were killed and their draining lymph node cells were tested for cytokine production. Another group of LEW rats was injected with TNFα intraperitoneally daily for a total of 10 injections, 3 before and 6 after Mtb challenge, and then observed for signs of AA. In parallel, TNFα-treated rats were examined for changes in other cytokines, in CD4+CD25+ T cell frequency, and in indoleamine 2,3-dioxygenase (IDO) mRNA expression levels. Results LEW rats displayed a TNFα secretion profile that was opposite to that of the WKY rats. Furthermore, TNFα treatment significantly downmodulated the severity of AA in LEW rats, and decreased the interferon (IFN)-γ secretion in response to the pathogenic determinant of the disease-related antigen. No significant alterations were observed in other parameters tested. Conclusion The role of endogenous TNFα in the induction and propagation of arthritis is well established. However, exogenous TNFα can downmodulate the course of AA, displaying an immunoregulatory functional attribute of this cytokine. PMID:18380898

  1. 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

  2. New advances in the mesenchymal stem cells therapy against skin flaps necrosis.

    PubMed

    Zhang, Fu-Gui; Tang, Xiu-Fa

    2014-09-26

    Mesenchymal stem cells (MSCs), multipotential cells that reside within the bone marrow, can be induced to differentiate into various cells, such as osteoblasts, adipocytes, chondrocytes, vascular endothelial progenitor cells, and other cell types. MSCs are being widely studied as potential cell therapy agents due to their angiogenic properties, which have been well established by in vitro and in vivo researches. Within this context, MSCs therapy appears to hold substantial promise, particularly in the treatment of conditions involving skin grafts, pedicle flaps, as well as free flaps described in literatures. The purpose of this review is to report the new advances and mechanisms underlying MSCs therapy against skin flaps necrosis.

  3. Characterization of tumor necrosis factor-deficient mice.

    PubMed

    Marino, M W; Dunn, A; Grail, D; Inglese, M; Noguchi, Y; Richards, E; Jungbluth, A; Wada, H; Moore, M; Williamson, B; Basu, S; Old, L J

    1997-07-22

    Although tumor necrosis factor (TNF) initially came to prominence because of its anti-tumor activity, most attention is now focused on its proinflammatory actions. TNF appears to play a critical role in both early and late events involved in inflammation, from localizing the noxious agent and amplifying the cellular and mediator responses at the local site and systemically, to editing (e.g., apoptosis) injured cells or effete immune cells and repairing inflammatory damage. We have generated mice deficient in TNF (TNF-/- mice) and have begun to examine the multiple functions attributed to TNF. TNF-/- mice develop normally and have no gross structural or morphological abnormalities. As predicted, they are highly susceptible to challenge with an infectious agent (Candida albicans), are resistant to the lethality of minute doses of lipopolysaccharide (LPS) following D-galactosamine treatment, have a deficiency in granuloma development, and do not form germinal centers after immunization. Phagocytic activity of macrophages appears relatively normal, as do T cell functions, as measured by proliferation, cytokine release, and cytotoxicity. B cell response to thymus-independent antigens is normal, but the Ig response to thymus-dependent antigen is reduced. Surprisingly, cytokine production induced by LPS appears essentially intact, with the exception of reduced colony-stimulating factor activity. Other unexpected findings coming from our initial analysis are as follows. (i) TNF has low toxicity in TNF-/- mice. (ii) TNF-/- mice show an anomalous late response to heat-killed Corynebacterium parvum. In contrast to the prompt response (granuloma formation, hepatosplenomegaly) and subsequent resolution phase in C. parvum-injected TNF+/+ mice, similarly treated TNF-/- mice show little or no initial response, but then develop a vigorous, disorganized inflammatory response leading to death. These results suggest that TNF has an essential homeostatic role in limiting the extent and

  4. Tumor necrosis factor-alpha and ceramides in insulin resistance.

    PubMed

    Brindley, D N; Wang, C N; Mei, J; Xu, J; Hanna, A N

    1999-01-01

    The present studies tested the hypothesis that some effects of tumor necrosis factor-alpha (TNF-alpha) are mediated by activation of sphingomyelinases and the production of ceramides. Differentiated 3T3-L1 adipocytes were incubated with short-chain ceramide analogs, (C2- and C6-ceramides: N-acetyl- and N-hexanoyl-sphingosines, respectively), and this treatment increased 2-deoxyglucose uptake in the absence of insulin progressively from 2-24 h. This effect was inhibited by blocking the activations of mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI 3-kinase), and ribosomal S6 kinase which mediated an increase in GLUT1 concentrations. Long-term increases in PI 3-kinase activity associated with insulin receptor substrate-1 (IRS-1) increased the proportion of GLUT1 and GLUT4 in plasma membranes. These events explain the increases in noninsulin-dependent glucose uptake and incorporation of this glucose into the fatty acid and glycerol moieties of triacylglycerol. The mechanisms by which TNF-alpha and ceramides increase PI 3-kinase activity were investigated further by using rat2 fibroblasts. Incubation for 20 min with TNF-alpha, bacterial sphingomyelinase, or C2-ceramides increased PI 3-kinase activity by about fivefold, and this effect depended upon a stimulation of tyrosine kinase activity and an increase in Ras-GTP. This demonstrates the existence of a novel signaling pathway for TNF-alpha that could contribute to the effects of this cytokine in stimulating basal glucose uptake. By contrast, treating the 3T3-L1 adipocytes for 2-24 h with C2-ceramide diminished insulin-stimulated glucose uptake by decreasing the insulin-induced translocation of GLUT1 and GLUT4 to plasma membranes. This inhibition was observed when there was no increase in basal glucose uptake, and it occurred downstream of PI 3-kinase. Our work provides further mechanisms whereby TNF-alpha and ceramides produce insulin resistance and decrease the effectiveness of insulin in

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

    PubMed Central

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

    2016-01-01

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

  6. Successful treatment of childhood onset refractory polyarteritis nodosa with tumor necrosis factor alpha blockade.

    PubMed

    Feinstein, Jeffrey; Arroyo, Ramon

    2005-08-01

    Polyarteritis nodosa is a rare systemic necrotizing vasculitis of small- and medium-sized arteries that affects patients of all ages. Its incidence ranges from 2 to 9 per million people. The 5-year survival rate is 13% in untreated patients and 77.6% with modern therapy. Standard treatment includes corticosteroids and cyclophosphamide. Despite aggressive medical management, 22.4% of patients die within 5 years, and of the survivors, medication-induced morbidity is frequent. There is great need for better treatment modalities in terms of safety and efficacy. We report the case of a 5-year-old boy with polyarteritis nodosa refractory to all known standard treatments. After 9 years of persistently active disease, at the age of 14, he was successfully managed with the tumor necrosis factor alpha antagonist, etanercept.

  7. 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.

  8. Activation of coagulation after administration of tumor necrosis factor to normal subjects.

    PubMed

    van der Poll, T; Büller, H R; ten Cate, H; Wortel, C H; Bauer, K A; van Deventer, S J; Hack, C E; Sauerwein, H P; Rosenberg, R D; ten Cate, J W

    1990-06-01

    Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays. Recombinant human tumor necrosis factor, administered as an intravenous bolus injection (50 micrograms per square meter of body-surface area), induced an early and short-lived rise in circulating levels of the activation peptide of factor X, reaching maximal values after 30 to 45 minutes (mean +/- SEM increase after 45 minutes, 34.2 +/- 18.2 percent; tumor necrosis factor vs. saline, P = 0.015). This was followed by a gradual and prolonged increase in the plasma concentration of the prothrombin fragment F1+2, peaking after four to five hours (mean increase after five hours, 348.0 +/- 144.8 percent; tumor necrosis factor vs. saline, P less than 0.0001). These findings signify the formation of factor Xa (activated factor X) and the activation of prothrombin. Activation of the intrinsic pathway could not be detected by a series of measurements of the plasma levels of factor XII, prekallikrein, factor XIIa-C1 inhibitor complexes, kallikrein-C1 inhibitor complexes, and the activation peptide of factor IX. The delay between the maximal activation of factor X and that of prothrombin amounted to several hours, indicating that neutralization of factor Xa activity was slow. We conclude that a single injection of tumor necrosis factor elicits a rapid and sustained activation of the common pathway of coagulation, probably induced through the extrinsic route. Our results suggest that tumor necrosis factor could play an important part in the early activation of the hemostatic mechanism in septicemia.

  9. Upregulation of tumor necrosis factor alpha and interleukin-1 beta in Q fever endocarditis.

    PubMed Central

    Capo, C; Zugun, F; Stein, A; Tardei, G; Lepidi, H; Raoult, D; Mege, J L

    1996-01-01

    The occurrence of Q fever endocarditis likely involves some alterations in the responses of monocytes, the in vivo targets of Coxiella burnetii. To test this hypothesis, the production of the inflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 was assessed in monocytes from patients with Q fever endocarditis. Spontaneous transcription and secretion of tumor necrosis factor and interleukin-1 were significantly higher in patient monocytes than in healthy controls. The interleukin-6 transcripts were also upregulated in patient cells. Moreover, in patients with recent endocarditis exhibiting high titers of immunoglobulin G directed to C. burnetii in phase I, monocytes released significantly higher levels of tumor necrosis factor and interleukin-1 than in patients with stabilized endocarditis. Immunoglobulin G titers and the overproduction of tumor necrosis factor and interleukin-1 were significantly correlated. Hence, the overproduction of inflammatory cytokines might be a marker of disease activity. PMID:8613372

  10. Brain necrosis after fractionated radiation therapy: Is the halftime for repair longer than we thought?

    SciTech Connect

    Bender, Edward T.

    2012-11-15

    Purpose: To derive a radiobiological model that enables the estimation of brain necrosis and spinal cord myelopathy rates for a variety of fractionation schemes, and to compare repair effects between brain and spinal cord. Methods: Sigmoidal dose response relationships for brain radiation necrosis and spinal cord myelopathy are derived from clinical data using nonlinear regression. Three different repair models are considered and the repair halftimes are included as regression parameters. Results: For radiation necrosis, a repair halftime of 38.1 (range 6.9-76) h is found with monoexponential repair, while for spinal cord myelopathy, a repair halftime of 4.1 (range 0-8) h is found. The best-fit alpha beta ratio is 0.96 (range 0.24-1.73)Conclusions: A radiobiological model that includes repair corrections can describe the clinical data for a variety of fraction sizes, fractionation schedules, and total doses. Modeling suggests a relatively long repair halftime for brain necrosis. This study suggests that the repair halftime for late radiation effects in the brain may be longer than is currently thought. If confirmed in future studies, this may lead to a re-evaluation of radiation fractionation schedules for some CNS diseases, particularly for those diseases where fractionated stereotactic radiation therapy is used.

  11. Mechanisms of tumor necrosis in photodynamic therapy with a chlorine photosensitizer: experimental studies

    NASA Astrophysics Data System (ADS)

    Privalov, Valeriy A.; Lappa, Alexander V.; Bigbov, Elmir N.

    2011-02-01

    A photodynamic therapy experiment on 118 inbred white mice with transplanted Ehrlich's tumor (mouse mammary gland adenocarcinoma) is performed to reveal mechanisms of necrosis formation. In 7-10 days the tumor of 1-1.5 cm diameter is formed under skin at the injection point, and PDT procedure is applied. There were used a chlorine type photosensitizer RadachlorineTM and 662 nm wavelength diode laser. The drug is injected by intravenously at the dose of 40 mg/kg; the irradiation is executed in 2-2.5 hours at the surface dose of about 200 J/cm2. Each of the mice had a photochemical reaction in form of destructive changes at the irradiation region with subsequent development of dry coagulation necrosis. After rejection of the necrosis there occurred epithelization of defect tissues in a tumor place. Histological investigations were conducted in different follow-up periods, in 5 and 30 min, 1, 3, 6, and 12 hours, 1, 3, 7 and 28 days after irradiation. They included optical microscopy, immune marker analysis, morphometry with measurements of volume density of epithelium, tumor stroma and necroses, vascular bed. The investigations showed that an important role in damaging mechanisms of photodynamic action belongs to hypoxic injuries of tumor mediated by micro vascular disorders and blood circulatory disturbances. The injuries are formed in a few stages: microcirculation angiospasm causing vessel paresis, irreversible stases in capillaries, diapedetic hemorrhages, thromboses, and thrombovasculitis. It is marked mucoid swelling and fibrinoid necrosis of vascular tissue. Progressive vasculitises result in total vessel obliteration and tumor necrosis.

  12. Comparison of drug survival rates for tumor necrosis factor antagonists in rheumatoid arthritis

    PubMed Central

    Martínez-Santana, Virginia; González-Sarmiento, E; Calleja-Hernández, MA; Sánchez-Sánchez, T

    2013-01-01

    Background Persistence of anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis (RA) is an overall marker of treatment success. Objective To assess the survival of anti-TNF treatment and to define the potential predictors of drug discontinuation in RA, in order to verify the adequacy of current practices. Design An observational, descriptive, longitudinal, retrospective study. Setting The Hospital Clínico Universitario de Valladolid, Valladolid, Spain. Patients RA patients treated with anti-TNF therapy between January 2011 and January 2012. Measurements Demographic information and therapy assessments were gathered from medical and pharmaceutical records. Data is expressed as means (standard deviations) for quantitative variables and frequency distribution for qualitative variables. Kaplan–Meier survival analysis was used to assess persistence, and Cox multivariate regression models were used to assess potential predictors of treatment discontinuation. Results In total, 126 treatment series with infliximab (n = 53), etanercept (n = 51) or adalimumab (n = 22) were administered to 91 patients. Infliximab has mostly been used as a first-line treatment, but it was the drug with the shortest time until a change of treatment. Significant predictors of drug survival were: age; the anti-TNF agent; and the previous response to an anti-TNF drug. Limitation The small sample size. Conclusion The overall efficacy of anti-TNF drugs diminishes with time, with infliximab having the shortest time until a change of treatment. The management of biologic therapy in patients with RA should be reconsidered in order to achieve disease control with a reduction in costs. PMID:24023512

  13. 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. PMID:25437087

  14. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists.

    PubMed

    Bendtzen, Klaus

    2013-04-01

    With the discovery of the central pathogenic role of tumor necrosis factor (TNF)-alpha in many immunoinflammatory diseases, specific inhibition of this pleiotropic cytokine has revolutionized the treatment of patients with several non-infectious inflammatory disorders. As a result, genetically engineered anti-TNF-alpha antibody constructs now constitute one of the heaviest medicinal expenditures in many countries. All currently used TNF antagonists may dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favorably, and safety can be severely impaired by immunogenicity, i.e., the ability of a drug to induce anti-drug antibodies (ADA). Assessment of ADA is therefore an important component of the evaluation of drug safety in both pre-clinical and clinical studies and in the process of developing less immunogenic and safer biopharmaceuticals. Therapeutics diagnostics, also called theranostics, i.e., monitoring functional drug levels and neutralizing ADA in the circulation, is central to more effective use of biopharmaceuticals. Hence, testing-based strategies rather than empirical dose-escalation may provide more cost-effective use of TNF antagonists as this allows therapies tailored according to individual requirements rather than the current universal approach to diagnosis. The objective of the present review is to discuss the reasons for recommending theranostics to implement an individualized use of TNF antagonists and to highlight some of the methodological obstacles that have obscured cost-effective ways of using these therapies.

  15. Tumor necrosis factor alpha and glutathione interplay in chronic heart failure.

    PubMed

    Adamy, C; Le Corvoisier, P; Candiani, G; Kirsch, M; Pavoine, C; Defer, N; Bourin, M C; Su, J B; Vermes, E; Hittinger, L; Pecker, E

    2005-09-01

    The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.

  16. The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis.

    PubMed

    Kodama, S; Davis, M; Faustman, D L

    2005-08-01

    Excess levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with certain autoimmune diseases. Under the rationale that elevated TNF-alpha levels are deleterious, several anti-TNF-alpha therapies are now available to block the action of TNF-alpha in patients with autoimmune diseases with a chronic inflammatory component to the destructive process. TNF-alpha antagonists have provided clinical benefit to many patients, but their use also is accompanied by new or aggravated forms of autoimmunity. Here we propose a mechanistically based hypothesis for the adverse events observed with TNF-alpha antagonists, and argue for the opposite therapeutic strategy: to boost or restore TNF-alpha activity as a treatment for some forms of autoimmunity. Activation defects in the transcription factor nuclear factor kappaB leave autoreactive T cells sensitive to TNF-alpha-induced apoptosis. Treatment with TNF-alpha, by destroying autoreactive T cells, appears to be a highly targeted strategy to interrupt the pathogenesis of type 1 diabetes, lupus and certain forms of autoimmunity.

  17. Shock wave therapy as a treatment of nonunions, avascular necrosis, and delayed healing of stress fractures.

    PubMed

    Furia, John P; Rompe, Jan D; Cacchio, Angelo; Maffulli, Nicola

    2010-12-01

    Shock wave therapy (SWT) stimulates angiogenesis and osteogenesis. SWT is commonly used to treat soft tissue musculoskeletal conditions such as fasciopathies and tendinopathies. Recent basic science and clinical data suggest that SWT can also be used to treat disorders of bone. Nonunions, avascular necrosis, and delayed healing of stress fractures have all been successfully treated with SWT. Success rates with SWT are equal to those with standard surgical treatment, but SWT has the advantage of decreased morbidity. The procedure is safe, well tolerated, yields few complications, and, typically, can be performed on an outpatient basis. SWT is a viable noninvasive alternative to stimulate healing of bone.

  18. Differences and Similarities in TRAIL- and Tumor Necrosis Factor-Mediated Necroptotic Signaling in Cancer Cells.

    PubMed

    Sosna, Justyna; 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

    2016-10-15

    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

  19. Magnetic Resonance Imaging of Therapy-Induced Necrosis Using Gadolinium-Chelated Polyglutamic Acids

    SciTech Connect

    Jackson, Edward F.; Esparza-Coss, Emilio; Wen Xiaoxia; Ng, Chaan S.; Daniel, Sherita L.; Price, Roger E.; Rivera, Belinda; Charnsangavej, Chusilp; Gelovani, Juri G.; Li Chun . E-mail: cli@di.mdacc.tmc.edu

    2007-07-01

    Purpose: Necrosis is the most common morphologic alteration found in tumors and surrounding normal tissues after radiation therapy or chemotherapy. Accurate measurement of necrosis may provide an early indication of treatment efficacy or associated toxicity. The purpose of this report is to evaluate the selective accumulation of polymeric paramagnetic magnetic resonance (MR) contrast agents-gadolinium p-aminobenzyl-diethylenetriaminepentaacetic acid-poly(glutamic acid) (L-PG-DTPA-Gd and D-PG-DTPA-Gd)-in necrotic tissue. Methods and Materials: Two different solid tumor models, human Colo-205 xenograft and syngeneic murine OCA-1 ovarian tumors, were used in this study. Necrotic response was induced by treatment with poly(L-glutamic acid)-paclitaxel conjugate (PG-TXL). T{sub 1}-weighted spin-echo images were obtained immediately and up to 4 days after contrast injection and compared with corresponding histologic specimens. Two low-molecular-weight contrast agents, DTPA-Gd and oligomeric(L-glutamic acid)-DTPA-Gd, were used as nonspecific controls. Results: Initially, there was minimal tumor enhancement after injection of either L-PG-DTPA-Gd or D-PG-DTPA-Gd, but rapid enhancement after injection of low-molecular-weight agents. However, polymeric contrast agents, but not low-molecular-weight contrast agents, caused sustained enhancement in regions of tumor necrosis in both tumors treated with PG-TXL and untreated tumors. These data indicate that high molecular weight, rather than in vivo biodegradation, is necessary for the specific localization of polymeric MR contrast agents to necrotic tissue. Moreover, biotinylated L-PG-DTPA-Gd colocalized with macrophages in the tumor necrotic areas, suggesting that selective accumulation of L- and D-PG-DTPA-Gd in necrotic tissue was mediated through residing macrophages. Conclusions: Our data suggest that MR imaging with PG-DTPA-Gd may be a useful technique for noninvasive characterization of treatment-induced necrosis.

  20. Safety and tolerability of tumor necrosis factor-α inhibitors in psoriasis: a narrative review.

    PubMed

    Semble, Ashley L; Davis, Scott A; Feldman, Steven R

    2014-02-01

    Tumor necrosis factor (TNF)-α inhibitors are an alternative to oral systemic therapies for psoriasis. Data regarding the safety of TNF-α inhibitors from randomized clinical trials may not fully reflect the effects on the clinic patient population receiving the therapy, but other sources of information are available. We performed a literature review to assess the safety and tolerability of the treatment of moderate-to-severe plaque psoriasis with TNF-α inhibitors. A literature search was conducted using PubMed for articles dating from January 2000 to October 2013. Randomized controlled, cohort, open-label, and observational studies were included, as well as case reports and letters to the editor. Articles found on PubMed describing the safety of anti-TNF-α therapy in psoriasis patients were included, while studies highlighting interleukin (IL)-12 and IL-23 inhibitors were excluded, as were non-English articles. In total, 58 articles were included in the review. TNF-α inhibitors exhibit both efficacy and tolerability in patients with moderate-to-severe plaque psoriasis. Adverse effects associated with these medications are not common and can be minimized with routine clinical monitoring and patient education. While the risk of severe adverse events is low, the lack of very large, long-term, randomized safety trials limits the ability to fully define the safety of these agents. TNF-α inhibitors have a good efficacy/safety ratio for use in patients with moderate-to-severe psoriasis. Serious adverse effects are not common, and common injection-site reactions are usually manageable. The benefits of TNF-α inhibitors outweigh the risks for moderate-to-severe psoriasis; however, there are potential adverse effects and the patient populations at highest risk include the elderly and those with a history of malignancy.

  1. The effects of treatment the avascular necrosis of the femoral head with extracorporeal focused shockwave therapy.

    PubMed

    Kusz, Damian; Franek, Andrzej; Wilk, Robert; Dolibog, Paweł; Błaszczak, Edward; Wojciechowski, Piotr; Król, Piotr; Dolibog, Patrycja; Kusz, Błażej

    2012-01-01

    Background.Avascular necrosis of the femoral head continues to represent a major challenge for the orthopaedist and trauma surgeon. A fully effective method of treatment is yet to be introduced. After femoral head collapse, only total hip replacement can help the patient. Our study aims to assess the effects of treatment of avascular necrosis of the femoral head with extra corporeal focused shockwave therapy.Material and methods. A prospective study was carried out in patients with avascular necrosis of the femoral head, ARCO stage I-III, diagnosed by MRI imaging. Shock waves are applied under x-ray guidance. Four points are marked on the skin above the lesion. Each spot receives a dose of 1500 pulses at an energy flux density of 0.4 mJ/mm2 and a frequency of 4 Hz. Each patient undergoes 5 therapy sessions. A posturometric and stabilometric assessment is carried out before and after the therapy. Other examinations include a tensometric evaluation of the strength of the treated limb, and an assessment of pain intensity (VAS scale)and hip function (Harris hip score). Follow-up visits are scheduled at 6 weeks and 3, 6 and 12 months post-treatment.Results. Nine patients were treated with shockwave therapy at the Department of Orthopaedics and Musculoskeletal Traumatology, Medical Faculty, Medical University of Silesia, between 5 May 2011 and 1 June 2012. The patients demonstrated pain reduction and improved mobility of the treated joint (VAS score decreasing from 6.75 +/- 0.71 to 2.5 +/- 1.7; Harris hip score increasing from 55.21 +/- 15.45 to 89.21 +/- 8.26). Tensometric platform testing carried out after the treatment revealed a statistically significant difference between mean velocity of the centre of pressure (CoP) movement when walking with eyes open and closed (p<0.05) and mean CoP movement along the x (walking with eyes closed) and y (free standing with eyes closed) axes.Conclusions. 1. Extracorporeal focused shockwave therapy resulted in considerable

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

    PubMed

    Wollina, Uwe; Gemmeke, Astrid; Koch, André

    2012-04-01

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

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

    PubMed Central

    Wollina, Uwe; Gemmeke, Astrid; Koch, André

    2012-01-01

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

  4. 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.

  5. Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes.

    PubMed

    Sauvé, Meghan; Hui, Sonya K; Dinh, Danny D; Foltz, Warren D; Momen, Abdul; Nedospasov, Sergei A; Offermanns, Stefan; Husain, Mansoor; Kroetsch, Jeffrey T; Lidington, Darcy; Bolz, Steffen-Sebastian

    2016-07-01

    Diabetes strongly associates with microvascular complications that ultimately promote multiorgan failure. Altered myogenic responsiveness compromises tissue perfusion, aggravates hypertension, and sets the stage for later permanent structural changes to the microcirculation. We demonstrate that skeletal muscle resistance arteries isolated from patients with diabetes have augmented myogenic tone, despite reasonable blood glucose control. To understand the mechanisms, we titrated a standard diabetes mouse model (high-fat diet plus streptozotocin [HFD/STZ]) to induce a mild increase in blood glucose levels. HFD/STZ treatment induced a progressive myogenic tone augmentation in mesenteric and olfactory cerebral arteries; neither HFD nor STZ alone had an effect on blood glucose or resistance artery myogenic tone. Using gene deletion models that eliminate tumor necrosis factor (TNF) or sphingosine kinase 1, we demonstrate that vascular smooth muscle cell TNF drives the elevation of myogenic tone via enhanced sphingosine-1-phosphate (S1P) signaling. Therapeutically antagonizing TNF (etanercept) or S1P (JTE013) signaling corrects this defect. Our investigation concludes that vascular smooth muscle cell TNF augments resistance artery myogenic vasoconstriction in a diabetes model that induces a small elevation of blood glucose. Our data demonstrate that microvascular reactivity is an early disease marker and advocate establishing therapies that strategically target the microcirculation. PMID:27207546

  6. Psoriasis Induced by Anti-Tumor Necrosis Factor Alpha Agents: A Comprehensive Review of the Literature.

    PubMed

    Ciccarelli, Fedra; De Martinis, Massimo; Sirufo, Maria Maddalena; Ginaldi, Lia

    2016-08-01

    Tumor necrosis factor alpha (TNF-α) inhibitors revolutionized the management of patients affected by autoimmune diseases such as inflammatory bowel diseases, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. The biologic agents targeted to block TNF-α such as infliximab, adalimumab, certulizumab pegol, etanercept, and golimumab, have a good safety profile; however, with increasing, broader, and prolonged use, patients could be exposed to an increased risk of adverse reactions including a wide spectrum of dermatological conditions of different etiology and morphology. Among these, of particular interest is the development of skin immune-mediated diseases that seem to be the consequence of the paradoxical inflammation induced by anti-TNF-α therapy. The majority of these lesions are identified as psoriasiform with three main morphologies and different frequency: pustular psoriasis, signs of psoriasis, and guttate; although erythrodermic or inverted psoriasis, among others, may be observed with less frequency. The increased incidence of these dermatological immune-mediated lesions highlight the importance of the skin as a main target of the side effect of anti-TNF-α agents, while the immunopathogenetic hypothesis of these paradoxical effects are quite intriguing. The aim of this review is to collect and to analyze existing knowledge to better understand the pathogenetic mechanism of these complications and suggest new fields of investigation, improve therapeutic strategies of autoimmune diseases, and prevent and/or better address such complications. PMID:27663916

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

    PubMed Central

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

    2016-01-01

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

  8. Down-regulation of tumor necrosis factor expression by pentoxifylline in cancer patients: a pilot study.

    PubMed

    Dezube, B J; Sherman, M L; Fridovich-Keil, J L; Allen-Ryan, J; Pardee, A B

    1993-01-01

    The wasting syndrome (cachexia) characterized by anorexia, malaise, and weight loss is observed in many patients with cancer or chronic infection. The excessive levels of tumor necrosis factor-alpha (TNF)/cachectin reported in 50% of cancer patients exhibiting clinically active disease may therefore mediate, at least in part, the cachexia associated with malignancy. Pentoxifylline, a substituted methylxanthine approved for treatment of intermittent claudication, has been shown in preclinical studies to down-regulate TNF RNA expression as well as TNF activity. We report that pentoxifylline suppressed TNF RNA levels on all three occasions in patients with initially elevated levels of TNF RNA. Pentoxifylline did not suppress TNF RNA to subnormal levels in all five patients with initially normal TNF RNA levels. Four patients reported an increased sense of well-being, improved appetite and ability to perform the activities of daily living. Two of these five patients with normal TNF levels each had a weight gain of more than 5% after 3 weeks of pentoxifylline therapy suggesting that, although TNF may be important in the pathogenesis of cancer cachexia, other anorexia-producing cytokines that are potentially affected by pentoxifylline may also be involved. No severe adverse effects were observed. Taken together these findings suggest that pentoxifylline can down-regulate TNF expression and improve the sense of well-being in cancer patients. A larger study with a randomized, double-blind, placebo-controlled design and more sophisticated estimates of quality of life will be needed to confirm these observations.

  9. Quiescent interplay between inducible nitric oxide synthase and tumor necrosis factor-alpha: influence on transplant graft vasculopathy in renal allograft dysfunction.

    PubMed

    Elahi, Maqsood M; Matata, Bashir M; Hakim, Nadey S

    2006-06-01

    A healthy endothelium is essential for vascular homeostasis, and preservation of endothelial cell function is critical for maintaining transplant allograft function. Damage to the microvascular endothelial cells is now regarded as a characteristic feature of acute vascular rejection, an important predictor of graft loss. It is also linked with transplant vasculopathy, often associated with chronic allograft nephropathy. Large bursts of nitric oxide in infiltrating monocytes/macrophages modulated by inducible nitric oxide synthase are considered pivotal in driving this mechanism. Indeed, it has been shown recently that increased circulating levels of tumor necrosis factor-alpha in the rejecting kidneys are largely responsible for triggering inducible nitric oxide synthase expression. This in turn suggests that several structural and functional features of graft rejection could be mediated by tumor necrosis factor-alpha. Despite the large body of evidence that supports immunologic involvement, knowledge concerning the cellular and biochemical mechanisms for nephritic cell dysfunction and death is incomplete. The role of tumor necrosis factor-alpha in mediating pathophysiological activity of inducible nitric oxide synthase during transplant vasculopathy remains contentious. Here, we discuss the effect of inducible nitric oxide synthase and tumor necrosis factor-alpha interaction on progressive damage to glomerular and vascular structures during renal allograft rejection. Selective inhibition of inducible nitrous oxide synthase and tumor necrosis factor-alpha as a potential therapy for ameliorating endothelial dysfunction and transplant graft vasculopathy is also discussed.

  10. 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

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

    PubMed

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

    1993-10-01

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

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

    PubMed Central

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

    1993-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  14. Prognostic and Therapeutic Values of Tumor Necrosis Factor-Alpha in Hepatocellular Carcinoma

    PubMed Central

    Wang, Hongmei; Liu, Jianmin; Hu, Xuemei; Liu, Shanshan; He, Baojun

    2016-01-01

    Background Hepatocellular carcinoma (HCC) causes many deaths worldwide every year, especially in Asia. It is characterized by high malignancy, recurrence, and short survival time. Inflammation is closely related to the initiation and development of HCC. Tumor necrosis factor-α (TNF-α), an essential inflammatory mediator, has been studied as a potential therapy target in many cancers. However, its potential role in HCC diagnosis and therapy is still unclear. Material/Methods In our study, we detected the TNF-α expression in both human HCC tumor tissue and HCC cell lines HepG2 and HuH7. Then, we detected the effect of anti-TNF-α treatment and it synergistic function with 5-FU in an HCC xenograft mouse model and in HCC cell lines. Results Survival analysis and Cox regression analysis based on 97 HCC patients indicated that a high level of TNF-α is an independent predictor of poor survival in HCC patients. Anti-TNF-α treatment by infliximab synergizes with Fluorouracil (5-FU) by promoting apoptosis of HCC tumor cells through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) effects. Conclusions Based on these data, we conclude that anti-TNF-α treatment could be a good way to increase the effect of classic chemotherapy of HCC patients, especially for the patients who have modest response to classic chemotherapy, such as 5-FU. TNF-α could also be used as a biomarker to help in early diagnosis of HCC. PMID:27739418

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

    MedlinePlus

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

  17. Tumor necrosis factor alpha gene -376 polymorphism and susceptibility to multiple sclerosis: an Egyptian study.

    PubMed

    Nada, Mona Abd el Fattah; Labib, Dalia Ahmed

    2011-03-01

    Tumor necrosis factor alpha, a proinflammatory cytokine, plays an important role in the clinical activity of relapsing-remitting multiple sclerosis and the development of progression. Dysregulation in the expression of tumor necrosis factor gene had been suggested in the pathogenesis of multiple sclerosis. Our aim was to investigate the relationship between tumor necrosis factor α-376 polymorphism with disease susceptibility and course of multiple sclerosis in Egyptian patients. Polymerase chain reaction and restriction fragment length polymorphism were carried out on 36 primary progressive multiple sclerosis patients, 36 age- and sex-matched remitting relapsing multiple sclerosis patients (diagnosed according to McDonald's Diagnostic criteria) and 30 age- and sex-matched healthy controls. The GG genotype and the guanine allele (G) were detected significantly more often in the primary progressive (p = 0.02; p = 0.004, respectively) and remitting relapsing (p = 0.015; p = 0.024, respectively) multiple sclerosis groups as compared with the healthy control group. The G allele in the examined position in tumor necrosis factor alpha might have a role as regards susceptibility in both remitting relapsing and primary progressive multiple sclerosis.

  18. Recombinant tumour necrosis factor inhibits malaria parasites in vivo but not in vitro.

    PubMed Central

    Taverne, J; Tavernier, J; Fiers, W; Playfair, J H

    1987-01-01

    As tumour necrosis serum kills malarial parasites in vitro and inhibits the multiplication of some species of Plasmodium in mice, we examined the effect of recombinant mouse tumour necrosis factor (rTNF) on P. yoelii both in vitro and in vivo. Parasites incubated overnight with rTNF showed no loss of viability, but repeated injection of rTNF into infected mice reduced parasitaemia and significantly prolonged survival of mice infected with a lethal variant of the parasite. We conclude that TNF acts on blood-stage malaria in vivo via a host cell and that another molecule in tumour necrosis serum is involved in killing the parasite in vitro. PMID:3621669

  19. A case of atypical progressive outer retinal necrosis after highly active antiretroviral therapy.

    PubMed

    Woo, Se Joon; Yu, Hyeong Gon; Chung, Hum

    2004-06-01

    This is a report of an atypical case of progressive outer retinal necrosis (PORN) and the effect of highly active antiretroviral therapy (HAART) on the clinical course of viral retinitis in an acquired immunodeficiency syndrome (AIDS) patient. A 22-year-old male patient infected with human immunodeficiency virus (HIV) presented with unilaterally reduced visual acuity and a dense cataract. After cataract extraction, retinal lesions involving the peripheral and macular areas were found with perivascular sparing and the mud-cracked, characteristic appearance of PORN. He was diagnosed as having PORN based on clinical features and was given combined antiviral treatment. With concurrent HAART, the retinal lesions regressed, with the regression being accelerated by further treatment with intravenous acyclovir and ganciclovir. This case suggests that HAART may change the clinical course of PORN in AIDS patients by improving host immunity. PORN should be included in the differential diagnosis of acute unilateral cataract in AIDS patients. PMID:15255240

  20. A case of atypical progressive outer retinal necrosis after highly active antiretroviral therapy.

    PubMed

    Woo, Se Joon; Yu, Hyeong Gon; Chung, Hum

    2004-06-01

    This is a report of an atypical case of progressive outer retinal necrosis (PORN) and the effect of highly active antiretroviral therapy (HAART) on the clinical course of viral retinitis in an acquired immunodeficiency syndrome (AIDS) patient. A 22-year-old male patient infected with human immunodeficiency virus (HIV) presented with unilaterally reduced visual acuity and a dense cataract. After cataract extraction, retinal lesions involving the peripheral and macular areas were found with perivascular sparing and the mud-cracked, characteristic appearance of PORN. He was diagnosed as having PORN based on clinical features and was given combined antiviral treatment. With concurrent HAART, the retinal lesions regressed, with the regression being accelerated by further treatment with intravenous acyclovir and ganciclovir. This case suggests that HAART may change the clinical course of PORN in AIDS patients by improving host immunity. PORN should be included in the differential diagnosis of acute unilateral cataract in AIDS patients.

  1. Interleukin-1 and tumor necrosis factor alpha inhibit repair of the porcine meniscus in vitro

    PubMed Central

    Hennerbichler, Alfred; Moutos, Franklin T.; Hennerbichler, Diana; Weinberg, J. Brice; Guilak, Farshid

    2011-01-01

    OBJECTIVE Injury or removal of the knee meniscus leads to progressive joint degeneration, and current surgical therapies for meniscal tears seek to maximally preserve meniscal structure and function. However, the factors that influence intrinsic repair of the meniscus are not well understood. The goal of this study was to investigate the capacity of meniscus tissue to repair a simulated defect in vitro and to examine the effect of pro-inflammatory cytokines on this process. METHODS Cylindrical explants were harvested from the outer one-third of medial porcine menisci. To simulate a full-thickness defect, a central core was removed and reinserted immediately into the defect. Explants were cultured for 2, 4, or 6 weeks in serum-containing media in the presence or absence of interleukin-1 (IL-1) or tumor necrosis factor alpha (TNF-alpha), and meniscal repair was investigated using mechanical testing and fluorescence confocal microscopy. RESULTS Meniscal lesions in untreated samples showed a significant capacity for intrinsic repair in vitro, with increasing cell accumulation and repair strength over time in culture. In the presence of IL-1 or TNF-alpha, no repair was observed despite the presence of abundant viable cells. CONCLUSIONS This study demonstrates that the meniscus exhibits an intrinsic repair response in vitro. However, the presence of pro-inflammatory cytokines completely inhibited repair. These findings suggest that increased levels of pro-inflammatory cytokines post-injury or under arthritic conditions may inhibit meniscal repair. Therefore, inhibition of these cytokines may provide a means of accelerating repair of damaged or injured menisci in vivo. PMID:17448702

  2. 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

  3. Macrophage response in patients diagnosed with aseptic necrosis of the femoral head presenting different risk factors.

    PubMed

    Kamal, Diana; Trăistaru, Rodica; Kamal, Constantin Kamal; Alexandru, Dragoş Ovidiu; Ion, Daniela Adriana; Grecu, Dan Cristian

    2015-01-01

    Aseptic necrosis of the femoral head is a condition caused by partial or total interruption of blood supply to the femoral head. The diminished blood supply causes necrosis of the cellular elements and of the bone marrow, followed by the collapse of the bone structure, events that ultimately lead to the destruction of the bone tissue, the appearance of local pain and loss of function in the affected coxofemoral joint. The importance of this condition is that it mainly affects young adults aged 30-50 years, active from a socio-professional standpoint, and increased life expectancy. The material studied to achieve CD68 immunostaining was represented by bone fragments from the area of necrosis and from the adjacent areas of the femoral heads, harvested from 39 patients when performing hip arthroplasty surgery. The patients were diagnosed with aseptic necrosis of the femoral head and hospitalized in the Clinic of Orthopedics and Traumatology, Emergency County Hospital of Craiova, Romania, from June 2014 to January 2015. The 39 patients included in the study were divided into four categories according to presented risk factors (alcohol, alcohol and smoking, trauma, corticosteroids). All the 39 cases had positive immunostaining for CD68, macrophage being highlighted both in the area of necrosis and in the adjacent areas. We noted significant differences in the number and arrangement of macrophages in patients presenting different risk factors. The highest number of macrophages was present in patients presenting a risk factor corticosteroids, and the lowest number of macrophages was found in patients who had trauma as the main risk factor.

  4. 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.

  5. Tumor necrosis factor-alpha processing inhibitor-1 inhibits skin fibrosis in a bleomycin-induced murine model of scleroderma.

    PubMed

    Terao, Mika; Murota, Hiroyuki; Kitaba, Shun; Katayama, Ichiro

    2010-01-01

    Elevated serum concentration of soluble tumor necrosis factor receptor p55 (sTNFRp55) is known to correlate with the severity of systemic sclerosis (SSc). However, it has not been verified whether this increase contributes to the pathogenesis of SSc. In this study, we found that sTNFRp55 also is increased in the bleomycin (BLM)-induced murine model of SSc. Therefore, we examined the effect of tumor necrosis factor-alpha processing inhibitor-1 (TAPI-1), the inhibitor of TNFRp55 sheddase, in this model. TAPI-1 was administered weekly to mice with skin fibrosis induced by daily BLM injections. TAPI-1 significantly suppressed BLM-induced skin thickness and the number of myofibroblasts. It also inhibited the increase of serum sTNFRp55 after 3 weeks of BLM injections. The mRNA expression of collagen type I alpha1, transforming growth factor-beta1 and alpha smooth muscle actin were decreased by TAPI-1 administration. Taken together, these findings indicate that targeting the TNFalpha converting enzyme might be a new type of therapy for patients with SSc. PMID:19758314

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

    PubMed Central

    Wang, Jun; Al-Lamki, Rafia S.

    2013-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  8. A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains.

    PubMed

    Zapata, J M; Pawlowski, K; Haas, E; Ware, C F; Godzik, A; Reed, J C

    2001-06-29

    We have identified three new tumor necrosis factor-receptor associated factor (TRAF) domain-containing proteins in humans using bioinformatics approaches, including: MUL, the product of the causative gene in Mulibrey Nanism syndrome; USP7 (HAUSP), an ubiquitin protease; and SPOP, a POZ domain-containing protein. Unlike classical TRAF family proteins involved in TNF family receptor (TNFR) signaling, the TRAF domains (TDs) of MUL, USP7, and SPOP are located near the NH(2) termini or central region of these proteins, rather than carboxyl end. MUL and USP7 are capable of binding in vitro via their TDs to all of the previously identified TRAF family proteins (TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, and TRAF6), whereas the TD of SPOP interacts weakly with TRAF1 and TRAF6 only. The TD of MUL also interacted with itself, whereas the TDs of USP7 and SPOP did not self-associate. Analysis of various MUL and USP7 mutants by transient transfection assays indicated that the TDs of these proteins are necessary and sufficient for suppressing NF-kappaB induction by TRAF2 and TRAF6 as well as certain TRAF-binding TNF family receptors. In contrast, the TD of SPOP did not inhibit NF-kappaB induction. Immunofluorescence confocal microscopy indicated that MUL localizes to cytosolic bodies, with targeting to these structures mediated by a RBCC tripartite domain within the MUL protein. USP7 localized predominantly to the nucleus, in a TD-dependent manner. Data base searches revealed multiple proteins containing TDs homologous to those found in MUL, USP7, and SPOP throughout eukaryotes, including yeast, protists, plants, invertebrates, and mammals, suggesting that this branch of the TD family arose from an ancient gene. We propose the moniker TEFs (TD-encompassing factors) for this large family of proteins.

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

    PubMed

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

    2006-01-01

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

  10. Lipopolysaccharide triggers invasive streptococcal disease in mice through a tumour necrosis factor-alpha-dependent mechanism.

    PubMed

    Diao, Hongyan; Kohanawa, Masashi; Yimin; Nakajima, Hirofumi; Sato, Yuichiro; Minagawa, Tomonori; Nakane, Akio

    2002-03-01

    Streptococcus pyogenes sometimes induces invasive streptococcal infection, including streptococcal toxic shock syndrome (STSS). Muscular necrosis is one of the peculiar symptoms of invasive streptococcal infection and STSS. We inoculated S. pyogenes into the muscles of mice. To do so, 5 x 10(8) bacteria in 0.2 ml phosphate-buffered saline were injected into the right hind thigh. None of the mice injected with the bacteria showed muscular necrosis and none died. Tumour necrosis factor-alpha (TNF-alpha) and infiltration of leucocytes were detected in the muscles of infected sites, although the condition of the infected mice did not deteriorate after anti-TNF-alpha monoclonal antibody treatment. The infected mice treated intraperitoneally with Escherichia coli lipopolysaccharide (LPS) showed augmentation of bacterial growth, muscular necrosis and death. TNF-alpha was detected in the sera of the infected mice treated with LPS, but not in the muscles of the infected sites. Infiltration of leucocytes into the infected muscle was not observed in the infected mice treated with LPS. Anti-TNF-alpha monoclonal antibody treatment decreased mortality in the infected mice treated with LPS. Moreover, the infected mice treated with recombinant TNF-alpha showed augmentation of muscular necrosis and death. These results suggest that systemic production of TNF-alpha induced by stimulation with LPS inhibits infiltration of leucocytes into the infected site and exacerbates muscular infection, and that TNF-alpha produced in streptococcal infection is not a defence factor for the host. Invasive streptococcal infection and STSS appear to be induced by both S. pyogenes and the host's immune system.

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

    PubMed

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

    1996-01-01

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

  12. K1 and K3 capsular antigens of Klebsiella induce tumor necrosis factor activities.

    PubMed

    Choy, Y M; Tsang, S F; Kong, S K; Leung, K N; Parolis, H; Lee, C Y; Fung, K P

    1996-01-01

    Capsular polysaccharide antigens isolated from Klebsiella pneumoniae sero-type 1 (K1) and sero-type 3 (K3) could induce tumor necrosis factor-alpha in ICR mice. K1 and K3 capsular antigens were found to be non-toxic by brine shrimp bioassay. When injected into Ehrlich ascites tumor-bearing mice, both K1 and K3 capsular antigens exhibited significant suppression in the growth of tumor cells. The significance of these observations is discussed.

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

    PubMed Central

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

    2015-01-01

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

  14. Induction of inflammatory cell infiltration and necrosis in normal mouse skin by the combined treatment of tumor necrosis factor and lithium chloride.

    PubMed Central

    Beyaert, R.; De Potter, C.; Vanhaesebroeck, B.; Van Roy, F.; Fiers, W.

    1991-01-01

    Previously we reported that lithium chloride (LiCl) potentiates tumor necrosis factor (TNF)-mediated cytotoxicity in vitro and in vivo. Here, using a murine normal skin model, it is shown that a subcutaneous injection of TNF plus LiCl induces acute dermal and subcutaneous inflammation and necrosis. Histology showed a marked initial dermal and subcutaneous neutrophil infiltrate by approximately 2 hours, followed by a predominantly mononuclear infiltrate by 24 hours, which remained present for several days. Tumor necrosis factor or LiCl alone induced negligible inflammation, disappearing after 6 hours; furthermore there was never necrosis or ulceration of the overlying skin in case of single-agent application. In vitro studies showed that the combination of TNF and LiCl, but not either agent alone, was directly cytotoxic to fibroblastic cells of murine skin. No inflammatory infiltration was visible in tumors treated intratumorally or perilesionally with TNF plus LiCl, although the latter treatment resulted in a perilesional leukocyte infiltration. Furthermore the combination of TNF and LiCl had no effect on macrophage cytotoxicity to L929 tumors. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 PMID:1848044

  15. Full-length membrane-bound tumor necrosis factor-α acts through tumor necrosis factor receptor 2 to modify phenotype of sensory neurons.

    PubMed

    Wu, Zetang; Wang, Shiyong; Gruber, Sandy; Mata, Marina; Fink, David J

    2013-09-01

    Neuropathic pain resulting from spinal hemisection or selective spinal nerve ligation is characterized by an increase in membrane-bound tumor necrosis factor-alpha (mTNFα) in spinal microglia without detectable release of soluble TNFα (sTNFα). In tissue culture, we showed that a full-length transmembrane cleavage-resistant TNFα (CRTNFα) construct can act through cell-cell contact to activate neighboring microglia. We undertook the current study to test the hypothesis that mTNFα expressed in microglia might also affect the phenotype of primary sensory afferents, by determining the effect of CRTNFα expressed from COS-7 cells on gene expression in primary dorsal root ganglia (DRG) neurons. Co-culture of DRG neurons with CRTNFα-expressing COS-7 cells resulted in a significant increase in the expression of voltage-gated sodium channel isoforms NaV1.7 and NaV1.8, and voltage-gated calcium channel subunit CaV3.2 at both mRNA and protein levels, and enhanced CCL2 expression and release from the DRG neurons. Exposure to sTNFα produced an increase only in CCL2 expression and release. Treatment of the cells with an siRNA against tumor necrosis factor receptor 2 (TNFR2) significantly reduced CRTNFα-induced gene expression changes in DRG neurons, whereas administration of CCR2 inhibitor had no significant effect on CRTNFα-induced increase in gene expression and CCL2 release in DRG neurons. Taken together, the results of this study suggest that mTNFα expressed in spinal microglia can facilitate pain signaling by up-regulating the expression of cation channels and CCL2 in DRG neurons in a TNFR2-dependent manner. PMID:23711481

  16. Clinical diagnosis of late temporal lobe necrosis following radiation therapy for nasopharyngeal carcinoma

    SciTech Connect

    Lee, A.W.; Ng, S.H.; Ho, J.H.; Tse, V.K.; Poon, Y.F.; Tse, C.C.; Au, G.K.; O, S.K.; Lau, W.H.; Foo, W.W.

    1988-04-15

    This is a preliminary report of 102 patients with clinical diagnosis of late temporal lobe necrosis after radical radiation therapy for nasopharyngeal carcinoma during 1964 to 1983. Histologic verification was available in 12 cases. All but three patients had been treated in our institute using schedules with doses larger than the conventional 200 cGy per fraction. The incidence rate was 1.03%. In our 80 patients with only one course of external irradiation, the doses to the temporal lobes ranged from 1665 to 2127 ret, or 1286 to 1778 brain tolerance unit (btu). The latent interval ranged from 9 months to 16 years. The median observation period is 33 months. The symptomatology, working diagnosis, treatment, and outcome are described. Surgery was hazardous because of the bilaterality of the involvement and exploration for mere verification of diagnosis was unjustified in typical cases. Treatment with corticosteroid achieved durable objective response in 25 (35%) of 72 patients. The importance of early detection and corticosteroid treatment is discussed.

  17. Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection.

    PubMed

    Beyer, Marc; Abdullah, Zeinab; Chemnitz, Jens M; Maisel, Daniela; Sander, Jil; Lehmann, Clara; Thabet, Yasser; Shinde, Prashant V; Schmidleithner, Lisa; Köhne, Maren; Trebicka, Jonel; Schierwagen, Robert; Hofmann, Andrea; Popov, Alexey; Lang, Karl S; Oxenius, Annette; Buch, Thorsten; Kurts, Christian; Heikenwalder, Mathias; Fätkenheuer, Gerd; Lang, Philipp A; Hartmann, Pia; Knolle, Percy A; Schultze, Joachim L

    2016-05-01

    Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity--infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)--we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.

  18. Tumor necrosis factor α is associated with viral control and early disease progression in patients with HIV type 1 infection.

    PubMed

    Vaidya, Sagar A; Korner, Christian; Sirignano, Michael N; Amero, Molly; Bazner, Sue; Rychert, Jenna; Allen, Todd M; Rosenberg, Eric S; Bosch, Ronald J; Altfeld, Marcus

    2014-10-01

    Inflammation in early human immunodeficiency virus type 1 (HIV-1) disease progression is not well characterized. Ninety patients with untreated primary HIV-1 infection were studied to determine associations of inflammatory proteins with early disease progression. High plasma tumor necrosis factor α (TNF-α) levels (≥8.5 pg/mL) were significantly associated with an increased viral load set point and shorter times to reaching a CD4(+) T-cell count of <500 cells/mm(3) and initiating antiretroviral therapy. The increased risk of reaching a CD4(+) T-cell count of <500 cells/mm(3) in the group with high TNF-α levels was driven by viral load but was independent of concurrent CD4(+) T-cell count. Thus, TNF-α appears to be an important mediator of inflammation in patients with poor viral control and early HIV-1 disease progression.

  19. An extraordinary form of the Melkersson-Rosenthal syndrome successfully treated with the tumour necrosis factor-α blocker adalimumab

    PubMed Central

    Stein, Juergen; Paulke, Alexander; Schacher, Beate; Noehte, Matthias

    2014-01-01

    Melkersson-Rosenthal syndrome (MRS) is a rare granulomatous inflammatory disease characterised by the triad of orofacial oedema, facial nerve palsy and furrowed tongue. We describe the case of a 29-year-old patient suffering from an oligosymptomatic form of the disease with orofacial oedema, cobblestone pattern on the buccal mucosa and swelling of the tongue, accompanied by intermittent fatigue, influenza-like symptoms, intermittent tinnitus and acute hearing loss. An increase of several autoimmune-associated antibodies was also detected. Treatment with prednisolone, azathioprine or methotrexate failed to adequately control all symptoms in the long term. In the absence of a specific and well-established therapy for MRS, treatment with adalimumab was administered. Under adalimumab, total remission of all symptoms was achieved, indicating that tumour necrosis factor-α blockers are a promising therapeutic option for patients with Melkersson-Rosenthal syndrome. PMID:24827666

  20. Successful treatment of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with tocilizumab: A case report

    PubMed Central

    Akasbi, Nessrine; Soyfoo, Muhammad S.

    2015-01-01

    Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disease linked to chromosome 12p13 and, more specifically, with mutations within the tumor necrosis factor receptor superfamily, member 1A gene (TNFRSF1A gene). It is characterized by the presence of fever, abdominal pain, myalgia, arthralgia or arthritis, and skin rash. In this report, we describe the case of a patient with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) treated successfully with the anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody tocilizumab, while treatment with anti-TNF α etanercept and infliximab had both failed.

  1. Defective production of interleukin-1 and tumour necrosis factor-alpha by stimulated monocytes from patients with systemic lupus erythematosus.

    PubMed

    Mũzes, G; Vien, C V; González-Cabello, R; Fehér, J; Gergely, P

    1989-01-01

    Interleukin-1 and tumour necrosis factor-alpha activity by E. coli lipopolysaccharide-triggered monocytes was studied in patients with systemic lupus erythematosus in various stages of activity. Monocytes from both groups of SLE patients produced significantly less tumour necrosis factor-alpha activity than those of age and sex matched healthy controls. However, interleukin-1 activity was only significantly reduced in patients with active stage of the disease. These findings indicate further immunoregulatory disturbances in monocyte function concerning SLE. PMID:2636360

  2. Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor.

    PubMed

    Farma, Jeffrey M; Puhlmann, Markus; Soriano, Perry A; Cox, Derrick; Paciotti, Giulio F; Tamarkin, Lawrence; Alexander, H Richard

    2007-06-01

    Tumor necrosis factor (TNF) causes regression of advanced cancers when used in isolation perfusion with melphalan; evidence suggests these effects are mediated via selective yet uncharacterized actions on tumor neovasculature. A novel derivative, colloidal gold bound TNF (cAu-TNF) has been shown to have similar antitumor effects as native TNF with less systemic toxicity in mice. These studies were done to determine their effects on tumor neovasculature, using in vivo video microscopy. Female C57BL/6 mice bearing 20 mm(2) MC38 or LLC tumors that are TNF sensitive and resistant tumors, respectively, had dorsal skinfold chambers implanted. The rate of interstitial accumulation of Texas red fluorescently labeled albumin in tumor and normal vasculature was measured after intravenous TNF, cAu-TNF or PBS. Changes in interstitial fluorescent intensity over time were quantified as a reflection of alterations in vascular permeability. MC38 bearing mice treated with TNF or cAu-TNF demonstrated a rapid, selective and significant increase in tracer accumulation in areas of neovasculature compared to those of normal vasculature. Experiments in LLC tumor bearing mice showed similar results. Monoclonal antibody against tissue factor partially abrogated the effects of TNF on MC38 neovasculature. These data provide direct evidence that TNF and cAu-TNF selectively and rapidly alter permeability in tumor neovasculature; a phenomenon that may be exploited to enhance selective delivery of chemotherapeutics to tumor.

  3. 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.

  4. An aptasensor for electrochemical detection of tumor necrosis factor in human blood.

    PubMed

    Liu, Ying; Zhou, Qing; Revzin, Alexander

    2013-08-01

    Electrochemical aptasensors can detect disease markers such as cytokines to provide point-of-care diagnosis that is low-cost, rapid, specific and sensitive. Herein, we describe the development of an aptamer-based electrochemical sensor for detection and analysis of tumor necrosis factor-alpha (TNF-α) - a key inflammatory cytokine - in whole human blood. When testing spiked blood, a TNF-α detection limit of 58 pM (10 ng mL(-1)) and a linear range of 6 nM (100 ng mL(-1)) could be achieved. Furthermore, detection of TNF-α in mitogen stimulated whole blood was demonstrated.

  5. 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.

  6. 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

  7. 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

  8. 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.

  9. Shedding of Tumor Necrosis Factor Receptor 1 Induced by Protein A Decreases Tumor Necrosis Factor Alpha Availability and Inflammation during Systemic Staphylococcus aureus Infection

    PubMed Central

    Giai, Constanza; Gonzalez, Cintia; Ledo, Camila; Garofalo, Ailin; Di Genaro, María Silvia; Sordelli, Daniel O.

    2013-01-01

    Staphylococcus aureus infections are an important public health concern due to their increasing incidence and high rates of mortality. The success of S. aureus as a pathogen is highly related to its enormous capacity to evade the host immune response. The critical role of tumor necrosis factor alpha (TNF-α) in the initial host defense against systemic staphylococcal infection has been demonstrated in experimental models and may partially explain the lack of significant benefits observed in clinical trials attempting to neutralize this cytokine in septic patients. S. aureus protein A plays a key role in regulating inflammation through its ability to bind and signal through the TNF-α receptor 1 (TNFR1). In this study, we demonstrate that S. aureus, via protein A-mediated signaling, induces early shedding of TNFR1, which precedes the secretion of TNF-α in vitro and in vivo. The results obtained using a protein A-deficient mutant and tnfr1−/− mice strongly suggest that the increased levels of soluble TNFR1 present during experimental S. aureus infection may neutralize circulating TNF-α and impair the host inflammatory response. Early shedding of TNFR1 induced by protein A may constitute a novel mechanism by which S. aureus subverts the host immune response. PMID:24002060

  10. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo.

    PubMed Central

    Van Zee, K J; Kohno, T; Fischer, E; Rock, C S; Moldawer, L L; Lowry, S F

    1992-01-01

    Tumor necrosis factor alpha (TNF alpha), a primary mediator of systemic responses to sepsis and infection, can be injurious to the organism when present in excessive quantities. Here we report that two types of naturally occurring soluble TNF receptors (sTNFR-I and sTNFR-II) circulate in human experimental endotoxemia and in critically ill patients and demonstrate that they neutralize TNF alpha-induced cytotoxicity and immunoreactivity in vitro. Utilizing immunoassays that discriminate between total sTNFR-I and sTNFR-I not bound to TNF alpha, we show that sTNFR-I-TNF alpha complexes may circulate even in the absence of detectable free TNF alpha. To investigate the therapeutic possibilities of sTNFR-I, recombinant protein was administered to nonhuman primates with lethal bacteremia and found to attenuate hemodynamic collapse and cytokine induction. We conclude that soluble receptors for TNF alpha are inducible in inflammation and circulate at levels sufficient to block the in vitro cytotoxicity associated with TNF alpha levels observed in nonlethal infection. Administration of sTNFR-I can prevent the adverse pathologic sequelae caused by the exaggerated TNF alpha production observed in lethal sepsis. Images PMID:1317575

  11. The effect of chronic periodontitis on serum levels of tumor necrosis factor-alpha in Alzheimer disease

    PubMed Central

    Farhad, Shirin Zahra; Amini, Shahram; Khalilian, Amir; Barekatain, Majid; Mafi, Morvarid; Barekatain, Mehrdad; Rafei, Ehsan

    2014-01-01

    Background: Despite the outbreak in dental science, oral and dental complications in Alzheimer are of the unsolved problems. It is assumed that tumor necrosis factor-α, which is a key factor in Alzheimer, has a relation with periodontal complications in patients with Alzheimer disease. The present study evaluated the effect of chronic periodontitis on serum levels of tumor necrosis factor-α in Alzheimer disease. Materials and Methods: This case-control study was performed on 80 patients with Alzheimer disease seeking medical care at Nour Hospital, Isfahan, Iran. Eighty patients with Alzheimer disease between 40 and 70 years old attended this study. Forty had chronic periodontitis (case group), and 40 patients had healthy periodontium (control group). Blood sample was taken, and serum levels of tumor necrosis factor-α were measured by means of an ELISA Reader device. Independent T-Test was used to analyze data, and P < 0.05 was considered significant. Results: The mean of tumor necrosis factor-α was 749.1 ng/μL in case group and 286.8 ng/μL in control group. Independent t-test showed that the mean of tumor necrosis factor-α in patients with Alzheimer and periodontitis was approximately three folds higher than the patients only with Alzheimer, and this difference was statistically significant (P < 0.001). Conclusion: According to the results of this study, it seems that there is a difference between serum levels of tumor necrosis factor-α in patient with Alzheimer and chronic periodontitis and patients with Alzheimer disease and healthy periodontium. Tumor necrosis factor-α level in serum may act as a diagnostic marker of periodontal disease in patients with Alzheimer disease PMID:25426144

  12. 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.

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

    PubMed Central

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

    2013-01-01

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

  14. 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.

  15. 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

  16. 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.

  17. Production of interferon and tumour necrosis factor by cloned human natural cytotoxic lymphocytes and T cells.

    PubMed

    Christmas, S E; Meager, A; Moore, M

    1987-08-01

    Cell lines and clones, derived from natural killer (NK) cell-enriched (B73.1+) peripheral blood lymphocytes (PBL) from several human donors, that expressed distinct surface phenotypes and were cytolytically active against K562 target cells were tested for their capacity to produce interferon (IFN) and tumour necrosis factor (TNF), IFN and TNF were measured firstly in biological assays and secondly in specific immunoassays for alpha-IFN, gamma-IFN and tumour necrosis factor (TNF alpha). It was found that the majority of NK-derived lines and clones were highly cytotoxic towards K562, but generally produced relatively low or undetectable levels of gamma-IFN and TNF alpha following stimulation with phytohaemagglutinin. No alpha-IFN was detected in supernatants from these cells. In comparison, cell lines and clones, derived from T lymphocyte (B73.1-) enriched PBL from the same donors were poorly cytotoxic towards K562, but generally produced higher levels of gamma-IFN and TNF than NK-derived cells. Thus, neither gamma-IFN nor TNF production were shown to correlate well with the capacity of NK-derived or T cell clones to effect cytotoxic action towards K562 in vitro. These results suggest that the co-production of gamma-IFN and TNF is not indicative of cytotoxic potential.

  18. Trophoblastic cell lines generated from tumour necrosis factor receptor-deficient mice reveal specific functions for the two tumour necrosis factor receptors.

    PubMed

    Rasmussen, C A; Pace, J L; Banerjee, S; Phillips, T A; Hunt, J S

    1999-01-01

    In mice and humans, expression of the tumour necrosis factor receptor-1 (TNF-R1) gene in placental trophoblast cells is constitutive whereas expression of the TNF-R2 gene is developmentally programmed. In order to study the individual functions of TNF-R1 and -R2 in this lineage, cell lines were generated from placental explants of homozygous matings of gestation day 10 outbred mice (Swiss-Webster), TNF-R1-deficient (TNF-R1-/-) and TNF-R2-/- transgenic mice as well as the background strain for the TNF-R2-/- mice (WT, C57BL/6x129). All of the cells exhibited trophoblast markers; they contained cytokeratin intermediate filaments, expressed alkaline phosphatase activity and displayed transferrin receptors, but were negative for vimentin filaments and the macrophage marker, F4/80. Analysis of DNA by polymerase chain reaction demonstrated the expected TNF-R genotype in each line. In experiments testing the effects of recombinant mouse TNF-alpha (rmTNF-alpha) on viability and proliferation of the cell lines, rmTNF-alpha modestly but dose-dependently inhibited the growth of WT and TNF-R2-/- cells while having no effect on TNF-R1-/- cells. Actinomycin D-treated WT and, to a lesser extent, TNF-R2-/- cells, were more sensitive to growth inhibition than untreated cells whereas TNF-R1-/- cell responses remained unchanged. These data indicated that rmTNF-alpha inhibits growth of trophoblastic cells through TNF-R1 and that newly synthesized protein(s) provide partial protection against toxicity. In contrast to the receptor species-specific effects on cell growth exerted by rmTNF-alpha, both TNF-R mediated inhibition of alkaline phosphatase activity. Collectively, the observations support the postulate that receptor expression is the key factor which determines the nature and extent of TNF-alpha effects on trophoblast cell growth and function.

  19. Combination Systemic and Intravitreal Antiviral Therapy in The Management of Acute Retinal Necrosis Syndrome (An American Ophthalmological Society Thesis)

    PubMed Central

    Flaxel, Christina J.; Yeh, Steven; Lauer, Andreas K.

    2013-01-01

    Purpose: To compare the outcomes of combination systemic and intravitreal antiviral therapy vs systemic antiviral therapy alone for treating acute retinal necrosis syndrome (ARN). We hypothesize that combination therapy might result in superior visual acuity (VA) and retinal detachment (RD) outcomes vs traditional systemic antiviral therapy alone. Methods: A retrospective, interventional, comparative single-center study of patients with ARN. We reviewed demographic data, herpesvirus diagnoses, polymerase chain reaction (PCR) results, VA, RD, and the use of systemic and intravitreal antiviral therapy. Outcome measures included VA improvement by 2 or more lines, severe visual loss, VA ≤20/200, and RD. Results: We studied 29 eyes of 24 patients, treated from 1987 through 2009. Mean age was 42.6 years and mean follow-up was 44.0 months. Twelve patients (14 eyes) were treated with combined systemic and intravitreal antiviral therapy and 12 patients (15 eyes) with systemic therapy alone. Kaplan-Meier survival analysis revealed that patients receiving combination intravitreal and systemic antiviral therapy were more likely to have VA improved by 2 lines or greater (P=.006). Patients receiving combination therapy also showed a decreased incidence of progression to severe visual loss (0.13/patient-years [PY]) compared to patients receiving systemic therapy alone (0.54/PY, P=.02) and had decreased incidence of RD (0.29/PY vs 0.74/PY, P=.03). Conclusions: Combination oral and intravitreal antiviral therapy may improve visual and functional outcomes in patients with ARN. Clinicians should consider prompt administration of combination systemic and intravitreal antiviral therapy as first-line treatment for patients with clinical features of ARN. PMID:24385671

  20. Tumor Necrosis Factor-α -and Interleukin-1-Induced Cellular Responses: Coupling Proteomic and Genomic Information

    PubMed Central

    Ott, Lee W.; Resing, Katheryn A.; Sizemore, Alecia W.; Heyen, Joshua W.; Cocklin, Ross R.; Pedrick, Nathan M.; Woods, H. Cary; Chen, Jake Y.; Goebl, Mark G.; Witzmann, Frank A.; Harrington, Maureen A.

    2010-01-01

    The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFα) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFα- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFα and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune response. The contrasting responses to LPS indicate that TNFα and IL-1 regulate different processes. A large-scale proteomic analysis of TNFα- and IL-1-induced responses was undertaken to identify processes uniquely regulated by TNFα and IL-1. When combined with genomic studies, our results indicate that TNFα, but not IL-1, mediates cell cycle arrest. PMID:17503796

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

    PubMed

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

    2006-06-01

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

  2. Leonurus sibiricus induces nitric oxide and tumor necrosis factor-alpha in mouse peritoneal macrophages.

    PubMed

    An, Hyo-Jin; Rim, Hong-Kun; Lee, Jong-Hyun; Suh, Se-Eun; Lee, Ji-Hyun; Kim, Na-Hyung; Choi, In-Young; Jeong, Hyun-Ja; Kim, Il Kwang; Lee, Ju-Young; An, Nyeon-Hyoung; Kim, Hyung-Ryong; Um, Jae-Young; Kim, Hyung-Min; Hong, Seung-Heon

    2008-10-01

    Using mouse peritoneal macrophages, we have examined the mechanism by which Leonurus sibiricus (LS) regulates nitric oxide (NO) production. When LS was used in combination with recombinant interferon-gamma (rIFN-gamma), there was a marked cooperative induction of NO production; however, LS by itself had no effect on NO production. The increased production of NO from rIFN-gamma plus LS-stimulated cells was almost completely inhibited by pretreatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor kappaB. Furthermore, treatment of peritoneal macrophages with rIFN-gamma plus LS caused a significant increase in tumor necrosis factor-alpha (TNF-alpha) production. PDTC also decreased the effect of LS on TNF-alpha production significantly. Because NO and TNF-alpha play an important role in immune function and host defense, LS treatment could modulate several aspects of host defense mechanisms as a result of stimulation of the inducible nitric oxide synthase.

  3. Skin Necrosis in a Patient with Factor V Leiden Mutation following Nipple Sparing Mastectomy

    PubMed Central

    Cinar, Can

    2015-01-01

    Summary: Nipple-sparing mastectomy (NSM) and immediate breast reconstruction have replaced radical surgical interventions for the treatment of selected patients with breast cancer undergoing prophylactic mastectomy. NSM is technically a difficult procedure. After dissection, the remaining breast skin and nipple-areola complex (NAC) must be thin enough to be free of tumor tissue and thick enough to preserve tissue perfusion. Factor V Leiden mutation is the most common cause of hereditary thrombophilia; thrombosis almost always develops in the venous system. The literature includes only a few case series of arterial thrombosis. The present study aimed to describe for the first time a patient with Factor V Leiden mutation that developed nipple-areola complex and skin necrosis, and multiple embolisms in the upper extremity arteries following NSM. PMID:26579335

  4. 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.

  5. Tumor necrosis factor-α -308G/A gene polymorphism in Egyptian children with immune thrombocytopenic purpura.

    PubMed

    El Sissy, Maha H; El Sissy, A H; Elanwary, Sherif

    2014-07-01

    Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by increased platelet destruction. Although the cause of ITP remains unclear, it is accepted that both environmental and genetic factors play an important role in the development of the disease. Children with ITP have a T-helper 1-type cytokine pattern with elevated levels of tumor necrosis factor-alpha (TNF-α) as in most autoimmune diseases. Researchers have shown that polymorphism in the TNF-α gene at position -308 affects gene transcriptions with increased TNF-α production. The current case-control study aimed at detecting the frequency of TNF-α -308G/A gene polymorphism as genetic markers in Egyptian children with ITP, and to clear out their possible role in choosing the treatment protocols of therapy, using PCR restriction fragment length polymorphism assay. Ninety-two ITP patients and 100 age and sex-matched healthy controls were recruited in the study. The results obtained revealed that the frequency of TNF-α -308A/A homotype in ITP patients was significantly higher than that of the controls, and conferred almost six-fold increased risk of ITP acquisition. The polymorphic A allele frequency was significantly higher in ITP patients than in the controls, conferring almost two-fold increased ITP risk. In conclusion, our study suggests the possibility that TNF-α -308 gene polymorphism may contribute to the susceptibility of childhood ITP in Egyptian children.

  6. Squamous cell carcinoma of the rectum: a consequence of immunosuppression resulting from inhibiting tumour necrosis factor (TNF)?

    PubMed Central

    Silverton, Alexandra; Raad, Roy A; Katz, Leah; Downey, Andrea; Muggia, Franco M

    2016-01-01

    Treatment with tumour necrosis factor (TNF) antagonists may lead to enhanced susceptibility to certain malignancies. In particular, an association is seen emerging between TNF antagonists and development of squamous cell carcinomas (SCCs) of the skin (in association with psoriasis), the oral cavity, and in the anogenital areas (possibly related to prior human papilloma virus infection). We present here a case of a 53-year old woman with a history of severe rheumatoid arthritis (RA), most recently treated with the TNF antagonist etanercept plus methotrexate, presented to our service after several months of increasing left pelvis and buttock pain. Evaluation with a computerised tomography (CT)-directed biopsy of a pelvic side wall mass revealed a metastatic SCC. On a fluorodeoxyglucose (FDG) positron-emission tomography (PET) an additional area of uptake was identified in the left posterior rectum corresponding to a 1 cm nodule palpable on digital exam. Colonoscopic biopsy revealed a basaloid SCC of the rectum as the likely primary site. Immunosuppression following TNF antagonist therapy may have given arise to this unrestrained neoplastic growth. It thereby underscores the need for an initial baseline study of risk factors and identification of patients who are at higher risk for development of a malignancy, in order to achieve a diagnosis at an early stage. PMID:27350791

  7. Plasma levels of tumour necrosis factor and its soluble receptors correlate with clinical features and outcome of Hodgkin's disease patients.

    PubMed Central

    Warzocha, K.; Bienvenu, J.; Ribeiro, P.; Moullet, I.; Dumontet, C.; Neidhardt-Berard, E. M.; Coiffier, B.; Salles, G.

    1998-01-01

    A prospective study was performed to assess the use of plasma measurement of tumour necrosis factor (TNF), lymphotoxin alpha (LT alpha) and their soluble receptors (p55 and p75) for prognostic risk assignment in 61 patients with Hodgkin's disease. Plasma levels of TNF, p55 and p75, but not of LT alpha, were higher in Hodgkin's disease patients than in healthy controls. Plasma levels of TNF, p55 and p75 were associated with several prognostic factors for Hodgkin's disease, including those related to the host (age, performance status) and to the tumour (disease stage, extranodal site involvement, bulky tumour, serum levels of LDH and beta2-microglobulin, histology). Elevated plasma levels of TNF, p55 and p75 were also associated with several parameters reflecting an immune activation, including the presence of B symptoms, elevated serum levels of gammaglobulins, alkaline phosphatase and fibrinogen, as well as peripheral monocytosis, anaemia and low serum albumin levels. Finally, elevated TNF ligand receptor plasma markers were associated with a lower incidence of complete response to therapy and predicted shorter free-from-progression survival and overall survival of the patients. These results indicate that the plasma levels of TNF and its soluble receptors correlate with clinical features and outcome of patients with Hodgkin's disease. PMID:9649158

  8. Relationship between tumor necrosis factor-α release and granulocyte and monocyte adsorption to cellulose acetate beads.

    PubMed

    Nishise, Shoichi; Abe, Yasuhiko; Nomura, Eiki; Sato, Takeshi; Sasaki, Yu; Iwano, Daisuke; Yoshizawa, Kazuya; Yagi, Makoto; Nishise, Yuko; Ueno, Yoshiyuki

    2014-06-01

    Tumor necrosis factor-α, (TNF)-α, a proinflammatory cytokine, is produced by activated granulocytes and monocytes (GMs) and implicated as a major factor in inflammatory bowel disease (IBD) pathogenesis. Reduction of TNF-α should improve IBD pathology. GM adsorptive apheresis (GMA) is an effective therapy for inflammatory disorders including IBD. GM adsorption to cellulose acetate (CA) beads induces anti-inflammatory cytokine release, although these effects on TNF-α release are not clarified. We hypothesized that GMA may inhibit TNF-α release. The aim of the present study was to clarify the effects of GM adsorption to CA beads on TNF-α release in vitro. Peripheral blood was incubated with and without CA beads and TNF-α was measured. For comparison, TNF-α was measured in another lipopolysaccharide (LPS)-containing peripheral blood sample incubated similarly. The amount of TNF-α in blood samples incubated with CA beads was significantly higher than in those incubated without beads, although it was significantly lower than TNF-α incubated with LPS-containing sample without beads. The amount of TNF-α after incubation with CA beads positively correlated with GM adsorption ratio. GM adsorption to CA beads induced a small amount of TNF-α release. This is the first report on TNF-α release induced via GM adsorption stimuli. The biological effects of TNF-α release during GM adsorption need to be clarified.

  9. Melatonin reversed tumor necrosis factor-alpha-inhibited osteogenesis of human mesenchymal stem cells by stabilizing SMAD1 protein.

    PubMed

    Lian, Chengjie; Wu, Zizhao; Gao, Bo; Peng, Yan; Liang, Anjing; Xu, Caixia; Liu, Lei; Qiu, Xianjian; Huang, Junjun; Zhou, Hang; Cai, Yifeng; Su, Peiqiang; Huang, Dongsheng

    2016-10-01

    Tumor necrosis factor-alpha (TNFα) plays a pivotal role in inflammation-related osteoporosis through the promotion of bone resorption and suppression of bone formation. Numerous drugs have been produced to treat osteoporosis by inhibiting bone resorption, but they offer few benefits to bone formation, which is what is needed by patients with severe bone loss. Melatonin, which can exert both anti-inflammatory and pro-osteogenic effects, shows promise in overcoming TNFα-inhibited osteogenesis and deserves further research. This study demonstrated that melatonin rescued TNFα-inhibited osteogenesis of human mesenchymal stem cells and that the interactions between SMURF1 and SMAD1 mediated the crosstalk between melatonin signaling and TNFα signaling. Additionally, melatonin treatment was found to downregulate TNFα-induced SMURF1 expression and then decrease SMURF1-mediated ubiquitination and degradation of SMAD1 protein, leading to steady bone morphogenetic protein-SMAD1 signaling activity and restoration of TNFα-impaired osteogenesis. Thus, melatonin has prospects for treating osteoporosis caused by inflammatory factors due to its multifaceted functions on regulation of bone formation, bone resorption, and inflammation. Further studies will focus on unveiling the specific mechanisms by which melatonin downregulates SMURF1 expression and confirming the clinical therapeutic value of melatonin in the prevention and therapy of bone loss associated with inflammation. PMID:27265199

  10. Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies.

    PubMed

    Bamberger, Sarah; Martinez Vinson, Christine; Mohamed, Damir; Viala, Jérôme; Carel, Jean-Claude; Hugot, Jean-Pierre; Simon, Dominique

    2016-01-01

    Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn's disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn's disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon's signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients. PMID:27636201

  11. Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies

    PubMed Central

    Mohamed, Damir; Viala, Jérôme; Carel, Jean-Claude; Hugot, Jean-Pierre; Simon, Dominique

    2016-01-01

    Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn’s disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn’s disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon’s signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients. PMID:27636201

  12. Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies.

    PubMed

    Bamberger, Sarah; Martinez Vinson, Christine; Mohamed, Damir; Viala, Jérôme; Carel, Jean-Claude; Hugot, Jean-Pierre; Simon, Dominique

    2016-01-01

    Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn's disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn's disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon's signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients.

  13. The Possible Role of Tumor Necrosis Factor-α in Diabetic Polyneuropathy

    PubMed Central

    Yagihashi, Soroku; Toyota, Takayoshi

    2003-01-01

    In this review, the authors provide evidences that imply the role of tumor necrosis factor-α (TNF-α) in the pathogenesis of diabetic complications, especially diabetic polyneuropathy. Under chronic hyperglycemia, endogenous TNF-α production is accelerated in microvascular and neural tissues, which may undergo an increased microvascular permeability, hypercoagulability, and nerve damage, thus initiating and promoting the development of characteristic lesions of diabetic microangiopathy and polyneuropathy. Enhanced TNF-α production may also promote atherosclerosis due to increased insulin resistance and the expression of adhesion molecules. Clinical application of specific agents that suppress production and/or activity of TNF-α may inhibit the development and exacerbation of chronic diabetic complications. PMID:14630568

  14. 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

  15. Production of tumor necrosis factor alpha, interleukin-1 alpha, and interleukin-6 during murine coccidioidomycosis.

    PubMed Central

    Cox, R A; Magee, D M

    1995-01-01

    The proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and interleukin-6 (IL-6) were induced in mice infected with Coccidioides immitis. Analyses of the cytokine profiles of two inbred mouse strains which differ in their susceptibility to pulmonary challenge with C. immitis revealed higher levels of IL-6 in lungs from DBA/2 mice (resistant strain) than in those from BALB/c mice (susceptible strain) beginning at day 6 and continuing through day 15 postinfection. Spleen cells from both mouse strains secreted TNF-alpha, IL-1 alpha, and IL-6 in vitro in response to stimulation with killed spherules but differed in that spleen cells from the resistant strain produced increased levels of these cytokines earlier after pulmonary challenge and at increased levels throughout the course of the disease. PMID:7558338

  16. Theiler's murine encephalomyelitis virus induces tumour necrosis factor-alpha in murine astrocyte cell cultures.

    PubMed Central

    Sierra, A; Rubio, N

    1993-01-01

    Cytokines have been postulated to exert an important modulatory and recruiting role in demyelination induced by Theiler's murine encephalomyelitis virus (TMEV) in SJL/J mice. Using a cytolytic bioassay and ELISA, we have detected and quantified a cytokine, tumour necrosis factor-alpha (TNF-alpha), in supernatants from astrocyte cultures infected in vitro with TMEV. TNF was detected only after TMEV-specific infection of astrocyte cultures (approximately 200-400 U/ml). In vitro TNF synthesis appeared in a dose- and time-dependent manner and was produced by both SJL/J (a strain susceptible to TMEV-induced demyelination) and BALB/c (a resistant strain) astrocytes. The precise nature of TNF activity was further assessed by fast protein liquid chromatography (FPLC) and antibody neutralization. These results indicate an active role for astrocytes as accessory immune cells in our experimental model for multiple sclerosis. PMID:8478023

  17. Endotoxin and tumor necrosis factor-alpha-induced interleukin-8 release in humans.

    PubMed

    van Deventer, S J; Hart, M; van der Poll, T; Hack, C E; Aarden, L A

    1993-02-01

    Neutrophil recruitment and activation are thought to play an important role in tissue damage observed in septicemia. Interleukin-8 (IL-8) is a small cytokine with important neutrophil-activating and chemoattractant properties. IL-8 release was studied after injection of human volunteers with low doses of either endotoxin (2 ng/kg of body weight) or tumor necrosis factor-alpha (TNF alpha) (50 micrograms/m2). After TNF-alpha injection, IL-8 appeared at 30 min, whereas increased levels were first observed after 90 min in endotoxin-challenged volunteers. Peak levels were measured at 120 min after both endotoxin (192 +/- 193 ng/L) and TNF alpha (500 +/- 236 ng/L) injection. These data indicate that IL-8 is released in humans after injection of endotoxin and TNF alpha and suggest that endotoxin-induced IL-8 release is mediated by TNF alpha.

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

    PubMed

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

    2016-08-01

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

  19. 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.

  20. A simple assay for tumor necrosis factor using HEp-2 target cells.

    PubMed

    Müzes, G; Vien, C V; Gonzalez-Cabello, R; Gergely, P; Feher, J

    1989-09-01

    We developed a sensitive bioassay system for the determination of tumor necrosis factor-alpha (TNF) using HEp-2 adherent human epipharynx carcinoma cells as targets. TNF from separated human monocytes was triggered by lipopolysaccharide (LPS). In a 24 hr 3H-thymidine incorporation assay, TNF-like activity was seen to reproducibly destroy radiolabeled target cells, i.e., inhibits thymidine incorporation and causes detachment of adherent HEp-2 cells. HEp-2 cells were insensitive to human interleukin-1 (IL-1) and interleukin-2 (IL-2). In contrast, human interferon-alpha and gamma were also cytotoxic for target cells. Monocyte supernatants stimulated by LPS, however, failed to contain detectable amounts of interferons. PMID:2484315

  1. Tungsten treatment prevents tumor necrosis factor-induced injury of brain endothelial cells.

    PubMed

    Terada, L S; Willingham, I R; Guidot, D M; Shibao, G N; Kindt, G W; Repine, J E

    1992-02-01

    Exposure to recombinant human tumor necrosis factor-alpha (TNF-alpha) or calcium ionophore (A23187) for 4 h increased (P less than 0.05) lactate dehydrogenase (LDH) release from cultured bovine brain endothelial cells (EC). In contrast, treatment with endotoxin or interleukin-1 did not increase (P greater than 0.05). LDH release from brain EC. Pretreatment with tungsten decreased (P less than 0.05) xanthine oxidase activity in brain EC and decreased (P less than 0.05) LDH release from brain EC following exposure to TNF. Our results suggest that TNF-alpha injures brain microvascular EC and that this effect may be mediated by xanthine oxidase.

  2. Hard metal pneumoconiosis and the association of tumor necrosis factor-alpha.

    PubMed

    Rolfe, M W; Paine, R; Davenport, R B; Strieter, R M

    1992-12-01

    Hard metal pneumoconiosis is a recently recognized occupational lung disease associated with the exposure to cobalt fumes in the workplace. Chronic exposure in susceptible individuals results in interstitial lung disease histopathologically manifested as interstitial fibrosis with an associated mononuclear cell infiltrate and the presence of "cannibalistic" multinucleated giant cells in the alveolar airspaces. The majority of patients present with symptoms of chronic cough and dyspnea. Interestingly, in addition, patients uniformly report significant weight loss out of proportion to their degree of respiratory impairment. In this case report we demonstrate the association of tumor necrosis factor-alpha (TNF) and hard metal (cobalt) pneumoconiosis and suggest that TNF may have a potential role in the etiology of the constitutional symptoms and the pathogenesis of interstitial lung disease.

  3. Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes

    SciTech Connect

    Carroll, M.C.; Katzman, P.; Alicot, E.M.; Koller, B.H.; Geraghty, D.E.; Orr, H.T.; Strominger, J.L.; Spies, T.

    1987-12-01

    The tumor necrosis factor (TNF) ..cap alpha.. and ..beta.. gene pair has been linked in the human major histocompatibility complex to HLA-B, HLA-C, and, tentatively, HLA-E and HLA-A on one side and to the class III complement/steroid 21-hydroxylase gene cluster on the other by pulsed-field gel electrophoresis. The TNF genes are located 200 kilobases (kb) centromeric of HLA-B and about 350 kb telomeric of the class III cluster. Together with previous data on the linkage and structures of the class II and class III regions, a restriction map of the entire human major histocompatibility complex of about 3500 kb has been prepared.

  4. Production of tumour necrosis factor and interleukin 1 by monocytes of patients with previous Yersinia arthritis.

    PubMed Central

    Repo, H; Jäättelä, M; Leirisalo-Repo, M; Hurme, M

    1988-01-01

    We studied production of tumour necrosis factor (TNF) and interleukin 1 (IL-1) by using purified peripheral blood monocytes of patients with previous yersinia arthritis (YA) and of healthy HLA-B27 positive and negative controls. Lipopolysaccharide-exposed cells of HLA-B27 positive and negative patients, and those of HLA-B27 positive controls, generated significantly more TNF than did HLA-B27 negative control cells. There was a positive correlation between the levels of TNF and IL-1. Our results give credence to the view that augmented production of phlogistic mediators may contribute to inflammatory symptoms in patients with HLA-B27 associated disease. PMID:3262459

  5. 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.

  6. 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

  7. 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.

  8. New Approaches in Tumor Necrosis Factor Antagonism for the Treatment of Psoriatic Arthritis: Certolizumab Pegol.

    PubMed

    Cauli, Alberto; Piga, Matteo; Lubrano, Ennio; Marchesoni, Antonio; Floris, Alberto; Mathieu, Alessandro

    2015-11-01

    The pathogenesis of psoriatic arthritis (PsA) is still under discussion but great advances have been made in the last 2 decades that confirm the central role of tumor necrosis factor-α (TNF-α) in its inflammatory milieu. New therapeutic approaches have been proposed, and new molecules with anti-TNF-α activity have been chemically altered to improve their pharmacological properties. Certolizumab pegol (CZP) is a PEGylated Fc-free anti-TNF that has been shown clinically to be effective in the treatment of rheumatoid arthritis (RA), skin psoriasis, and PsA. This article summarizes available data on its clinical efficacy and safety profile in the treatment of patients with PsA.

  9. 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.

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

    PubMed Central

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

    1991-01-01

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

  11. Dengue haemorrhagic fever and dengue shock syndrome: are they tumour necrosis factor-mediated disorders?

    PubMed

    Yadav, M; Kamath, K R; Iyngkaran, N; Sinniah, M

    1991-12-01

    A consecutive series of 24 patients with clinical features of primary dengue infection and 22 controls (14 patients with viral fever of unknown origin and 8 healthy subjects) were assayed for serum levels of tumour necrosis factor (TNF). The acute sera of the 24 patients with clinical dengue infection were positive for dengue virus-specific IgM antibody. Clinically, 8 had dengue fever (DF), 14 dengue haemorrhagic fever (DHF) and 2 dengue shock syndrome (DSS). All 16 patients with DHF/DSS had significantly elevated serum TNF levels but the 8 DF patients had TNF levels equivalent to that in the 22 controls. A case is made for augmented TNF production having a role for the pathophysiological changes observed in DHF/DSS and mediator modulation as a possible therapeutic approach to treatment.

  12. Elevated tumour necrosis factor in dengue fever and dengue haemorrhagic fever.

    PubMed

    Vitarana, T; de Silva, H; Withana, N; Gunasekera, C

    1991-06-01

    Acute and convalescent phase blood samples from five dengue fever (DF) patients and four dengue haemorrhagic fever (DHF) patients were tested for the presence of tumour necrosis factor (TNF). While all blood samples showed elevated levels, the acute phase blood sample levels were much higher. The mean TNF level in the acute samples of the five DF cases was 862 while in the DHF cases the level was 1722 pg/ml. Though the sample size is small, the difference appears to be statistically significant. Unlike in DF the distinctive features in DHF are the occurrence of shock, thrombocytopaenic purpura and sometimes disseminated intravascular coagulation (DIC). Increased TNF levels have not been reported in the literature in association with DHF, although it has been shown to contribute to these features which appear in some other diseases.

  13. RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord.

    PubMed

    Brohawn, David G; O'Brien, Laura C; Bennett, James P

    2016-01-01

    ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned >50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG's). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network "hub" gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF's involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful

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

    PubMed

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

    1990-01-01

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

  15. 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

  16. Genetic association studies of tumour necrosis factor alpha and beta and tumour necrosis factor receptor 1 and 2 polymorphisms across the clinical spectrum of multiple sclerosis.

    PubMed

    McDonnell, G V; Kirk, C W; Middleton, D; Droogan, A G; Hawkins, S A; Patterson, C C; Graham, C A

    1999-11-01

    Allelic association studies with microsatellite markers around the tumour-necrosis factor (TNF) genes have demonstrated significantly different allele distributions of TNF markers (a and b) between relapsing-remitting/secondary progressive multiple sclerosis (MS) (RR/SPMS) patients and normal controls. Considering the suspected genetic and immunological heterogeneity in MS, we tested this association in primary progressive MS (PPMS) patients. Elevated levels of serum soluble TNF receptors (sTNF-R) are reported in patients with gadolinium enhancing lesions, and animal models suggest a possible therapeutic role of sTNF-RI in MS. Thus we performed similar association studies using markers for the TNF-R genes. Gene association studies were carried out on 199-216 normal controls, 174 RR/SPMS patients and 102 PPMS patients using polymorphic dinucleotide repeat TNF markers (a, b and d), and separate markers for TNF-RI and TNF-RII. Forward primers were fluorescently labelled, polymerase chain reaction (PCR) products were analysed on a fluorescent fragment analyser, and Genescan 672 software was used for allele sizing. Samples were typed for HLA-DR antigens using PCR technology and sequence-specific oligonucleotide probes. TNFa marker allele distributions differed significantly between PPMS patients and controls (P = 0.028), largely attributable to an increase in the 118-bp TNFa allele in PPMS patients (P = 0.00024). Allele distributions were similar in PPMS and RR/SPMS patients (P = 0.91). Logistic regression analysis, however, indicated that these associations were not independent of that with HLA-DRB1*15. For the TNFb marker, the 127-bp allele showed association with both patient categories (PPMS vs. controls, P = 0.010; RR/SPMS vs. controls, P = 0.027), whilst the 128-bp allele occurred more frequently in controls (PPMS vs. controls, P = 0.036: RR/SPMS vs. controls, P = 0.0009). As with the TNFa 118 bp allele, the association with TNFb was not independent of the HLA

  17. 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

  18. Tumor necrosis factor-alpha and nerve growth factor synergistically induce iNOS in pheochromocytoma cells.

    PubMed

    Macdonald, N J; Taglialatela, G

    2000-11-01

    Inducible nitric oxide synthase (iNOS) has been reported in tangle-bearing neurons of patients with Alzheimer's disease (AD), and can be induced by tumor necrosis factor-alpha (TNFalpha). High CNS levels of TNFalpha are associated with neurodegenerative diseases such as AD, where neurons dependent on neurotrophins such as nerve growth factor (NGF) are particularly affected. In this study we determined the effect of TNFalpha on iNOS in NGF-responsive pheochromocytoma (PC12) cells. We found that while TNFalpha and NGF alone were unable to induce iNOS, their simultaneous addition resulted in iNOS induction and the release of nitric oxide. Our results suggest that synergistic iNOS induction by TNFalpha and NGF may occur in selective population of NGF-responsive neurons in the presence of elevated CNS levels of TNFalpha.

  19. Depression and Insomnia in Patients With Psoriasis and Psoriatic Arthritis Taking Tumor Necrosis Factor Antagonists

    PubMed Central

    Wu, Chun-Ying; Chang, Yun-Ting; Juan, Chao-Kuei; Shen, Jui-Lung; Lin, Yu-Pu; Shieh, Jeng-Jer; Liu, Han-Nan; Chen, Yi-Ju

    2016-01-01

    Abstract Psoriasis patients with moderate to severe disease often present with depression and insomnia. Treatment targeting both psoriasis and psychological comorbidities is needed to improve the quality of life of these patients. In this nationwide cohort study, a total of 980 patients with psoriatic arthritis or psoriasis who had received nonbiological disease-modifying antirheumatic drugs and biologics therapy between 2009 and 2012 were identified. The prevalence rates of patients taking medications for depression and insomnia were compared before and after biologics therapy. Logistic regression method was used to investigate the risk factors for depression and insomnia. Further stratified analyses were performed to examine the prevalence of use of medications for depression and insomnia among different patient subgroups. The prevalence of patients taking regular antidepressants before starting biologics therapy was about 20%. There was a more than 40% reduction in this prevalence after biologics therapy for 2 years. Age higher than 45 years, female sex, presence of comorbidities, and psoriatic arthritis were independently associated with depression and insomnia. Further stratified analyses revealed a more rapid and significant reduction in depression/insomnia in those undergoing continuous biologics therapy, younger than 45 years, without psoriatic arthritis and not taking concomitant methotrexate, when compared with their counterparts. The results suggest that biologics therapy may be associated with reduced rates of depression and insomnia, and a reduced rate of regular antidepressants use in psoriasis patients. PMID:27258525

  20. 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.

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed

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

    2014-10-01

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

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

    PubMed

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

    2015-11-01

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

  5. 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.

  6. Individual medicine in inflammatory bowel disease: monitoring bioavailability, pharmacokinetics and immunogenicity of anti-tumour necrosis factor-alpha antibodies.

    PubMed

    Bendtzen, Klaus; Ainsworth, Mark; Steenholdt, Casper; Thomsen, Ole Østergaard; Brynskov, Jørn

    2009-01-01

    Antibody constructs targeting tumour necrosis factor-alpha (TNF) have become important in the management of several chronic immunoinflammatory diseases. Four recombinant anti-TNF drugs are currently approved for clinical use in patients with various chronic inflammatory diseases, three of which are effective in chronic inflammatory bowel disease. These proteins can dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favourably to anti-TNF antibodies. For example, patients suffering from Crohn's disease do not benefit from etanercept, and some patients treated with the other anti-TNF constructs either do not respond at all (primary response failure), or they respond initially but have later relapses (secondary response failure) despite increased dosage and/or more frequent administration of the drugs. The reason(s) for these response failures are not clear but inter-individual and even intra-individual differences in bioavailability and pharmacokinetics may contribute. Furthermore, immunogenicity of the drugs, causing patients to develop anti-drug antibodies (ADAs), contributes to treatment failure. Monitoring patients for circulating levels of functional anti-TNF drugs and ADAs is therefore warranted so that treatment can be tailored to the individual patient (individual medicine or personal medicine) in order that effective and economical long-term therapy can be given with minimal risks to the patients.

  7. Effect of chronic excess of tumour necrosis factor-alpha on contractile proteins in rat skeletal muscle.

    PubMed

    Cheema, I R; Hermann, C; Postell, S; Barnes, P

    2000-01-01

    The effect of chronic tumour necrosis factor-alpha (TNF-alpha) treatment on the synthesis of specific myofibrillar proteins such as heavy chain myosin, light chain myosin and G-actin in rat diaphragm were evaluated. Muscles (diaphragm) from control and experimental groups (TNF-alpha i.v. at 50 microg/kg body wt for 5 days) were incubated in the presence of 35S-methionine for 2 h. Myofibrillar protein extracts were prepared and protein was electrophoresed on sodium dodecyl sulphate-polyacrylamide gels. Heavy chain myosin, light chain myosin and G-actin were identified by Western blot analysis using specific monoclonal antibodies. Polyacrylamide gel electrophoresis (PAGE) followed by Western blot analysis revealed two types of heavy chain myosin (206 and 212 kD), all four types of light chain myosin (15, 16.5, 18 and 20 kD) and a single type of G-actin (42 kD). Chronic TNF-alpha treatment produced a significant decline in the synthesis of all types of myofibrillar proteins, namely heavy chain myosin, light chain myosin and G-actin. TNF-alpha impaired peptide-chain initiation in diaphragm muscle which was reversed by the branched-chain amino acids (BCAA) therapy of TNF-alpha treated rats. These findings indicate a significant role for TNF-alpha in the translational regulation of protein synthesis in skeletal muscle.

  8. Influence of Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Interleukin 10 Genes on the Risk of Liver Cirrhosis in HIV-HCV Coinfected Patients

    PubMed Central

    Corchado, Sara; Márquez, Mercedes; Montes de Oca, Montserrat; Romero-Cores, Paula; Fernández-Gutiérrez, Clotilde; Girón-González, José-Antonio

    2013-01-01

    Objective Analysis of the contribution of genetic (single nucleotide polymorphisms (SNP) at position -238 and -308 of the tumor necrosis factor alpha (TNF-α) and -592 of the interleukin-10 (IL-10) promotor genes) and of classical factors (age, alcohol, immunodepression, antirretroviral therapy) on the risk of liver cirrhosis in human immunodeficiency (HIV)-hepatitis C (HCV) virus coinfected patients. Patients and Methods Ninety one HIV-HCV coinfected patients (50 of them with chronic hepatitis and 41 with liver cirrhosis) and 55 healthy controls were studied. Demographic, risk factors for the HIV-HCV infection, HIV-related (CD4+ T cell count, antiretroviral therapy, HIV viral load) and HCV-related (serum ALT concentration, HCV viral load, HCV genotype) characteristics and polymorphisms at position -238 and -308 of the tumor necrosis factor alfa (TNF- α) and -592 of the interleukin-10 (IL-10) promotor genes were studied. Results Evolution time of the infection was 21 years in both patients’ groups (chronic hepatitis and liver cirrhosis). The group of patients with liver cirrhosis shows a lower CD4+ T cell count at the inclusion in the study (but not at diagnosis of HIV infection), a higher percentage of individuals with previous alcohol abuse, and a higher proportion of patients with the genotype GG at position -238 of the TNF-α promotor gene; polymorphism at -592 of the IL-10 promotor gene approaches to statistical significance. Serum concentrations of profibrogenic transforming growth factor beta1 were significantly higher in healthy controls with genotype GG at -238 TNF-α promotor gene. The linear regression analysis demonstrates that the genotype GG at -238 TNF-α promotor gene was the independent factor associated to liver cirrhosis. Conclusion It is stressed the importance of immunogenetic factors (TNF-α polymorphism at -238 position), above other factors previously accepted (age, gender, alcohol, immunodepression), on the evolution to liver cirrhosis

  9. Reoxygenation enhances tumour necrosis factor alpha-induced degradation of the extracellular matrix produced by chondrogenic cells.

    PubMed

    Markway, B D; Cho, H; Anderson, D E; Holden, P; Ravi, V; Little, C B; Johnstone, B

    2016-01-01

    Mesenchymal stem cells (MSCs) have been considered as a potential source for cell-based therapies in arthritic diseases for both their chondrogenic and anti-inflammatory properties. Thus, we examined how MSC-based neocartilage responds to tumour necrosis factor alpha (TNF-α) compared to articular chondrocyte (AC)-based neocartilage. Since oxygen tension is altered in arthritic joints, we also examined how increased oxygen tension influences this process. Monolayer-expanded healthy human ACs and bone marrow MSCs were cultured in chondrogenic medium in three-dimensional culture under hypoxia. They were then exposed to TNF-α under hypoxic or increased oxygen tension. We found no inherent anti-inflammatory potential of MSC-derived neocartilage as it pertains to the enzymes studied here: more degradative enzymes were upregulated by TNF-α in MSCs than in ACs, regardless of the oxygen tension. MSCs were also more sensitive to reoxygenation during TNF-α exposure, as indicated by increased proteoglycan loss, increased aggrecanase-generated metabolites, and further upregulation of the major aggrecanases, ADAMTS4 and ADAMTS5. There was also evidence of matrix metalloproteinase (MMP)-mediated aggrecan interglobular domain cleavage and type II collagen loss in response to TNF-α in both MSCs and ACs, but more MMPs were further upregulated by reoxygenation in MSCs than in ACs. Our study provides further evidence that consideration of oxygen tension is essential for studying cartilage degradation; for example, neocartilage produced from MSCs may be more sensitive to the negative effects of repeated hypoxia/reoxygenation events than AC-derived neocartilage. Consideration of the differences in responses may be important for cell-based therapies and selection of adjunctive chondroprotective agents. PMID:27341301

  10. Tumor necrosis factor-α accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages.

    PubMed

    Redente, Elizabeth F; Keith, Rebecca C; Janssen, William; Henson, Peter M; Ortiz, Luis A; Downey, Gregory P; Bratton, Donna L; Riches, David W H

    2014-04-01

    Idiopathic pulmonary fibrosis (IPF) is a relentless, fibrotic parenchymal lung disease in which alternatively programmed macrophages produce profibrotic molecules that promote myofibroblast survival and collagen synthesis. Effective therapies to treat patients with IPF are lacking, and conventional therapy may be harmful. We tested the hypothesis that therapeutic lung delivery of the proinflammatory cytokine tumor necrosis factor (TNF)-α into wild-type fibrotic mice would reduce the profibrotic milieu and accelerate the resolution of established pulmonary fibrosis. Fibrosis was assessed in bleomycin-instilled wild-type and TNF-α(-/-) mice by measuring hydroxyproline levels, static compliance, and Masson's trichrome staining. Macrophage infiltration and programming status was assessed by flow cytometry of enzymatically digested lung and in situ immunostaining. Pulmonary delivery of TNF-α to wild-type mice with established pulmonary fibrosis was found to reduce their fibrotic burden, to improve lung function and architecture, and to reduce the number and programming status of profibrotic alternatively programmed macrophages. In contrast, fibrosis and alternative macrophage programming were prolonged in bleomycin-instilled TNF-α(-/-) mice. To address the role of the reduced numbers of alternatively programmed macrophages in the TNF-α-induced resolution of established pulmonary fibrosis, we conditionally depleted macrophages in MAFIA (MAcrophage Fas-Induced Apoptosis) mice. Conditional macrophage depletion phenocopied the resolution of established pulmonary fibrosis observed after therapeutic TNF-α delivery. Taken together, our results show for the first time that TNF-α is involved in the resolution of established pulmonary fibrosis via a mechanism involving reduced numbers and programming status of profibrotic macrophages. We speculate that pulmonary delivery of TNF-α or augmenting its signaling pathway represent a novel therapeutic strategy to resolve

  11. Molecular characterization of tumor necrosis factor receptor-associated factor 6 (TRAF6) in pearl oyster Pinctada martensii.

    PubMed

    Jiao, Y; Tian, Q L; Du, X D; Wang, Q H; Huang, R L; Deng, Y W; Shi, S L

    2014-01-01

    Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a key signaling adaptor molecule for tumor necrosis factor receptor superfamily and Toll-like receptor/interleukin-1 receptor family members. It signals the upstream receptors and is involved in a wide range of biological functions, such as immunity and bone metabolism. In this report, the TRAF6 gene from the pearl oyster Pinctada martensii (designated as PmTRAF6) was identified and characterized. The obtained full-length PmTRAF6 cDNA was 2273 bp, containing a 5'-untranslated region (UTR) of 297 bp, a 3'-UTR of 128 bp with a 42-bp poly (A) tail, and an open reading frame of 1848 bp that encoded 616-amino acid residues. The deduced protein sequence of PmTRAF6 contained a conserved TRAF family motif including a RING-type zinc finger, two TRAF-type zinc fingers, and a coiled-coil region followed by one meprin and TRAF homology domain. Multiple-sequence alignment indicated that TRAF6 was highly conserved among species, and PmTRAF6 showed 53% sequence identity to Azumapecten farreri and Mizuhopecten yessoensis. Furthermore, an amino acid sequence containing a low-complexity region was inserted in the TRAF6s from mollusk. Quantitative real-time polymerase chain reaction analysis demonstrated that PmTRAF6 was constitutively expressed in all tissues studied, with the most abundant mRNA expression in hepatopancreas and gill in P. martensii. After lipopolysaccharide stimulation, the expression of PmTRAF6 mRNA was dramatically upregulated. These results suggested that the obtained PmTRAF6 was a member of the TRAF6 family and perhaps involved in the innate immune response of pearl oyster. PMID:25511039

  12. Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury

    PubMed Central

    Togbe, Dieudonnée; Schnyder-Candrian, Silvia; Schnyder, Bruno; Doz, Emilie; Noulin, Nicolas; Janot, Laure; Secher, Thomas; Gasse, Pamela; Lima, Carla; Coelho, Fernando Rodrigues; Vasseur, Virginie; Erard, François; Ryffel, Bernhard; Couillin, Isabelle; Moser, Rene

    2007-01-01

    Recent studies on endotoxin/lipopolysaccharide (LPS)-induced acute inflammatory response in the lung are reviewed. The acute airway inflammatory response to inhaled endotoxin is mediated through Toll-like receptor 4 (TLR4) and CD14 signalling as mice deficient for TLR4 or CD14 are unresponsive to endotoxin. Acute bronchoconstriction, tumour necrosis factor (TNF), interleukin (IL)-12 and keratinocyte-derived chemokine (KC) production, protein leak and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF). In particular, LPS-induced TNF is required for bronchoconstriction, but dispensable for inflammatory cell recruitment. Lipopolysaccharide induces activation of the p38 mitogen-activated protein kinase (MAPK). Inhibition of pulmonary MAPK activity abrogates LPS-induced TNF production, bronchoconstriction, neutrophil recruitment into the lungs and broncho-alveolar space. In conclusion, TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin are dependent on TLR4/CD14/MD2 expression using the adapter proteins TIRAP and MyD88, while TRIF, IL-1R1 or IL-18R signalling pathways are dispensable. Further downstream in this axis of signalling, TNF blockade reduces only acute bronchoconstriction, while MAPK inhibition abrogates completely endotoxin-induced inflammation. PMID:18039275

  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. Tumor necrosis factor amplifies measles virus-mediated Ia induction on astrocytes.

    PubMed Central

    Massa, P T; Schimpl, A; Wecker, E; ter Meulen, V

    1987-01-01

    We describe the induction of Ia on cultured astrocytes by measles virus and the amplification of this induction by tumor necrosis factor (TNF). Measles virus induces Ia on rat astrocytes by direct interaction with these cells. TNF does not induce significant levels of Ia at any dose from 1 to 10,000 units/ml. As little as 10 units of TNF per ml, however, amplifies Ia-inducing signals generated by measles virus in astrocytes. In contrast, TNF and measles virus induce class I major histocompatibility complex (MHC) antigens, when applied individually, and TNF amplification of measles virus class I MHC induction is not apparent. The induction of either Ia or class I MHC antigens on rat astrocytes by measles virus does not depend on glial-derived soluble factors generated during infection. Since brain cells are normally lacking MHC antigens upon which T cells depend for interaction with antigen presenting cells, these data indicate that the ability of measles virus to directly stimulate MHC antigen expression and the ability of TNF to amplify Ia expression locally in the brain may be important in initiating cell-mediated immune response to viral infection. PMID:3118363

  15. Expression of tumor necrosis factor alpha converting enzyme in endocrine cancers.

    PubMed

    Kirkegaard, Tove; Naresh, Anjali; Sabine, Vicky S; Tovey, Sian M; Edwards, Joanne; Dunne, Barbara; Cooke, Timothy G; Jones, Frank E; Bartlett, John M S

    2008-05-01

    Tumor necrosis factor alpha converting enzyme (TACE) mediates shedding of human epidermal growth factor receptor-4 (HER4). Recent data suggest that released HER4 intracellular domain (4ICD) induces apoptosis in breast cancer. TACE expression, as measured by immunohistochemical analysis, was observed in 183 of 383 breast carcinomas, 39 of 217 ovarian carcinomas, and 16 of 24 and 17 of 24 hormonesensitive and hormone-insensitive prostate carcinomas, respectively. HER4 expression was detected in breast carcinomas by using 2 antibodies recognizing an extracellular or intracellular epitope. TACE expression was predominantly seen in tumors with high levels of 4ICD and membranous HER4. Apoptotic activity was measured by the terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay and cleaved caspase-3 staining in breast carcinomas. There was no significant association between cleaved caspase-3 or TUNEL positivity and 4ICD, whereas TUNEL positivity was seen predominantly in tumors with high levels of internalized HER4. The data presented herein show TACE expression in endocrine cancers and further support a role for TACE in breast cancer apoptosis.

  16. Successful plasma exchange combined with rituximab therapy in aggressive APS-related cutaneous necrosis.

    PubMed

    Costa, Rubens; Fazal, Salman; Kaplan, Robert B; Spero, Joel; Costa, Ricardo

    2013-03-01

    Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disorder characterized by venous and/or arterial thrombosis or recurrent fetal loss associated with the presence of antiphospholipid antibodies and/or a lupus anticoagulant. The skin appears to be an important target organ and many cases of APS may present with skin manifestations. These lesions may be manifold and may take the form of livedo reticularis, livedo racemosa, ulcerations, digital gangrene, subungeal splinter hemorrhages, superficial venous thrombosis, thrombocytopenic purpura, pseudovasculitic manifestations, extensive cutaneous necrosis, or primary anetoderma. We report a case of fulminant APS-related cutaneous necrosis. A 38-year-old Caucasian male with a past history of APS, multiple deep vein thrombi/pulmonary emboli, presented with necrotic lesions on his right upper and right lower extremities. Initially, baseline anticoagulation was increased without improvement. Subsequently, plasma exchange was initiated on a daily schedule. Furthermore, rituximab 1,000 mg IV was administered on days 1 and 15. After six consecutive daily sessions of plasma exchange, there was significant regression of the necrotic lesions. After a 22-day hospital stay, the patient was discharged to home on fondaparinux. The patient presented approximately 2 months later after missing follow-up appointments. At the time, his initial lesions looked remarkably improved.

  17. Isolation and characterization of tumor necrosis factor receptor-associated factor 6 (TRAF6) from grouper, Epinephelus tauvina.

    PubMed

    Wei, Jingguang; Guo, Minglan; Gao, Pin; Ji, Huasong; Li, Pengfei; Yan, Yang; Qin, Qiwei

    2014-07-01

    Tumor necrosis factor receptor-associated factor 6 (TRAF6) is one of the key adapter molecules in Toll-like receptor signal transduction that triggers downstream cascades involved in innate immunity. In the present study, a TRAF6 (named as Et-TRAF6) was identified from the marine fish grouper, Epinephelus tauvina by RACE PCR. The full-length cDNA of Et-TRAF6 comprised 1949 bp with a 1713 bp open reading frame (ORF) that encodes a putative protein of 570 amino acids. Similar to most TRAF6s, Et-TRAF6 includes one N-terminal RING domain (78aa-116aa), two zinc fingers of TRAF-type (159aa-210aa and 212aa-269aa), one coiled-coil region (370aa-394aa), and one conserved C-terminal meprin and TRAF homology (MATH) domain (401aa-526aa). Quantitative real-time PCR analysis revealed that Et-TRAF6 mRNA is expressed in all tested tissues, with the predominant expression in the stomach and intestine. The expression of Et-TRAF6 was up-regulated in the liver after challenge with Lipoteichoic acid (LTA), Peptidoglycan (PGN), Zymosan, polyinosine-polycytidylic acid [Poly(I:C)] and Polydeoxyadenylic acid · Polythymidylic acid sodium salt [Poly(dA:dT)]. The expression of Et-TRAF6 was also up-regulated in the liver after infection with Vibrio alginolyticus, Singapore grouper iridovirus (SGIV) and grouper nervous necrosis virus (GNNV). Recombinant Et-TRAF6 (rEt-TRAF6) was expressed in Escherichia BL21 (DE3) and purified for mouse anti-Et-TRAF6 serum preparation. Intracellular localization revealed that Et-TRAF6 is distributed in both cytoplasm and nucleus, and predominantly in the cytoplasm. These results together indicated that Et-TRAF6 might be involved in immune responses toward bacterial and virus challenges.

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

    PubMed

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

    2016-09-15

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

  19. Loss of Tumor Necrosis Factor α Potentiates Transforming Growth Factor β-mediated Pathogenic Tissue Response during Wound Healing

    PubMed Central

    Saika, Shizuya; Ikeda, Kazuo; Yamanaka, Osamu; Flanders, Kathleen C.; Okada, Yuka; Miyamoto, Takeshi; Kitano, Ai; Ooshima, Akira; Nakajima, Yuji; Ohnishi, Yoshitaka; Kao, Winston W.-Y.

    2006-01-01

    Animal cornea is an avascular transparent tissue that is suitable for research on wound healing-related scarring and neovascularization. Here we show that loss of tumor necrosis factor α (TNFα) potentiates the undesirable, pathogenic response of wound healing in an alkali-burned cornea in mice. Excessive invasion of macrophages and subsequent formation of a vascularized scar tissue were much more marked in TNFα-null knockout (KO) mice than in wild-type mice. Such an unfavorable outcome in KO mice was abolished by Smad7 gene introduction, indicating the involvement of transforming growth factor β or activin/Smad signaling. Bone marrow transplantation from wild-type mice normalized healing of the KO mice, suggesting the involvement of bone marrow-derived inflammatory cells in this phenomenon. Co-culture experiments showed that loss of TNFα in macrophages, but not in fibroblasts, augmented the fibroblast activation as determined by detection of α-smooth muscle actin, the hallmark of myofibroblast generation, mRNA expression of collagen Iα2 and connective tissue growth factor, and detection of collagen protein. TNFα in macrophages may be required to suppress undesirable excessive inflammation and scarring, both of which are promoted by transforming growth factor β, and for restoration of tissue architecture in a healing alkali-burned cornea in mice. PMID:16723700

  20. 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

  1. 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.

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

    PubMed Central

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

    2004-01-01

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

  3. Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency.

    PubMed

    Yu, Bangning; Becnel, Jaime; Zerfaoui, Mourad; Rohatgi, Rasika; Boulares, A Hamid; Nichols, Charles D

    2008-11-01

    The G protein-coupled serotonin 5-hydroxytryptamine (5-HT)(2A) receptor is primarily recognized for its role in brain neurotransmission, where it mediates a wide variety of functions, including certain aspects of cognition. However, there is significant expression of this receptor in peripheral tissues, where its importance is largely unknown. We have now discovered that activation of 5-HT(2A) receptors in primary aortic smooth muscle cells provides a previously unknown and extremely potent inhibition of tumor necrosis factor (TNF)-alpha-mediated inflammation. 5-HT(2A) receptor stimulation with the agonist (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI] rapidly inhibits a variety of TNF-alpha-mediated proinflammatory markers, including intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin (IL)-6 gene expression, nitric-oxide synthase activity, and nuclear translocation of nuclear factor kappaB, with IC(50) values of only 10 to 20 pM. It is significant that proinflammatory markers can also be inhibited by (R)-DOI hours after treatment with TNF-alpha. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-alpha-mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Our results indicate that activation of 5-HT(2A) receptors represents a novel, and extraordinarily potent, potential therapeutic avenue for the treatment of disorders involving TNF-alpha-mediated inflammation. Note that because (R)-DOI can significantly inhibit the effects of TNF-alpha many hours after the administration of TNF-alpha, potential therapies could be aimed not only at preventing inflammation but also treating inflammatory injury that has already occurred or is ongoing. PMID

  4. Crocin suppresses tumor necrosis factor-alpha-induced cell death of neuronally differentiated PC-12 cells.

    PubMed

    Soeda, S; Ochiai, T; Paopong, L; Tanaka, H; Shoyama, Y; Shimeno, H

    2001-11-01

    Crocus sativus L. is used in Chinese traditional medicine to treat some disorders of the central nervous system. Crocin is an ethanol-extractable component of Crocus sativus L.; it is reported to prevent ethanol-induced impairment of learning and memory in mice. In this study, we demonstrate that crocin suppresses the effect of tumor necrosis factor (TNF)-alpha on neuronally differentiated PC-12 cells. PC-12 cells dead from exposure to TNF-alpha show apoptotic morphological changes and DNA fragmentation. These hallmark features of cell death did not appear in cells treated in the co-presence of 10 microM crocin. Moreover, crocin suppressed the TNF-alpha-induced expression of Bcl-Xs and LICE mRNAs and simultaneously restored the cytokine-induced reduction of Bcl-X(L) mRNA expression. The modulating effects of crocin on the expression of Bcl-2 family proteins led to a marked reduction of a TNF-alpha-induced release of cytochrome c from the mitochondria. Crocin also blocked the cytochrome c-induced activation of caspase-3. To learn how crocin exhibits these anti-apoptotic actions in PC-12 cells, we tested the effect of crocin on PC-12 cell death induced by daunorubicin. We found that crocin inhibited the effect of daunorubicin as well. Our findings suggest that crocin inhibits neuronal cell death induced by both internal and external apoptotic stimuli.

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

    PubMed

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

    2016-01-01

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

  6. Critical Roles for Interleukin 1 and Tumor Necrosis Factor α in Antibody-induced Arthritis

    PubMed Central

    Ji, Hong; Pettit, Allison; Ohmura, Koichiro; Ortiz-Lopez, Adriana; Duchatelle, Veronique; Degott, Claude; Gravallese, Ellen; Mathis, Diane; Benoist, Christophe

    2002-01-01

    In spontaneous inflammatory arthritis of K/BxN T cell receptor transgenic mice, the effector phase of the disease is provoked by binding of immunoglobulins (Igs) to joint surfaces. Inflammatory cytokines are known to be involved in human inflammatory arthritis, in particular rheumatoid arthritis, although, overall, the pathogenetic mechanisms of the human affliction remain unclear. To explore the analogy between the K/BxN model and human patients, we assessed the role and relative importance of inflammatory cytokines in K/BxN joint inflammation by transferring arthritogenic serum into a panel of genetically deficient recipients. Interleukin (IL)-1 proved absolutely necessary. Tumor necrosis factor (TNF)–α was also required, although seemingly less critically than IL-1, because a proportion of TNF-α–deficient mice developed robust disease. There was no evidence for an important role for IL-6. Bone destruction and reconstruction were also examined. We found that all mice with strong inflammation exhibited the bone erosion and reconstruction phenomena typical of K/BxN arthritis, with no evidence of any particular requirement for TNFα for bone destruction. The variability in the requirement for TNF-α, reminiscent of that observed in treated rheumatoid arthritis patients, did not appear genetically programmed but related instead to subtle environmental changes. PMID:12093872

  7. Interleukin 1 or tumor necrosis factor-alpha: which is the real target in rheumatoid arthritis?

    PubMed

    Dayer, Jean-Michel

    2002-09-01

    Much debate has focused on the relative importance of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in the pathophysiology of rheumatoid arthritis (RA). The production of these cytokines by synovial macrophages is tightly regulated by cell-cell contact with T cells. During this contact, several surface molecules are implicated in contact mediated cytokine production, including CD40 ligand, CD11b/c, and CD69. Apolipoprotein A-I, an acute phase reactant (APR) that declines during systemic inflammation (reverse APR), inhibits cytokine production by interfering in the T cell-monocyte interaction. Although the effects of IL-1 and TNF-alpha overlap, they have somewhat differing roles in RA on the basis of evidence from several animal models. TNF-alpha appears to play a more important role in triggering events leading to inflammation both locally and systemically, whereas IL-1 is more involved at the local level in processes leading to cartilage and bone destruction and in impeding cartilage repair. However, IL-1 and TNF-alpha strongly synergize in numerous biological functions, both in vitro and in vivo. Blockade of IL-1 and TNF-alpha simultaneously provides favorable effects in collagen and adjuvant induced arthritis, illustrating the importance of both cytokines.

  8. Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis.

    PubMed

    Ji, Hong; Pettit, Allison; Ohmura, Koichiro; Ortiz-Lopez, Adriana; Duchatelle, Veronique; Degott, Claude; Gravallese, Ellen; Mathis, Diane; Benoist, Christophe

    2002-07-01

    In spontaneous inflammatory arthritis of K/BxN T cell receptor transgenic mice, the effector phase of the disease is provoked by binding of immunoglobulins (Igs) to joint surfaces. Inflammatory cytokines are known to be involved in human inflammatory arthritis, in particular rheumatoid arthritis, although, overall, the pathogenetic mechanisms of the human affliction remain unclear. To explore the analogy between the K/BxN model and human patients, we assessed the role and relative importance of inflammatory cytokines in K/BxN joint inflammation by transferring arthritogenic serum into a panel of genetically deficient recipients. Interleukin (IL)-1 proved absolutely necessary. Tumor necrosis factor (TNF)-alpha was also required, although seemingly less critically than IL-1, because a proportion of TNF-alpha-deficient mice developed robust disease. There was no evidence for an important role for IL-6. Bone destruction and reconstruction were also examined. We found that all mice with strong inflammation exhibited the bone erosion and reconstruction phenomena typical of K/BxN arthritis, with no evidence of any particular requirement for TNFalpha for bone destruction. The variability in the requirement for TNF-alpha, reminiscent of that observed in treated rheumatoid arthritis patients, did not appear genetically programmed but related instead to subtle environmental changes.

  9. Effects on leukocytes after injection of tumor necrosis factor into healthy humans.

    PubMed

    van der Poll, T; van Deventer, S J; Hack, C E; Wolbink, G J; Aarden, L A; Büller, H R; ten Cate, J W

    1992-02-01

    Tumor necrosis factor (TNF) has been implicated as a proximal mediator of the septic syndrome. To evaluate the possible role of TNF in leukocyte activation in septicemia, we performed a cross-over saline-controlled study in six healthy men who were intravenously injected with recombinant human TNF (50 micrograms/m2), and analyzed changes in circulating white blood cells and parameters for neutrophil and monocyte activation. TNF elicited a very rapid neutropenia, reaching a nadir after 15 minutes, followed by a neutrophilia. Lymphocytes showed a sustained decrease, whereas monocytes declined transiently. TNF injection was also associated with neutrophil activation, as reflected by a mean fivefold increase in the plasma concentrations of elastase-alpha 1-antitrypsin complexes and a mean sevenfold increase in plasma lactoferrin levels. Serum neopterin, a marker of monocyte activation, was significantly increased 24 hours after the administration of TNF. These changes occurred in the absence of detectable complement activation, as indicated by unchanged C3a-desarg plasma values. Serum interleukin-6 showed a nearly 40-fold increase after TNF injection, whereas interleukin-1 remained undetectable throughout. We conclude that the systemic release of TNF, triggered early after invasive infection, may be involved in the alterations in circulating leukocyte numbers and in the activation of leukocytes, during the development of the septic syndrome.

  10. Tumor necrosis factor unresponsiveness after surgery in bile duct-ligated rats.

    PubMed

    Houdijk, A P; Boermeester, M A; Wesdorp, R I; Hack, C E; Van Leeuwen, P A

    1996-12-01

    In obstructive jaundice, postoperative complications are related to gut-derived endotoxemia and possibly mediated by cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6). This study investigated the course of IL-6 and TNF after surgery in bile duct-ligated rats (BDL) treated with and without an enteral endotoxin binder (cholestyramine). Endotoxin in rat plasma was determined by blocking cytokine production in whole blood cell cultures stimulated by rat plasma using antibodies directed against the endotoxin (CD14) receptor. Surgery elicited a significant IL-6 response in saline-treated BDL rats (BDL-SAL). TNF, however, remained at its low preoperative levels. Cholestyramine treatment resulted in undetectable preoperative TNF and IL-6 levels, but levels of both cytokines were significantly raised after surgery. Endotoxin, as determined by the CD14 blockade test, was identified in the BDL-SAL group, before (time 0) and after surgery (2 and 4 h), whereas in the cholestyramine group endotoxin was only present at 2 h after surgery. The lack of a postoperative plasma TNF response in the BDL-SAL group in the continuous presence of endotoxin suggests endotoxin tolerance for TNF production in obstructive jaundice.

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

    PubMed Central

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

    1993-01-01

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

  12. The promoting effect of tumour necrosis factor alpha in radiation-induced cell transformation.

    PubMed Central

    Guo, R. F.; Gong, Y. F.

    1998-01-01

    The ability of tumour necrosis factor alpha (TNF-alpha), a potent endogenous inflammatory agent, to promote malignant transformation of Syrian hamster embryo cells (SHE) initiated by a 0.5-Gy dose of alpha-particles was investigated. Opsonized zymosan particles, which were phagocytosed by a human macrophage-like cell line, triggered TNF-alpha production from U937 cells. This cell supernatant could significantly increase the transformation frequency (TF) of primary SHE cells previously irradiated by a 0.5-Gy dose of alpha-particles. The TF decreased significantly if monoclonal antibody against TNF-alpha was added to the supernatant. Similarly, recombinant human TNF-alpha (rhTNF-alpha) increased the TF of alpha-irradiated primary SHE cells to an even greater extent. Addition of TNF-alpha to subcultures of irradiated SHE cells permitted the continuous propagation of these primary cells. In contrast, both TNF-alpha-treated control and alpha-irradiated cells without subsequent TNF-alpha treatment senesced after 7-15 passages. Irradiated SHE cells treated continuously with TNF-alpha could be subcultured over 40 passages and produced fibrosarcomas upon inoculation into nude mice. Our results provide the first evidence that TNF-alpha released by activated macrophages may contribute to the process of malignant transformation initiated by low-dose alpha-particles. PMID:9579824

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-07-01

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

  15. Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events.

    PubMed

    Bhaskar, Kiran; Maphis, Nicole; Xu, Guixiang; Varvel, Nicholas H; Kokiko-Cochran, Olga N; Weick, Jason P; Staugaitis, Susan M; Cardona, Astrid; Ransohoff, Richard M; Herrup, Karl; Lamb, Bruce T

    2014-02-01

    Massive neuronal loss is a key pathological hallmark of Alzheimer's disease (AD). However, the mechanisms are still unclear. Here we demonstrate that neuroinflammation, cell autonomous to microglia, is capable of inducing neuronal cell cycle events (CCEs), which are toxic for terminally differentiated neurons. First, oligomeric amyloid-beta peptide (AβO)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-α (TNFα) and the c-Jun Kinase (JNK) signaling pathway. Second, adoptive transfer of CD11b+ microglia from AD transgenic mice (R1.40) induced neuronal cyclin D1 expression via TNFα signaling pathway. Third, genetic deficiency of TNFα in R1.40 mice (R1.40-Tnfα(-/-)) failed to induce neuronal CCEs. Finally, the mitotically active neurons spatially co-exist with F4/80+ activated microglia in the human AD brain and that a portion of these neurons are apoptotic. Together our data suggest a cell-autonomous role of microglia, and identify TNFα as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD.

  16. Paradoxical role of tumor necrosis factor alpha in fumonisin-induced hepatotoxicity in mice.

    PubMed

    Sharma, Raghubir P; He, Quanren; Meredith, Filmore I; Riley, Ronald T; Voss, Kenneth A

    2002-12-01

    Tumor necrosis factor alpha (TNFalpha) is involved in fumonisin-induced hepatotoxic effects in mice. The hepatic response to fumonisin B(1) (FB(1)) was reduced in transgenic animals lacking either of the two TNFalpha receptors. In the present study, we hypothesized that the effect of a similar fumonisin treatment in animals lacking either TNFalpha or both TNFalpha receptors would be considerably less than their wild type (WT) counterparts. The FB(1)-induced increase in circulating liver enzymes was enhanced by deletion of TNFalpha or unchanged in mice lacking both TNFalpha receptors. These findings corresponded with the degree of toxicity as established by microscopic examination of liver. FB(1) induced the expression of TNFalpha in the liver of all strains, except the animals with a deleted TNFalpha gene. The FB(1)-mediated increases in liver sphingosine or sphinganine paralleled the hepatotoxic responses. It is apparent that the presence of TNFalpha is not necessary for FB(1)-induced hepatotoxicity in mice and a lack of the function of this cytokine may aggravate the hepatotoxic responses to fumonisins, perhaps by preventing repair mechanisms or by expression of other signaling molecules. These observations were in accordance with our previous finding where over-expression of TNFalpha also protected against FB(1)-mediated hepatotoxicity, and with the reported beneficial functions of low-level TNFalpha in tissue regeneration.

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

    PubMed

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

    2014-02-01

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

  18. A Case of Sarcoidosis Associated With Anti–Tumor Necrosis Factor Treatment

    PubMed Central

    Hanazay, Cigdem; Kokturk, Nurdan; Turktas, Haluk

    2015-01-01

    Sarcoidosis is a systemic chronic granulomatous disease of unknown etiology. It predominantly involves the lungs but can affect many organs or tissues in the body, such as the lymphatic system, skin, eyes, and liver. Typical histopathological lesions are noncaseating granulomas in the affected organ or tissue. Indications, type of treatment, and duration of sarcoidosis treatment is currently debated. Despite studies showing that anti–tumor necrosis factor-α (TNF-α) treatment can successfully be used in refractory sarcoidosis, there are some case reports regarding the development of sarcoidosis with these agents. There have been reports of 47 anti-TNF-associated cases of sarcoidosis until 2012. The patient is a 54-year-old Caucasian male. During routine examinations of the patient who had been followed for psoriasis vulgaris for 20 years and who had been on several anti-TNF regimens thereafter, new pulmonary pathologies due to sarcoidosis were detected. We present here a case of sarcoidosis that developed after infliximab treatment and showed obvious radiologic regression with discontinuation of treatment. During anti-TNF treatment, it should be kept in mind that autoimmune and granulomatous diseases may develop and particular care should be given to patient follow-ups. PMID:26425632

  19. LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner

    PubMed Central

    Mattijssen, Sandy

    2015-01-01

    LARP4 is a protein with unknown function that independently binds to poly(A) RNA, RACK1, and the poly(A)-binding protein (PABPC1). Here, we report on its regulation. We found a conserved AU-rich element (ARE) in the human LARP4 mRNA 3′ untranslated region (UTR). This ARE, but not its antisense version or a point-mutated version, significantly decreased the stability of β-globin reporter mRNA. We found that overexpression of tristetraprolin (TTP), but not its RNA binding mutant or the other ARE-binding proteins tested, decreased cellular LARP4 levels. RNA coimmunoprecipitation showed that TTP specifically associated with LARP4 mRNA in vivo. Consistent with this, mouse LARP4 accumulated to higher levels in TTP gene knockout (KO) cells than in control cells. Stimulation of WT cells with tumor necrosis factor alpha (TNF-α), which rapidly induces TTP, robustly decreased LARP4 with a coincident time course but had no such effect on LARP4B or La protein or on LARP4 in the TTP KO cells. The TNF-α-induced TTP pulse was followed by a transient decrease in LARP4 mRNA that was quickly followed by a subsequent transient decrease in LARP4 protein. Involvement of LARP4 as a target of TNF-α–TTP regulation provides a clue as to how its functional activity may be used in a physiologic pathway. PMID:26644407

  20. Quantitative Proteomics Reveals the Induction of Mitophagy in Tumor Necrosis Factor-α-activated (TNFα) Macrophages*

    PubMed Central

    Bell, Christina; English, Luc; Boulais, Jonathan; Chemali, Magali; Caron-Lizotte, Olivier; Desjardins, Michel; Thibault, Pierre

    2013-01-01

    Macrophages play an important role in innate and adaptive immunity as professional phagocytes capable of internalizing and degrading pathogens to derive antigens for presentation to T cells. They also produce pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that mediate local and systemic responses and direct the development of adaptive immunity. The present work describes the use of label-free quantitative proteomics to profile the dynamic changes of proteins from resting and TNF-α-activated mouse macrophages. These analyses revealed that TNF-α activation of macrophages led to the down-regulation of mitochondrial proteins and the differential regulation of several proteins involved in vesicle trafficking and immune response. Importantly, we found that the down-regulation of mitochondria proteins occurred through mitophagy and was specific to TNF-α, as other cytokines such as IL-1β and IFN-γ had no effect on mitochondria degradation. Furthermore, using a novel antigen presentation system, we observed that the induction of mitophagy by TNF-α enabled the processing and presentation of mitochondrial antigens at the cell surface by MHC class I molecules. These findings highlight an unsuspected role of TNF-α in mitophagy and expanded our understanding of the mechanisms responsible for MHC presentation of self-antigens. PMID:23674617

  1. Tumor vascular targeting with tumor necrosis factor alpha and chemotherapeutic drugs.

    PubMed

    Corti, Angelo; Ponzoni, Mirco

    2004-12-01

    The poor selectivity of chemotherapeutic drugs for neoplastic cells may lead to dose-limiting side effects that compromise clinical outcomes. Moreover, heterogeneous tumor perfusion and vascular permeability, and increased interstitial pressure, could represent critical barriers that limit the penetration of drugs into neoplastic cells distant from tumor vessels and, consequently, the effectiveness of chemotherapy. We have recently developed two strategies for increasing the local concentration of chemotherapeutic drugs in tumors and their therapeutic index, based on tumor vascular targeting. First, we have found that vascular targeting with minute amounts of tumor necrosis factor alpha (TNF-alpha), an inflammatory cytokine able to increase vascular permeability, alters tumor barriers and increases the penetration of chemotherapeutic drugs in subcutaneous tumors in mouse models. Targeted delivery of TNF-alpha to tumor vessels was achieved by coupling this cytokine with cyclic CNGRC peptide, an aminopeptidase N (CD13) ligand that targets the tumor neovasculature. Second, we have observed that encapsulation of doxorubicin into liposomes able to home to tumor vessels markedly improves drug uptake by neuroblastoma tumors, in an orthotopic xenograft model, and its therapeutic index. Targeted delivery of liposomes was achieved by coupling linear GNGRG peptide to the surface of liposomal doxorubicin. Vascular targeting, either indirectly with NGR-TNF-alpha or directly with NGR-targeted liposomes, could be a novel strategy for increasing the therapeutic index of chemotherapeutic drugs.

  2. Effects of tumor necrosis factor on the hypothalamic-pituitary-testicular axis in healthy men.

    PubMed

    van der Poll, T; Romijn, J A; Endert, E; Sauerwein, H P

    1993-03-01

    Tumor necrosis factor (TNF) has been implicated as a mediator of many diseases associated with alterations in hypothalamic-pituitary-testicular (HPT) function. To assess the effects of TNF on the HPT axis, we performed a saline-controlled cross-over study in six healthy men, sequentially measuring serum concentrations of gonadotropins, testosterone, and sex hormone-binding globulin (SHBG) after a bolus intravenous injection of recombinant human TNF (50 micrograms/m2). TNF induced an early and transient increase in serum luteinizing hormone (LH) levels from 6.0 +/- 1.0 to a maximum of 8.0 +/- 1.0 U/L after 30 minutes (P < .005), whereas the concentrations of follicle-stimulating hormone (FSH) remained unchanged. The increase in LH concentrations was followed by a transient decrease in serum testosterone levels from 18.2 +/- 0.3 to 9.1 +/- 1.2 nmol/L after 4 hours (P < .0001). Remarkably, LH levels had returned to control values when the testosterone level reached its nadir. SHBG levels were not affected by TNF. Our results suggest that TNF affects the HPT axis at multiple levels and may be involved either directly or indirectly in the decrease in circulating testosterone concentrations in systemic illnesses.

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

    PubMed

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

    2014-02-01

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

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

    SciTech Connect

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

    1990-08-01

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

  5. Tumor necrosis factor alpha regulates in vivo intrapulmonary expression of ICAM-1.

    PubMed Central

    Mulligan, M. S.; Vaporciyan, A. A.; Miyasaka, M.; Tamatani, T.; Ward, P. A.

    1993-01-01

    Lung injury following deposition of IgG immune complexes is neutrophil-dependent and requires both tumor necrosis factor alpha (TNF alpha) and CD18. In the current studies, we have evaluated the relationship between TNF alpha and expression of intracellular adhesion molecule-1 (ICAM-1) in vitro and in vivo. In both rat pulmonary artery endothelial cells and human umbilical vein endothelial cells, TNF alpha induced an early (within 60 minutes) increase in ICAM-1 expression, followed by a peak at 6 to 8 hours, with relatively stable expression at 24 hours. Expression of E-selectin did not show the early phase (within 60 minutes) of up-regulation, peaked at 4 hours, and then declined thereafter. Using a radioimmunochemical assay in vivo, it was demonstrated that intrapulmonary deposition of IgG immune complexes caused a progressive increase in ICAM-1 expression in lung over an 8-hour period. In animals pretreated with antibody to TNF alpha, the intrapulmonary expression of ICAM-1 was significantly reduced. These results were confirmed by immunoperoxidase analysis of lung tissue. It was also shown that airway instillation of TNF alpha caused up-regulation of ICAM-1 in lung. These data support the concept that deposition of IgG immune complexes in lung induces intrapulmonary up-regulation of ICAM-1 in a manner that is TNF alpha-dependent. Images Figure 2 Figure 7 PMID:7685152

  6. Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

    PubMed Central

    Dong, Yun; Fischer, Roman; Naudé, Petrus J. W.; Maier, Olaf; Nyakas, Csaba; Duffey, Maëlle; Van der Zee, Eddy A.; Dekens, Doortje; Douwenga, Wanda; Herrmann, Andreas; Guenzi, Eric; Kontermann, Roland E.; Pfizenmaier, Klaus; Eisel, Ulrich L. M.

    2016-01-01

    Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNFR2, an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNFR2 into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases. PMID:27791020

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

    PubMed Central

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

    2015-01-01

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

  8. 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.

  9. Identification and characterization of a tumor necrosis factor receptor like protein encoded by Singapore grouper iridovirus.

    PubMed

    Huang, Xiaohong; Huang, Youhua; Cai, Jia; Wei, Shina; Gao, Ren; Qin, Qiwei

    2013-12-26

    Virus encoded tumor necrosis factor receptors (TNFRs) have been demonstrated to facilitate virus to escape from apoptosis or other host immune response for viral replication. Singapore grouper iridovirus (SGIV), a large DNA virus which belongs to genus Ranavirus, is a major pathogen resulting in heavy economic losses to grouper aquaculture. Here, SGIV ORF096 (VP96) encoding a putative homolog of TNFR was identified and characterized. Multiple sequence alignment indicated that SGIV-VP96 contained two extracellular cysteine-rich domains (CRDs) with conserved four or six cysteine residues, but lacked the transmembrane domain at the C-terminus. SGIV-VP96 was identified as an early (E) gene and localized in the cytoplasm in transfected or infected cells. Overexpression of SGIV-VP96 in vitro enhanced cell proliferation, and improved cell survival against SGIV infection. Furthermore, virus infection induced apoptosis and caspase-3 activity were inhibited in SGIV-VP96 expressing FHM cells compared to the control cells. Taken together, our results suggested that SGIV might utilize virus encoded TNFR like genes to modulate the host apoptotic response for effective virus replication.

  10. Tumour necrosis factor-α inhibition can stabilize disease in progressive vitiligo.

    PubMed

    Webb, K C; Tung, R; Winterfield, L S; Gottlieb, A B; Eby, J M; Henning, S W; Le Poole, I C

    2015-09-01

    Tumour necrosis factor (TNF)-α, a proinflammatory cytokine central to many autoimmune diseases, has been implicated in the depigmentation process in vitiligo. We review its role in vitiligo by exploring its pro- and anti-inflammatory properties and examine the effects of blocking its actions with TNF-α antagonist therapeutics in reports available in the literature. We found that TNF-α inhibition halts disease progression in patients with progressive vitiligo but that, paradoxically, treatment can be associated with de novo vitiligo development in some patients when used for other autoimmune conditions, particularly when using adalimumab and infliximab. These studies reinforce the importance of stating appropriate outcomes measures, as most pilot trials propose to measure repigmentation, whereas halting depigmentation is commonly overlooked as a measure of success. We conclude that TNF-α inhibition has proven useful for patients with progressive vitiligo, where TNF-α inhibition is able to quash cytotoxic T-cell-mediated melanocyte destruction. However, a lingering concern for initiating de novo disease will likely prevent more widespread application of TNF inhibitors to treat vitiligo.

  11. 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.

  12. Functional identification of the alveolar edema reabsorption activity of murine tumor necrosis factor-alpha.

    PubMed

    Elia, Nadia; Tapponnier, Maxime; Matthay, Michael A; Hamacher, Jurg; Pache, Jean-Claude; Brundler, Marie-Anne; Totsch, Martin; De Baetselier, Patrick; Fransen, Lucie; Fukuda, Norimasa; Morel, Denis R; Lucas, Rudolf

    2003-11-01

    Tumor necrosis factor-alpha (TNF-alpha) activates sodium channels in Type II alveolar epithelial cells, an important mechanism for the reported fluid resorption capacity of the cytokine. Both TNF-alpha receptor-dependent and -independent effects were proposed for this activity in vitro, the latter mechanism mediated by the lectin-like domain of the molecule. In this study, the relative contribution of the receptor-dependent versus receptor-independent activities was investigated in an in situ mouse lung model and an ex vivo rat lung model. Fluid resorption due to murine TNF-alpha (mTNF-alpha) was functional in mice that were genetically deficient in both types of mTNF-alpha receptor, establishing the importance of mTNF-alpha receptor-independent effects in this species. In addition, we assessed the capacity of an mTNF-alpha-derived peptide (mLtip), which activates sodium transport by a receptor-independent mechanism, to reduce lung water content in an isolated, ventilated, autologous blood-perfused rat lung model. The results show that in this model, mLtip, in contrast to mTNF-alpha, produced a progressive recovery of dynamic lung compliance and airway resistance after alveolar flooding. There was also a significant reduction in lung water. These results indicate that the receptor-independent lectin-like domain of mTNF-alpha has a potential physiological role in the resolution of alveolar edema in rats and mice.

  13. Two soluble antigens of Plasmodium falciparum induce tumor necrosis factor release from macrophages.

    PubMed Central

    Taverne, J; Bate, C A; Kwiatkowski, D; Jakobsen, P H; Playfair, J H

    1990-01-01

    The production of cytokines such as tumor necrosis factor (TNF) may contribute to the pathology of malaria. We showed previously that crude preparations of heat-stable exoantigens from parasite cultures induce the release of TNF in vitro and in vivo. When separated from the culture medium by affinity chromatography, in which immune immunoglobulin G was used as ligand, the mixture of exoantigens of Plasmodium falciparum retained the capacity to induce the secretion of TNF, both by human monocytes from Gambian children and by mouse macrophages. Two individual antigens, Ag1 and Ag7, further purified by affinity chromatography and identified by crossed immunoelectrophoresis, also stimulated TNF production by both types of cell but differed in other functional properties. Thus, the activity of Ag7, but not that of Ag1, was inhibited by polymyxin B, and antisera made against boiled exoantigens of the rodent parasite Plasmodium yoelii which blocked the ability of these antigens to induce the production of TNF also inhibited the activity of Ag7 without affecting Ag1. Since the prevalence of antibody against Ag7 in sera from children in endemic areas appears to correlate with the development of immunity against the manifestations of the disease, this antigen may be one cause of pathology, perhaps through its ability to induce the production of TNF. Its serological relationship with rodent exoantigens suggests that it might be a candidate for an anti-disease vaccine which has the advantage that its active moiety is not subject to significant antigen polymorphism. PMID:2201638

  14. Effects of tumor necrosis factor α on leptin-sensitive intestinal vagal mechanoreceptors in the cat.

    PubMed

    Quinson, Nathalie; Vitton, Véronique; Bouvier, Michel; Grimaud, Jean-Charles; Abysique, Anne

    2013-11-01

    The involvement of tumour necrosis factor α (TNF-α) in inflammatory bowel disease (IBD) has been established, and anti-TNF-α has been suggested as a therapeutic approach for the treatment of these pathologies. We studied the effects of TNF-α on leptin-sensitive intestinal vagal units to determine whether TNF-α exerts its effects through the intestinal vagal mechanoreceptors and to investigate its interactions with substances regulating food intake. The activity of intestinal vagal mechanoreceptors was recorded via microelectrodes implanted into the nodose ganglion in anesthetized cats. TNF-α (1 μg, i.a.) increased the discharge frequency of leptin-activated units (type 1 units; P < 0.05) and had no effect on the discharge frequency of leptin-inhibited units (type 2 units). When TNF-α was administered 20 min after sulfated cholecystokinin-8 (CCK), its excitatory effects on type 1 units were significantly enhanced (P < 0.0001) and type 2 units were significantly (P < 0.05) activated. Pre-treatment with Il-1ra (250 μg, i.a.) blocked the excitatory effects of TNF-α on type 1 units whereas the excitatory effects of TNF-α administration after CCK treatment on type 2 units were not modified. The activation of leptin-sensitive units by TNF-α may explain, at least in part, the weight loss observed in IBD.

  15. 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

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

    PubMed

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

    2016-01-01

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

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

    SciTech Connect

    Chang, M.P.

    1988-01-01

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

  18. Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression.

    PubMed Central

    Naylor, M S; Stamp, G W; Foulkes, W D; Eccles, D; Balkwill, F R

    1993-01-01

    The gene for tumor necrosis factor, TNF, was expressed in 45 out of 63 biopsies of human epithelial ovarian cancer. In serous tumors, there was a positive correlation between level of TNF expression and tumor grade. TNF mRNA was found in epithelial tumor cells and infiltrating macrophages, whereas TNF protein localized primarily to a subpopulation of macrophages within and in close proximity to tumor areas. mRNA and protein for the p55 TNF receptor gene localized to the tumor epithelium and tumor, but not to stromal macrophages. The p75 TNF receptor was confined to infiltrating cells. Cells expressing TNF mRNA were also found in ovarian cancer ascites and TNF protein was detected in some ascitic fluids. In 2 out of 12 biopsies of normal ovary, TNF mRNA was detected in a minority of cells in the thecal layer of the corpus luteum. Serum levels of TNF and its soluble receptor did not correlate with extent of TNF expression in matched biopsies. Northern and Southern analysis revealed no gross abnormality of the TNF gene. The coexpression of TNF and its receptor in ovarian cancer biopsies suggests the capacity for autocrine/paracrine action. TNF antagonists may have therapeutic potential in this malignancy. Images PMID:8387543

  19. Noise and fidelity of information transmission through the Tumor Necrosis Factor signaling circuit

    NASA Astrophysics Data System (ADS)

    Levchenko, Andre

    2013-03-01

    Molecular noise restricts the ability of an individual cell to resolve input signals of different strengths and gather information about the external environment. We developed an integrative theoretical and experimental framework, based on the formalism of information theory, to quantitatively predict and measure the amount of information transduced by molecular and cellular networks. Analyzing tumor necrosis factor (TNF) signaling revealed that individual TNF signaling pathways transduce information sufficient for accurate binary decisions, and an upstream bottleneck limits the information gained via multiple integrated pathways. Negative feedback to this bottleneck could both alleviate and enhance its limiting effect, despite decreasing noise. Bottlenecks likewise constrain information attained by networks signaling through multiple genes or cells. We further use this new analysis formalism to ``map'' the noise amplitude across different parts of the network. Finally, we show that the redundancy in signaling due to the existence of parallel pathways is not absolute, and that parallel pathways can transmit different types of information about the input, i.e., the duration vs. amplitude.

  20. Wound healing potential of pterospermum acerifolium wild. With induction of tumor necrosis factor - α

    PubMed Central

    Senapati, Aswini Kumar; Giri, Ranjan Kumar; Panda, Dibya Sundar; Satyanarayan, Sremantula

    2011-01-01

    Pterospermum acerifolium, a well-known plant in Indian medicine possesses various therapeutic properties including healing properties and cytokine induction. Wound healing activity of ethanolic extract of P. acerifolium flower along with its effect on tumor necrosis factor-α (TNF-α) was assessed using excision model of wound repair in Wistar albino rats. After application of the P. acerifolium extract, rate of epithelization with an increase in wound contraction was observed. Animals tropically treated with 10% P. acerifolium extract in petroleum jelly, the wound healing process was observed faster as compared to control group which were treated with petroleum jelly alone. A significant accelerated healing was noticed in animals which were additionally prefed with 250mg/kg body weight of ethanolic P. acerifolium extract daily for 20 consecutive days along with the topical application 10% P. acerifolium extract. During wound healing phase TNF-α level was found to be up regulated by P. acerifolium treatment. Early wound healing may be pronounced due to P. acerifolium extract elevating TNF−α production PMID:24826024

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

    PubMed Central

    Madkour, Nermeen; Kazerooni, Rashid

    2014-01-01

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

  2. Dehydroepiandrosterone protects mice from endotoxin toxicity and reduces tumor necrosis factor production.

    PubMed Central

    Danenberg, H D; Alpert, G; Lustig, S; Ben-Nathan, D

    1992-01-01

    Recent reports have demonstrated an immunomodulating activity of dehydroepiandrosterone (DHEA) different from that described for glucocorticoids. The present study was designed to test DHEA's activity in endotoxic shock and to investigate its effect on endotoxin-induced production of tumor necrosis factor (TNF). Mortality of CD-1 mice exposed to a lethal dose of lipopolysaccharide (LPS; 800 micrograms per mouse) was reduced from 95 to 24% by treatment with a single dose of DHEA, given 5 min before LPS. LPS administration resulted in high levels of TNF, a response that was significantly blocked by DHEA, both in vivo and in vitro. DHEA treatment also reduced LPS-induced increments in serum corticosterone levels, a parameter considered not to be mediated by TNF. In another experimental model, mice sensitized with D-galactosamine, followed by administration of recombinant human TNF, were subjected to 89% mortality rate, which was reduced to 55% in DHEA-treated mice. These data show that DHEA protects mice from endotoxin lethality. The protective effect is probably mediated by reduction of TNF production as well as by effecting both TNF-induced and non-TNF-induced phenomena. PMID:1444309

  3. Synthesis and Characterization of a Thermally Responsive Tumor Necrosis Factor Antagonist

    PubMed Central

    Shamji, Mohammed F.; Chen, Jun; Friedman, Allan H.; Richardson, William J.; Chilkoti, Ashutosh; Setton, Lori A.

    2008-01-01

    Numerous antagonists of tumor necrosis factor alpha (TNFα) have been developed to attenuate inflammation and accompanying pain in many disease processes. Soluble TNF receptor type II (sTNFRII) is one such antagonist that sequesters TNFα away from target receptors and attenuates its activity. Systemic delivery of soluble TNF receptors or other antagonists may have deleterious side effects associated with immune suppression, so that strategies for locally targeted drug delivery are of interest. Elastin-like polypeptides (ELPs) are biopolymers capable of in situ drug depot formation through thermally-driven supramolecular complexes at physiological temperatures. A recombinant fusion protein between ELP and sTNFRII was designed and evaluated for retention of bivalent functionality. Thermal sensitivity was observed by formation of supramolecular submicron-sized particles at 32°C, with gradual resolubilization from the depot observed at physiological temperatures. In vitro refolding of the sTNFRII domain was required and the purified product exhibited an equilibrium dissociation constant for interacting with TNFα that was seven-fold higher than free sTNFRII. Furthermore, anti-TNF activity was observed in inhibiting TNFα-mediated cytotoxicity in the murine L929 fibrosarcoma assay. Potential advantages of this ELP-sTNFRII fusion protein as an anti-TNFa drug depot include facility of injection, in situ depot formation, low endotoxin content, and functionality against TNFα. PMID:18547669

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

    PubMed

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

    2016-07-01

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

  5. Polysaccharide peptide induces a tumor necrosis factor-α-dependent drop of body temperature in rats.

    PubMed

    Jedrzejewski, Tomasz; Piotrowski, Jakub; Wrotek, Sylwia; Kozak, Wieslaw

    2014-08-01

    Polysaccharide peptide (PSP) extracted from the Coriolus versicolor mushroom is frequently suggested as an adjunct to the chemo- or radiotherapy in cancer patients. It improves quality of the patients' life by decreasing pain, fatigue, loss of appetite, nausea, and vomiting. However, the effect of PSP on body temperature has not thus far been studied, although it is well known that treatment with other polysaccharide adjuvants, such as lipopolysaccharides, may induce fever. The aim of the present study, therefore, was to investigate the influence of PSP on temperature regulation in rats. We report that intraperitoneal injection of PSP provoked a dose-dependent decrease of temperature in male Wistar rats equipped with biotelemetry devices to monitor deep body temperature (Tb). The response was rapid (i.e., with latency of 15-20min), transient (lasting up to 5h post-injection), and accompanied by a significant elevation of the blood tumor necrosis factor-α (TNF-α) level. Pretreatment of the rats with anti-TNF-α antibody prevented the PSP-induced drop in Tb. Based on these data, we conclude that rats may develop an anapyrexia-like response to the injection of peptidopolysaccharide rather than fever, and the response was TNF-α-dependent.

  6. Interleukin-1 and tumour necrosis factor cause hypotension in the conscious rabbit.

    PubMed

    Weinberg, J R; Wright, D J; Guz, A

    1988-09-01

    1. The cardiovascular effects of intravenous injections of interleukin-1 (IL-1) and tumour necrosis factor (TNF) have been investigated in the conscious rabbit. They have been compared with the effects of bacterial lipopolysaccharide (LPS) because both IL-1 and TNF are released from macrophages by LPS. 2. IL-1, TNF and Escherichia coli J5-LPS all caused hypotension when given intravenously in a dose with low mortality. The time course of the hypotension caused by IL-1 and LPS was similar, although the maximal fall in mean blood pressure occurred earlier after IL-1. TNF produced a more sustained fall in blood pressure. Hypotension was not accompanied by a compensatory tachycardia after any of the test substances. Hypotension was associated with a fever after TNF, hypothermia after LPS and no significant change in temperature after IL-1. 3. The packed cell volume did not change during hypotension in any of the study groups, implying that the hypotension was not due to fluid loss resulting from increased capillary permeability. 4. IL-1 and TNF are candidates for the role of effectors of LPS-induced hypotension.

  7. Augmentation of the neutrophil response to Naegleria fowleri by tumor necrosis factor alpha.

    PubMed Central

    Ferrante, A

    1989-01-01

    Conditioned medium from phytohemagglutinin-stimulated human mononuclear leukocytes, previously shown to activate neutrophils for amoeba killing, was found to contain high levels of tumor necrosis factor alpha (TNF-alpha) by an enzyme-linked immunosorbent assay. The effects of human recombinant TNF-alpha on the response of human neutrophils to the pathogenic free-living amoeba Naegleria fowleri was studied in vitro. The data showed that recombinant human TNF-alpha augmented the neutrophil respiratory burst (assessed by the cytochrome c reduction assay and lucigenin-dependent chemiluminescence assay) in response to amoebae opsonized with human serum. The priming effects of TNF-alpha were transient; marked enhancement was found with short 5- to 30-min preincubations of neutrophils with the cytokine. The enhancement of oxygen radical production was evident with 20 U of TNF-alpha per 10(6) neutrophils and continued to increase with up to 100 U. TNF-alpha also augmented the neutrophil lysosomal enzyme release in response to N. fowleri. The results support previous reports suggesting an important role of neutrophil cytokine activation for effective immunity against free-living amoebae. PMID:2777375

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

    PubMed Central

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

    2006-01-01

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

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

    PubMed

    Gordon, C J; Rowsey, P J

    1999-05-01

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

  10. Prostaglandin E2 inhibits tumor necrosis factor-alpha RNA through PKA type I.

    PubMed

    Stafford, Jennifer B; Marnett, Lawrence J

    2008-02-01

    Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that may contribute to the pathogenesis of septic shock, rheumatoid arthritis, cancer, and diabetes. Prostaglandins endogenously produced by macrophages act in an autocrine fashion to limit TNF-alpha production. We investigated the timing and signaling pathway of prostaglandin-mediated inhibition of TNF-alpha production in Raw 264.7 and J774 macrophages. TNF-alpha mRNA levels were rapidly modulated by PGE(2) or carbaprostacylin. PGE(2) or carbaprostacyclin prevented and rapidly terminated on-going TNF-alpha gene transcription within 15 min of prostaglandin treatment. Selective activation of PKA type I, but not PKA type II or Epac, with chemical analogs of cAMP was sufficient to inhibit LPS-induced TNF-alpha mRNA levels. The mechanisms by which prostaglandins limit TNF-alpha mRNA levels may underlie endogenous regulatory mechanisms that limit inflammation, and may have important implications for understanding chronic inflammatory disease pathogenesis. PMID:18060853

  11. In vitro and in vivo induction of tumor necrosis factor alpha by Borrelia burgdorferi.

    PubMed Central

    Defosse, D L; Johnson, R C

    1992-01-01

    Tumor necrosis factor alpha (TNF-alpha) is an immunoregulatory cytokine with many biological activities including the mediation of inflammation. We examined sera and synovial fluids from patients seropositive for infection with Borrelia burgdorferi using a radioimmunoassay specific for TNF-alpha. Significant elevation of TNF-alpha was found in the sera and synovial fluids of patients examined, while controls showed no elevation. Sera of mice infected with B. burgdorferi contained elevated levels of TNF-alpha which varied during the course of a 24-day infection. To determine whether B. burgdorferi is capable of inducing TNF-alpha production, spirochetes were added to adherent human peripheral blood mononuclear cells or mouse peritoneal exudate cells and 24 h later supernatants were assayed. TNF-alpha induction occurred in a dose-dependent manner. The maximum stimulation occurred when a ratio of 1 to 10 spirochetes per mononuclear cell was used. At optimal concentrations, induction was not diminished by inactivation of spirochetes or pretreatment with polymyxin B. These results suggest that an increase in TNF-alpha production may occur as a result of infection with B. burgdorferi. PMID:1541526

  12. Capacity of tumor necrosis factor to augment lymphocyte-mediated tumor cell lysis of malignant mesothelioma

    SciTech Connect

    Bowman, R.V.; Manning, L.S.; Davis, M.R.; Robinson, B.W. )

    1991-01-01

    Recombinant human tumor necrosis factor (rHuTNF) was evaluated both for direct anti-tumor action against human malignant mesothelioma and for its capacity to augment the generation and lytic phases of lymphocyte-mediated cytotoxicity against this tumor. rHuTNF was directly toxic by MTT assay to one of two mesothelioma cell lines evaluated, but had no effect on susceptibility to subsequent lymphocyte-mediated lysis of either line. TNF alone was incapable of generating anti-mesothelioma lymphokine-activated killer cell (LAK) activity. Furthermore, it did not augment the degree or LAK activity produced by submaximal interleukin-2 (IL-2) concentrations nor did it augment lysis of mesothelioma cells by natural killer (NK) or LAK effector cells during the 4-hr 51chromium release cytolytic reaction. The studies also suggest that mesothelioma targets are less responsive to TNF plus submaximal IL-2 concentrations than the standard LAK sensitive target Daudi, raising the possibility that intermediate LAK sensitive tumors such as mesothelioma may require separate and specific evaluation in immunomodulation studies. This in vitro study indicates that use of low-dose rHuTNF and IL-2 is unlikely to be an effective substitute for high-dose IL-2 in generation and maintenance of LAK activity in adoptive immunotherapy for mesothelioma.

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

    USGS Publications Warehouse

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

    2007-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  15. Inositol lipid metabolism in vasopressin stimulated hepatocytes from rats infused with tumor necrosis factor

    SciTech Connect

    Spitzer, J.A.; Rodriguez de Turco, E.B. )

    1989-05-30

    We studied the effect of i.v. infusion of human recombinant tumor necrosis factor alpha (rHuTNF alpha, Cetus, 15 micrograms/100 g bw over 3 h) on vasopressin (VP)-stimulated {sup 32}P-inositol lipid turnover and the release of {sup 3}H-inositol phosphates in isolated rat hepatocytes. The early VP-induced decrease (within 30 s) in {sup 32}P-phosphatidylinositol 4-phosphate and {sup 32}P-phosphatidylinositol 4,5-bisphosphate labeling was significantly reduced (-40%) and at the same time the uptake of {sup 32}P into phosphatidic acid was 50% lower than in saline-infused (matched control) rats. Within 5 min of VP-stimulation, lower {sup 32}P phosphatidylinositol (-40%) and higher {sup 32}P-phosphatidic acid (+30%) labeling were observed in rHuTNF alpha-infused rats. Infusion of rHuTNF alpha also affected the VP-induced release of {sup 3}H-inositol phosphates. The accumulation of {sup 3}H-inositol-labeled water soluble products was decreased by 25% and 17% at 30 s and 10 min, respectively. These data show that rHuTNF alpha mimics early perturbations induced by Escherichia coli endotoxin infusion in VP-stimulated inositol lipid metabolism in rat hepatocytes.

  16. Effects of biological drug adalimumab on tumour necrosis factor-alpha-converting enzyme activation.

    PubMed

    Lisi, Sabrina; Sisto, Margherita

    2010-01-01

    Tumour necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE) is a membrane-bound metalloprotease and disintegrin. It is produced by a number of host cells and is known to shed and release cell-bound cytokines, particularly members of the TNF family. No investigations into the regulation of this enzyme by autoantibodies have been reported. In this study, we tested the hypothesis that anti-Ro/SSA autoantibodies, purified from IgG fractions of patients with primary Sjögren's syndrome, are capable to regulate TACE expression and activation in human salivary gland epithelial cells (SGEC). We also evaluated the potential physiological and therapeutic consequences of TNF-alpha blocking by the biological agent adalimumab, the first fully human (100% human peptide sequences) therapeutic anti-TNF-alpha antibody, on post-translational regulation of TACE. Taken together, our results show a dose-dependent increase in TACE expression in anti-Ro/SSA Abs-treated SGEC, followed by internalization, pro-domain shedding and activation of TACE protein. Adalimumab treatment brought TACE expression to levels than those observed in untreated SGEC. These findings, showing the presence of autoantibodies-dependent mechanisms by which TACE levels are regulated in human SGECs, may have implications in the context of current investigations on the pathological role of autoantibodies.

  17. Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells.

    PubMed

    Libby, P; Ordovas, J M; Auger, K R; Robbins, A H; Birinyi, L K; Dinarello, C A

    1986-08-01

    Interleukin 1 (IL-1) can induce potentially pathogenic functions of vascular endothelial cells. This mediator was formerly thought to be produced primarily by activated macrophages. We report here that bacterial endotoxin and recombinant human tumor necrosis factor cause accumulation of IL-1 beta mRNA in adult human vascular endothelial cells. IL-1 alpha mRNA was also detected when endothelial cells were exposed to endotoxin under "superinduction" conditions in the presence of cycloheximide. Metabolic labeling of these cells during endotoxin stimulation demonstrated increased synthesis and secretion of immunoprecipitable IL-1 protein that comigrated electrophoretically with the predominant monocyte species. In parallel with increased IL-1 mRNA and protein, endothelial cells exposed to endotoxin also release biologically active IL-1 that was neutralized by anti-IL-1-antibody. Because bloodborne agents must traverse the endothelium before entering tissues, endothelial IL-1 production induced by microbial products or other injurious stimuli could initiate local responses to invasion. Endothelial cells are both a source of and target for IL-1; accordingly, this novel autocrine mechanism might play an early role in the pathogenesis of vasculitis, allograft rejection, and arteriosclerosis.

  18. 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.

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

    PubMed Central

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

    1994-01-01

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

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

    PubMed

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

    2016-01-01

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

  1. Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor.

    PubMed

    Takahashi, N; Waelput, W; Guisez, Y

    1999-01-01

    Tumor necrosis factor (TNF) is a central mediator of a number of important pathologies such as the systemic inflammatory response syndrome. Administration of high TNF doses induces acute anorexia, metabolic derangement, inflammation, and eventually shock and death. The in vivo effects of TNF are largely mediated by a complex network of TNF-induced cytokines and hormones acting together or antagonistically. Since TNF also induces leptin, a hormone secreted by adipocytes that modulates food intake and metabolism, we questioned the role of leptin in TNF-induced pathology. To address this question, we tested mouse strains that were defective either in leptin gene (ob/ob) or in functional leptin receptor gene (db/db), and made use of a receptor antagonist of leptin. Ob/ob and db/db mice, as well as normal mice treated with antagonist, exhibited increased sensitivity to the lethal effect of TNF. Exogenous leptin afforded protection to TNF in ob/ob mice, but failed to enhance the protective effect of endogenous leptin in normal mice. We conclude that leptin is involved in the protective mechanisms that allow an organism to cope with the potentially autoaggressive effects of its immune system.

  2. 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.

  3. Drug-induced lupus: Including anti-tumour necrosis factor and interferon induced.

    PubMed

    Araújo-Fernández, S; Ahijón-Lana, M; Isenberg, D A

    2014-05-01

    Drug-induced lupus erythematosus is defined as a syndrome with clinical and serological features similar to systemic lupus erythematosus that is temporally related to continuous drug exposure and which resolves after discontinuation of this drug. More than 90 drugs, including biological modulators such as tumour necrosis factor-α inhibitors and interferons, have been identified as likely 'culprits'. While there are no standard diagnostic criteria for drug-induced lupus erythematosus, guidelines that can help to distinguish drug-induced lupus erythematosus from systemic lupus erythematosus have been proposed and several different patterns of drug-induced lupus erythematosus are emerging. Distinguishing drug-induced lupus erythematosus from systemic lupus erythematosus is important because the prognosis of drug-induced lupus erythematosus is usually good when the drug is withdrawn. This review discusses the differences between drug-induced lupus erythematosus and systemic lupus erythematosus, the mechanisms of action of drug-induced lupus erythematosus and drugs that are usually associated with drug-induced lupus erythematosus, with particular focus on the biological treatments.

  4. Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever.

    PubMed

    García-Trejo, Alma Rosa; Falcón-Lezama, Jorge A; Juárez-Palma, Lilia; Granados, Julio; Zúñiga-Ramos, Joaquín; Rangel, Hilda; Barquera, Rodrigo; Vargas-Alarcón, Gilberto; Ramos, Celso

    2011-01-01

    Increased levels of tumor necrosis factor alpha (TNF-α) in patients with dengue have been reported. Various polymorphisms have been identified in the promoter region of the TNF-α gene that may affect its transcription. The purpose of the present study was to evaluate the relationship between polymorphisms of TNF-α gene and the genetic susceptibility to dengue fever in a group of patients from Morelos State, Mexico. The TNF-α polymorphisms (positions -238 and -308) were determined by PCR-RFLP technique in 130 patients with dengue (85 with dengue fever and 45 with dengue hemorrhagic fever) and 169 healthy controls. The patients were selected from cases reported in Morelos State from 1997 to 2003. The whole group of dengue patients showed a decreased frequency of TNF-α -238 A allele when compared to healthy controls (p = 0.01, OR = 0.19, 95%CI = 0.02-0.78). When the analysis was made separately in dengue fever and dengue hemorrhagic fever patients, the decreased frequency of TNF-α -238 A allele only remained significant in patients with DHF when compared to healthy controls (p = 0.034). This work suggests a possible association of TNF-α -238 A allele with protection to develop symptomatic disease.

  5. Leukotriene B4 and tumor necrosis factor release from leukocytes: effect of peritoneal dialysate.

    PubMed

    Jörres, A; Jörres, D; Gahl, G M; Kessel, M; Müller, C; Köttgen, E; Serke, S; Schulz, E; Mahiout, A

    1991-01-01

    The effect of peritoneal dialysate on the capacity of peripheral blood polymorphonuclear (PMNL) and mononuclear leukocytes (MNC) to release leukotriene B4 (LTB4) and tumor necrosis factor alpha (TNF alpha) was investigated in vitro. Following density gradient separation, aliquots of 5 x 10(6) PMNL or MNC were incubated in peritoneal dialysis fluid containing 1.5% glucose or Hanks' buffer (= control) for 1-2 h at 37 degrees C. TNF alpha and LTB4 production was stimulated with Escherichia coli lipopolysaccharide (LPS) and calcium ionophore A23187, respectively. MNC incubated in buffer and LPS produced (mean +/- SD) 1,006 +/- 522 pg TNF alpha/5 x 10(6) cells; no significant amounts of TNF alpha were detectable in the presence of dialysate. An inhibition of TNF alpha release was also observed in MNC exposed to bicarbonate-buffered dialysates (pH 7.40) and 4.25% and 1.5% glucose solution with physiologic osmolality. Incubation of PMNL in Hanks' buffer followed by A23187 stimulation led to production of 29.1 +/- 19.2 ng LTB4/5 x 10(6) cells, whereas glucose-incubated cells were refractory to ionophore stimulation (less than 0.1 ng LTB4/5 x 10(6) cells). The failure of dialysate-exposed leukocytes to release inflammatory mediators in response to adequate stimuli may contribute to the impairment of cellular host defense in the setting of continuous ambulatory peritoneal dialysis.

  6. Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease.

    PubMed Central

    Murch, S H; Braegger, C P; Walker-Smith, J A; MacDonald, T T

    1993-01-01

    This study determined the location and tissue density of cells immunoreactive for tumour necrosis factor alpha (TNF alpha) in intestinal specimens from 24 patients with chronic inflammatory bowel disease (15 with Crohn's disease, nine with ulcerative colitis) and 11 controls. There was significantly increased density of TNF alpha immunoreactive cells in the lamina propria of both ulcerative colitis and Crohn's disease specimens, although the distribution of these cells differed in the two conditions. In ulcerative colitis most of the TNF alpha immunoreactivity was seen in the subepithelial macrophages, with comparatively less in the deep lamina propria, while in Crohn's disease immunoreactive cells were distributed evenly throughout the lamina propria. Increased submucosal immunoreactivity was found only in Crohn's disease, in which TNF alpha positive macrophages tended to cluster around arterioles and venules, often infiltrating and disrupting vascular endothelium. It is suggested that this degree of TNF alpha production probably contributes significantly to the pathogenesis of both Crohn's disease and ulcerative colitis, by impairing the integrity of epithelial and endothelial membranes, increasing inflammatory cell recruitment, and by prothrombotic effects on the vascular endothelium. Images Figure 2 PMID:8031350

  7. AMPK dependent protective effects of metformin on tumor necrosis factor-induced apoptotic liver injury.

    PubMed

    Cai, Lu; Hu, Kai; Lin, Ling; Ai, Qing; Ge, Pu; Liu, Yiqing; Dai, Jie; Ye, Bin; Zhang, Li

    2015-09-25

    Tumor necrosis factor α (TNF-α)-induced cellular apoptosis represents a common pathological mechanism underlying the progression of various liver disorders. Recently studies revealed that the anti-diabetic metformin provided protective benefits in several animal models of liver injury. In the present study, the potential modulatory effects of metformin on TNF-α-dependent apoptotic liver damage was investigated in mice with TNF-α/d-galactosamine (D-Gal)-induced liver injury. The results indicated that treatment with metformin significantly suppressed the elevation of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the activation of caspase cascade and the induction of cleaved caspase-3. Morphological analysis showed that metformin alleviated histopathological abnormalities and reduced TUNEL-positive apoptotic cells. Co-administration of the AMPK inhibitor compound C completely abolished the inhibitory effects of metformin on caspase cascade activation, significantly reversed the beneficial effects of metformin on histopathological abnormalities and hepatocytes apoptosis, and partially abolished the suppressive effects of metformin on plasma ALT elevation. These data indicated that metformin effectively alleviated TNF-α/D-Gal-induced apoptotic liver injury and these beneficial effects were at least partially mediated by AMPK.

  8. Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinoma

    PubMed Central

    Al-Lamki, Rafia S; Wang, Jun; Yang, Jun; Burrows, Natalie; Maxwell, Patrick H; Eisen, Timothy; Warren, Anne Y; Vanharanta, Sakari; Pacey, Simon; Vandenabeele, Peter; Pober, Jordan S; Bradley, John R

    2016-01-01

    Compared to normal kidney, renal clear cell carcinomas (ccRCC) contain increased numbers of interstitial, non-hematopoietic CD133+cells that express stem cell markers and exhibit low rates of proliferation. These cells fail to form tumors upon transplantation but support tumor formation by differentiated malignant cells. We hypothesized that killing of ccRCC CD133+ (RCCCD133+) cells by cytotoxic agents might be enhanced by inducing them to divide. Since tumor necrosis factor-alpha (TNF), signalling through TNFR2, induces proliferation of malignant renal tubular epithelial cells, we investigated whether TNFR2 might similarly affect RCCCD133+cells. We compared treating organ cultures of ccRCC vs adjacent nontumour kidney (NK) and RCCCD133+ vs NK CD133+ (NKCD133+) cell cultures with wild-type TNF (wtTNF) or TNF muteins selective for TNFR1 (R1TNF) or TNFR2 (R2TNF). In organ cultures, R2TNF increased expression of TNFR2 and promoted cell cycle entry of both RCCCD133+ and NKCD133+ but effects were greater in RCCCD133+. In contrast, R1TNF increased TNFR1 expression and promoted cell death. Importantly, cyclophosphamide triggered much more cell death in RCCCD133+ and NKCD133+cells pre-treated with R2TNF as compared to untreated controls. We conclude that selective engagement of TNFR2 by TNF can drives RCCCD133+ proliferation and thereby increase sensitivity to cell cycle-dependent cytotoxicity. PMID:26992212

  9. Tumor necrosis factor haplotype diversity in Mestizo and native populations of Mexico.

    PubMed

    Castro-Martínez, X H; Leal-Cortés, C; Flores-Martínez, S E; García-Zapién, A G; Sánchez-Corona, J; Portilla-de Buen, E; Gómez-Espinel, I; Zamora-Ginez, I; Pérez-Fuentes, R; Islas-Andrade, S; Revilla-Monsalve, C; Guerrero-Romero, F; Rodríguez-Morán, M; Mendoza-Carrera, F

    2014-04-01

    The so-called tumor necrosis factor (TNF) block includes the TNFA, lymphotoxin alpha and beta (LTA and LTB) genes with single-nucleotide polymorphisms (SNP) and microsatellites with an allele frequency that exhibits interpopulation variability. To date, no reports have included both SNPs and microsatellites at the TNF block to study Mestizo or Amerindian populations from Mexico. In this study, samples of five Mexican Mestizo populations (Durango, Guadalajara, Monterrey, Puebla, and Tierra Blanca) and four native-Mexican populations (North Lacandonians, South Lacandonians, Tepehuanos, and Yaquis) were genotyped for two SNPs (LTA+252A>G and TNFA-308G>A) and four microsatellites (TNFa, d, e, and f), to analyze the genetic substructure of the Mexican population. Allele and haplotype frequencies, linkage disequilibrium (LD), and interpopulation genetic relationships were calculated. There was significant LD along almost all of the TNF block but the lowest D' values were observed for the TNFf-TNFd pair. Mestizos showed higher allele and haplotype diversity than did natives. The genetic differentiation level was reduced among Mestizos; however, a slightly, but significant genetic substructure was observed between northern and southern Mexican Mestizos. Among the Amerindian populations, the genetic differentiation level was significantly elevated, particularly in both North and South Lacandonians. Furthermore, among Southern Lacandonians, inhabitants of Lacanja town were the most differentiated from all the Mexicans analyzed. The data presented here will serve as a reference for further population and epidemiological studies including these TNF polymorphisms in the Mexican population.

  10. Endotoxin, interleukin-1, and tumor necrosis factor cause neutrophil-dependent microvascular leakage in postcapillary venules.

    PubMed Central

    Yi, E. S.; Ulich, T. R.

    1992-01-01

    Acute inflammation is characterized mainly by the egress of neutrophils from postcapillary venules and by increased vascular permeability leading to the formation of edema. The microvascular site of increased vascular permeability in local acute inflammatory lesions was investigated after the injection of endotoxin (LPS), interleukin-1 (IL-1), and tumor necrosis factor (TNF) into the dermis overlying the cremasteric and rectus abdominis muscles of rats. LPS caused leakage of colloidal carbon peaking at 3 to 4 hours at the level of the postcapillary venules and capillary leak was variably observed at later time points. IL-1 and TNF also caused postcapillary venular leakage. IL-1 was as potent as LPS and more so than TNF. The microvascular leak caused by LPS, IL-1, and TNF was accompanied by the tissue accumulation of neutrophils, and was neutrophil-dependent because LPS, IL-1, and TNF did not cause vascular labelling in neutropenic rats. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:1546745

  11. 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.

  12. Italian experience on use of E.S.W. therapy for avascular necrosis of femoral head.

    PubMed

    Russo, Sergio; Sadile, Francesco; Esposito, Roberto; Mosillo, Giuseppe; Aitanti, Emanuele; Busco, Gennaro; Wang, Ching-Jen

    2015-12-01

    Osteonecrosis (avascular necrosis) of the femoral head is a clinical disease due to a severe bone vascular alteration associated with intense pain and loss of joint function, with an incidence of 0.1% and unknown aetiology. Many classifications exist to describe it and in the final stages the patient will need a total hip arthroplasty. In the early stages, ESWT has given excellent responses.
 The Neapolitan school studied more than 600 patients who had very good results in I and II stages of Ficat and Arlet Classification, with an improve of outcomes in VAS and HSS scores. Moreover it has shown a complete restoration of the signal intensity of the femoral head in MRI.

  13. 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

  14. Effect of particle size on hydroxyapatite crystal-induced tumor necrosis factor alpha secretion by macrophages.

    PubMed

    Nadra, Imad; Boccaccini, Aldo R; Philippidis, Pandelis; Whelan, Linda C; McCarthy, Geraldine M; Haskard, Dorian O; Landis, R Clive

    2008-01-01

    Macrophages may promote a vicious cycle of inflammation and calcification in the vessel wall by ingesting neointimal calcific deposits (predominantly hydroxyapatite) and secreting tumor necrosis factor (TNF)alpha, itself a vascular calcifying agent. Here we have investigated whether particle size affects the proinflammatory potential of hydroxyapatite crystals in vitro and whether the nuclear factor (NF)-kappaB pathway plays a role in the macrophage TNFalpha response. The particle size and nano-topography of nine different crystal preparations was analyzed by X-ray diffraction, Raman spectroscopy, scanning electron microscopy and gas sorbtion analysis. Macrophage TNFalpha secretion was inversely related to hydroxyapatite particle size (P=0.011, Spearman rank correlation test) and surface pore size (P=0.014). A necessary role for the NF-kappaB pathway was demonstrated by time-dependent I kappaB alpha degradation and sensitivity to inhibitors of I kappaB alpha degradation. To test whether smaller particles were intrinsically more bioactive, their mitogenic activity on fibroblast proliferation was examined. This showed close correlation between TNFalpha secretion and crystal-induced fibroblast proliferation (P=0.007). In conclusion, the ability of hydroxyapatite crystals to stimulate macrophage TNFalpha secretion depends on NF-kappaB activation and is inversely related to particle and pore size, with crystals of 1-2 microm diameter and pore size of 10-50 A the most bioactive. Microscopic calcific deposits in early stages of atherosclerosis may therefore pose a greater inflammatory risk to the plaque than macroscopically or radiologically visible deposits in more advanced lesions.

  15. Association of Tumor Necrosis Factor Alpha Gene Polymorphisms with Inflammatory Bowel Disease in Iran

    PubMed Central

    NADERI, Nosratollah; FARNOOD, Alma; DADAEI, Tahereh; HABIBI, Manijeh; BALAII, Hedie; FIROUZI, Farzad; MAHBAN, Aydin; SOLTANI, Masoumeh; ZALI, Mohammadreza

    2014-01-01

    Abstract Background Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology, in which genetic factors, seem to play an important role in the disease predisposition and course. Assessment of tumor necrosis factor (TNF-α) gene polymorphisms in many populations showed a possible association with IBD. Considering the genetic variety in different ethnic groups, the aim of the present study was to investigate the association of five important single nucleo-tide polymorphisms (SNPs) in the promoter region of (TNF-α) gene with IBD in Iran. Methods In this case-control study, 156 Ulcerative colitis (UC) patients, 50 Crohn’s disease (CD) patients and 200 sex and age matched healthy controls of Iranian origin were enrolled. The study was performed during a two year period (2008–2010) at Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. DNA samples were evaluated for (TNF-α) gene polymorphisms (including -1031, -863, -857, -308 and -238) by PCR and RFLP methods. Results The frequency of the mutant allele of -1031 polymorphism was significantly higher in Iranian patients with Crohn’s disease compared to healthy controls (P=0.01, OR=1.92; 95% CI: 1.14-3.23). None of the other evaluated polymorphisms demonstrated a significant higher frequency of mutant alleles in Iranian IBD patients compared to controls. Conclusion Among the five assessed (SNPs), only -1031 polymorphism of (TNF-α) gene may play a role in disease susceptibility for Crohn’s disease in Iran. This pattern of distribution of (TNF-α) gene polymorphisms could be specific in this population. PMID:26060764

  16. Disturbance of Tumor Necrosis Factor Alpha-Mediated Beta Interferon Signaling in Cervical Carcinoma Cells

    PubMed Central

    Bachmann, Anastasia; Hanke, Brigitte; Zawatzky, Rainer; Soto, Ubaldo; van Riggelen, Jan; zur Hausen, Harald; Rösl, Frank

    2002-01-01

    In the present study we show that malignant human papillomavirus (HPV)-positive cells lost their ability to synthesize endogenous beta interferon (IFN-β) upon tumor necrosis factor alpha (TNF-α) treatment. IFN-β transcription, however, was reinducible in nonmalignant HPV-positive cells, which was confirmed in functional protection assays against encephalomyocarditis virus or vesicular stomatitis virus infections. Addition of neutralizing antibodies against IFN-β blocked the antiviral effect, excluding the possibility that other IFN types were involved. Conversely, both malignant and immortalized cells could be protected against viral cytolysis when either IFN-β, IFN-α, or IFN-γ was added exogenously. This indicates that only the cross talk between TNF-α and the IFN-β pathways, and not IFN-α/β and IFN-γ signaling in general, is perturbed in cervical carcinoma cells. Notably, full virus protection was restricted exclusively to nonmalignant cells, indicating that the antiviral effect correlates with the growth-inhibitory and virus-suppressive properties of TNF-α. The IFN-regulatory factors IRF-1 and p48 (ISGF3γ) emerged as key regulatory molecules in the differential IFN-β response, since their transcription was either absent or only inefficiently enhanced in tumorigenic cells upon treatment with TNF-α. Inducibility of both genes, however, became reestablished in cervical carcinoma cells, which were complemented to nontumorigenicity after somatic cell hybridization. Complementation was paralleled by the entire reconstitution of cytokine-mediated IFN-β expression and the ability of TNF-α to exert an antiviral state. In contrast, under conditions where tumor suppression was not accomplished upon somatic cell hybridization, neither expression of IRF-1, p48, and IFN-β nor antiviral activity could be restored. PMID:11739693

  17. Tumor Necrosis Factor: A Mechanistic Link between Angiotensin-II-Induced Cardiac Inflammation and Fibrosis

    PubMed Central

    Duerrschmid, Clemens; Trial, JoAnn; Wang, Yanlin; Entman, Mark L.; Haudek, Sandra B.

    2015-01-01

    Background Continuous angiotensin-II (Ang-II) infusion induced the uptake of monocytic fibroblast precursors that initiated the development of cardiac fibrosis; these cells and concurrent fibrosis were absent in mice lacking tumor necrosis factor-alpha receptor 1 (TNFR1). We now investigated their cellular origin and temporal uptake, and the involvement of TNFR1 in monocyte-to-fibroblast differentiation. Methods and Results Within a day, Ang-II induced a pro-inflammatory environment characterized by production of inflammatory chemokines, cytokines, and TH1-interleukins and uptake of bone marrow-derived M1-cells. After a week, the cardiac environment changed to profibrotic with growth-factor and TH2-interleukin synthesis, uptake of bone marrow-derived M2-cells, and presence of M2-related fibroblasts. TNFR1 signaling was not necessary for early M1 uptake, but its absence diminished the amount of M2-cells. TNFR1-KO hearts also showed reduced levels of cytokine expression, but not of TH-related lymphokines. Reconstitution of wild-type bone marrow into TNFR1-KO mice was sufficient to restore M2 uptake, upregulation of pro-inflammatory and pro-fibrotic genes, and development of fibrosis in response to Ang-II. We also developed an in vitro mouse monocyte-to-fibroblast-maturation assay that confirmed the essential role of TNFR1 in the sequential progression of monocyte activation and fibroblast formation. Conclusions Development of cardiac fibrosis in response to Ang-II was mediated by myeloid precursors and consisted of two stages. A primary M1 inflammatory response was followed by a subsequent M2 fibrotic response. While the first phase appeared to be independent of TNFR1 signaling, the later phase (and development of fibrosis) was abrogated by deletion of TNFR1. PMID:25550440

  18. Anaemia and resistance to malaria in transgenic mice expressing human tumour necrosis factor.

    PubMed Central

    Taverne, J; Sheikh, N; de Souza, J B; Playfair, J H; Probert, L; Kollias, G

    1994-01-01

    Transgenic mice carrying a modified human tumour necrosis factor (huTNF)/beta-globin gene construct linked to the T-cell-specific locus control region of the human CD2 gene express huTNF in their T cells which is released into the circulation and causes the development of a wasting syndrome. We now report that the mice develop anaemia, probably through enhanced erythrophagocytosis rather than inhibition of reticulocyte production. Thus autologous erythrocytes, as well as sheep erythrocytes, were cleared more rapidly from the circulation of transgenic mice than from littermate controls. By contrast, peritoneal macrophages from transgenic mice were less phagocytic in vitro than cells from controls. They also secreted less murine (mu)TNF when stimulated by either bacterial lipopolysaccharide or toxic malarial antigens. The yields of muTNF approached normal levels, however, when these refractory cells from the transgenic mice were stimulated in the presence of a high concentration of indomethacin, suggesting that the production of muTNF was inhibited by enhanced synthesis of prostaglandins. The parasitaemia of transgenic mice infected with Plasmodium yoelii was about 10-fold less at its peak than in controls, although it followed the same time-course, and the multiplication of P. chabaudi was inhibited to an even greater degree. This control of parasitaemia may also be explained by enhancement of macrophage activity, mediated by huTNF acting on the murine p55 receptor, presumably by increasing the removal of parasites by phagocytosis or their killing by toxic products released by the activated macrophages. These observations suggest that a factor in the anaemia of human malaria may be macrophage activation caused by the secretion of TNF that occurs in this disease. PMID:7959874

  19. Tumour necrosis factor-alpha (TNF-alpha) in patients who have asbestosis and develop cancer.

    PubMed Central

    Partanen, R; Koskinen, H; Hemminki, K

    1995-01-01

    OBJECTIVES--Concentrations of tumour necrosis factor-alpha (TNF-alpha) were assayed by radioimmunoassay in serum samples collected between 1981 and 1987 from 111 patients with asbestosis who were at a high risk of cancer. Follow up of these patients until 1993 showed that 38 had developed cancer (27 lung, three mesotheliomas, and eight diverse malignancies). RESULTS--The mean serum concentrations of TNF-alpha given in fmol/100 microliters serum in all the cases with cancer (14.1) and the cases with lung cancer (13.6) were significantly higher (P < 0.05) than the mean concentrations in the exposed controls (10.5). A positive increase was considered to be any value that was > 2 SDs above the mean of the exposed controls. 22% (six of 27) of the cases with lung cancer were positive compared with 4% (three of 73) of the exposed controls, a significant difference (P < 0.001). The serum concentrations of TNF-alpha correlated moderately with cancer (r = 0.3), lung cancer (r = 0.3), and Neu oncoproteins and epidermal growth factor receptor (EGFR) (r = 0.3, 0.5 respectively). Also, there was a significant correlation between development of cancer and severity or progression of asbestosis. There was no correlation between the concentrations of TNF-alpha and severity or progression of asbestosis. CONCLUSIONS--These results showed high concentrations of TNF-alpha in the patients who had cancer. TNF-alpha may offer an auxiliary method in early diagnosis of cancers related to asbestosis. PMID:7795753

  20. Tumour necrosis factor-alpha interacts with laminin and functions as a pro-adhesive cytokine.

    PubMed

    Hershkoviz, R; Goldkorn, I; Lider, O

    1995-05-01

    Certain cytokines, chemokines and growth factors interact with components of the extracellular matrix (ECM) and, in particular, sulphated polysaccharides and proteoglycans. Recently, we demonstrated that tumour necrosis factor-alpha (TNF-alpha), an inflammatory cytokine, can bind fibronectin (FN), a cell-adhesive glycoprotein of the ECM, and that TNF-alpha bound to FN enhances the binding of T cells to the glycoprotein. In the present study, we studied the interactions of TNF-alpha and laminin (LN), another glycoprotein present in basement membranes and extracellular matrices. 125I-labelled TNF-alpha was found to bind to immobilized LN, and more avidly to the E1 and P1 fragments of LN, which contain its integrin- and non-integrin-dependent cell-adhesive sites, suggesting that cryptic TNF-alpha-binding sites are exposed upon proteolytic fragmentation of LN by enzymes such as elastase or pepsin. The bound cytokine did not dissociate from the LN and its fragments during a 24-hr period, indicating that in vivo LN can serve to restrict TNF-alpha adjacent to inflammatory sites. The LN-associated TNF-alpha retained at least some of its biological activities, since both diffusible and, to a greater extent, LN-bound TNF-alpha elevated the beta 1-integrin-dependent adhesion to LN of phorbol ester-activated human CD4+ T cells. Thus, LN and TNF-alpha may act in concert to transmit synergistic activating signals to infiltrating leucocytes, and thereby regulate immune cell reactions in extravascular inflammatory tissue. PMID:7635514

  1. Risk factors for outbreaks of infectious pancreatic necrosis (IPN) and associated mortality in Norwegian salmonid farming.

    PubMed

    Bang Jensen, Britt; Kristoffersen, Anja B

    2015-06-01

    Infectious pancreatic necrosis (IPN) has for many years been considered one of the most important restraints to the production of salmonids in European aquaculture. In Norway, the disease is responsible for high losses in post-smolts in the first few weeks after sea transfer. Despite the importance of IPN, there are few epidemiological studies on risk factors and mitigation strategies. In this paper, we present analyses of data from all cohorts put to sea in 2009 to 2012 on Norwegian marine salmonid farms. The data used were obtained from national registers on salmonid production and disease outbreaks. The results showed that the risk of IPN outbreak was higher for spring versus autumn cohorts, Atlantic salmon versus rainbow trout and for cohorts on farms with previous history of IPN. The risk increased with increasing cohort size and infection pressure, whereas increasing temperature and weight at sea transfer decreased the risk. Estimations from a model of cumulative mortality within the first 6 mo after sea transfer showed that mortality in cohorts with IPN increased to approximately 7.2% as compared to a 'baseline' cohort with a mortality of 3.4%. If the cohort had both IPN and pancreas disease (PD), the estimated mortality increased to 12.9%, and cohorts with both IPN, PD and heart and skeletal muscle inflammation (HSMI) had an estimated mortality of 16.6%, when all other significant factors were kept constant (these were cohort type, year, temperature at sea transfer and weight at sea transfer). Our results provide valuable inputs for mitigation strategies and for economic modelling of consequences of disease.

  2. Glia-pinealocyte network: the paracrine modulation of melatonin synthesis by tumor necrosis factor (TNF).

    PubMed

    da Silveira Cruz-Machado, Sanseray; Pinato, Luciana; Tamura, Eduardo Koji; Carvalho-Sousa, Cláudia Emanuele; Markus, Regina P

    2012-01-01

    The pineal gland, a circumventricular organ, plays an integrative role in defense responses. The injury-induced suppression of the pineal gland hormone, melatonin, which is triggered by darkness, allows the mounting of innate immune responses. We have previously shown that cultured pineal glands, which express toll-like receptor 4 (TLR4) and tumor necrosis factor receptor 1 (TNFR1), produce TNF when challenged with lipopolysaccharide (LPS). Here our aim was to evaluate which cells present in the pineal gland, astrocytes, microglia or pinealocytes produced TNF, in order to understand the interaction between pineal activity, melatonin production and immune function. Cultured pineal glands or pinealocytes were stimulated with LPS. TNF content was measured using an enzyme-linked immunosorbent assay. TLR4 and TNFR1 expression were analyzed by confocal microscopy. Microglial morphology was analyzed by immunohistochemistry. In the present study, we show that although the main cell types of the pineal gland (pinealocytes, astrocytes and microglia) express TLR4, the production of TNF induced by LPS is mediated by microglia. This effect is due to activation of the nuclear factor kappa B (NF-kB) pathway. In addition, we observed that LPS activates microglia and modulates the expression of TNFR1 in pinealocytes. As TNF has been shown to amplify and prolong inflammatory responses, its production by pineal microglia suggests a glia-pinealocyte network that regulates melatonin output. The current study demonstrates the molecular and cellular basis for understanding how melatonin synthesis is regulated during an innate immune response, thus our results reinforce the role of the pineal gland as sensor of immune status.

  3. Effects of botulinum toxin type D on secretion of tumor necrosis factor from human monocytes

    SciTech Connect

    Imamura, K.; Spriggs, D.; Ohno, T.; Kufe, D.

    1989-05-01

    Botulinum toxins are potent neurotoxins which block the release of neurotransmitters. The effects of these toxins on hematopoietic cells, however, are unknown. Monocytes secrete a variety of polypeptide growth factors, including tumor necrosis factor (TNF). In the study reported here, the effects of botulinum toxin type D on the secretion of TNF from human monocytes were examined. The results demonstrate that biotulinum toxin type D inhibits the release of TNF from monocytes activated by lipopolysaccharide (LPS) but not by 12-O-tetradecanoylphorbol-13-acetate. Botulinum toxin type D had no detectable effect on intracellular TNF levels in LPS-treated monocytes, indicating that the effects of this toxin involve the secretory process. This inhibitory effect of botulinum toxin type D on TNF secretion from LPS-treated monocytes was partially reversed by treatment with 12-O-tetradecanoylphorbol-13-acetate or introduction of guanosine 5'-(/gamma/-thio)t-riphosphate into these cells. The results demonstrate that TNF secretion is regulated by at least two distinct guanine nucleotide-binding proteins, one responsible for the activation of phospholiphase C and another which acts as a substrate for botulinum toxin type D. ADP-ribosylation of monocyte membranes by botulinum toxin type D demonstrated the presence of three substrates with M/sub r/s of 45,000, 21,000, and 17,000. While the role of these substrates in exocytosis is unknown, the results suggest that the M/sub r/ 21,000 substrate is involved in a process other than TNF secretion.

  4. Biosimilars in immune-mediated inflammatory diseases: initial lessons from the first approved biosimilar anti-tumour necrosis factor monoclonal antibody.

    PubMed

    Isaacs, J D; Cutolo, M; Keystone, E C; Park, W; Braun, J

    2016-01-01

    The introduction of targeted biological therapies has revolutionised the management of immune-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis, ankylosing spondylitis, psoriasis and inflammatory bowel disease. Following treatment with these therapies, many patients experience significant improvements in different aspects of their disease, including symptoms, work productivity and other outcomes relevant for individuals and society. However, due to the complexity of biological drug development and manufacturing processes, the costs of these therapies are relatively high. Indeed, the financial burden on healthcare systems due to biological therapies is considerable and lack of patient access to effective treatment remains a concern in many parts of the world. As many reference biological therapies have now reached or are near to patent expiry, a number of 'biosimilar' drugs have been developed for use in various clinical settings, and some of these drugs are already in use in several countries. While the potential pharmacoeconomic benefits of cost-effective biosimilars seem clear, several issues have been raised regarding, for example, the definition of biosimilarity and the validity of indication extrapolation, as well as the 'switchability' and relative immunogenicity of biosimilars and their reference drugs. In this review, these issues will be discussed with reference to CT-P13, a biosimilar of the anti-tumour necrosis factor monoclonal antibody infliximab, which is approved in Europe and elsewhere for the treatment of various IMIDs. Other important issues, including those related to data collection during nonclinical and clinical development of biosimilars, are also discussed. PMID:26403380

  5. Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma.

    PubMed Central

    Leek, R. D.; Landers, R.; Fox, S. B.; Ng, F.; Harris, A. L.; Lewis, C. E.

    1998-01-01

    Angiogenesis is an essential requirement for tumour growth and metastasis and is regulated by a complex network of factors produced by both stromal cells and neoplastic cells within solid tumours. The cytokine tumour necrosis factor alpha (TNF-alpha) and the enzyme thymidine phosphorylase (TP) are two factors known to promote tumour angiogenesis. We have demonstrated recently that high numbers of tumour-associated macrophages (TAMs) are significantly associated with increased tumour angiogenesis and poor prognosis in invasive carcinoma of the breast. We have also shown that TAMs are a major source of TNF-alpha in invasive breast carcinomas, and that macrophage-like stromal cells as well as tumour cells synthesize TP in such tumours. However, little is known of the factors that regulate the production or activity of these factors in the tumour microenvironment. As TNF-alpha has been shown to up-regulate TP expression in tumour cells in vitro we performed an immunohistochemical study to investigate the possibility that TNF-alpha may be involved in the regulation of TP expression by malignant breast epithelial cells in vivo. To do this, we used a cocktail of non-neutralizing monoclonal anti-TNF-alpha antibodies to visualize both TNF-alpha-expressing macrophages and TNF-alpha bound to its receptors on tumour cells and endothelial cells in a series of 93 invasive carcinomas of the breast. A semiquantitative grading system was then used to compare these staining patterns with that for TP in the same biopsies. TNF-alpha immunoreactivity was also compared with various important tumour variables known to relate to outcome in this disease (microvessel density, node status, grade, stage, receptor status and macrophage infiltration), as well as relapse-free and overall survival data for these patients. Our data show significant positive correlations between TNF-alpha bound to its receptors on tumour cells and: (1) TP protein production by tumour cells, and (2) axillary lymph

  6. Transfer factor therapy in ataxia--telangiectasia.

    PubMed Central

    Berkel, A I; Ersoy, F; Epstein, L B; Spitler, L E

    1977-01-01

    The effects of weekly doses of transfer factor in four patients with ataxia--telangiectasia were investigated following a total course of 2 months therapy. Transfer factor administration showed no influence on the absolute lymphocyte counts, T-cell rosettes or antibody titres to EBV, but it caused conversion of skin-test reactivity and production of MIF to various antigens. There was a dissociation in blastic transformation response, the skin-test responses and MIF production. Serum interferon levels were low before, and 2, 6 and 24 hr after, therapy. Clinically no improvement in infections was observed following transfer factor therapy. PMID:201409

  7. RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

    PubMed Central

    Brohawn, David G.; O’Brien, Laura C.; Bennett, James P.

    2016-01-01

    ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned >50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be

  8. Acute Retinal Necrosis Associated with Epstein-Barr Virus in a Patient Undergoing Immunosuppressive Therapy

    PubMed Central

    Oe, Chiaki; Hiraoka, Miki; Tanaka, Sachie; Ohguro, Hiroshi

    2016-01-01

    Acute retinal necrosis (ARN) is a rapidly progressive and severe retinitis resulting in a poor visual outcome. Infections caused by herpes viruses such as herpes simplex virus (HSV) types 1 and 2 or the varicella zoster virus (VZV) are known to be implicated in the development of ARN. In the present study, an 80-year-old female with ARN was examined. She had been affected with rheumatoid arthritis and had taken methotrexate for over 10 years. Her right eye showed clinical features of ARN, and her left eye showed mild retinitis. The genomic DNA in the aqueous humor and vitreous fluid from her right eye were analyzed by a comprehensive polymerase chain reaction (PCR) assay to screen infectious pathogens including viruses. The Epstein-Barr virus (EBV) was detected from both specimens, but neither HSV or VZV nor cytomegalovirus was detected. She underwent intraocular surgery following systemic corticosteroid and acyclovir applications. However, although the retinitis of her right eye was extinguished, the final visual outcome was blindness due to optic nerve atrophy. There are few reports indicating that EBV is associated with ARN development. The present findings suggest that EBV alone can be the causative agent of ARN. PMID:27194989

  9. Acute Retinal Necrosis Associated with Epstein-Barr Virus in a Patient Undergoing Immunosuppressive Therapy.

    PubMed

    Oe, Chiaki; Hiraoka, Miki; Tanaka, Sachie; Ohguro, Hiroshi

    2016-01-01

    Acute retinal necrosis (ARN) is a rapidly progressive and severe retinitis resulting in a poor visual outcome. Infections caused by herpes viruses such as herpes simplex virus (HSV) types 1 and 2 or the varicella zoster virus (VZV) are known to be implicated in the development of ARN. In the present study, an 80-year-old female with ARN was examined. She had been affected with rheumatoid arthritis and had taken methotrexate for over 10 years. Her right eye showed clinical features of ARN, and her left eye showed mild retinitis. The genomic DNA in the aqueous humor and vitreous fluid from her right eye were analyzed by a comprehensive polymerase chain reaction (PCR) assay to screen infectious pathogens including viruses. The Epstein-Barr virus (EBV) was detected from both specimens, but neither HSV or VZV nor cytomegalovirus was detected. She underwent intraocular surgery following systemic corticosteroid and acyclovir applications. However, although the retinitis of her right eye was extinguished, the final visual outcome was blindness due to optic nerve atrophy. There are few reports indicating that EBV is associated with ARN development. The present findings suggest that EBV alone can be the causative agent of ARN.

  10. Molecular characterization and functional analysis of tumor necrosis factor receptor-associated factor 2 in the Pacific oyster.

    PubMed

    Huang, Baoyu; Zhang, Linlin; Du, Yishuai; Li, Li; Tang, Xueying; Zhang, Guofan

    2016-01-01

    Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are a family of crucial adaptors, playing vital roles in mediating signal transduction in immune signaling pathways, including RIG-I-like receptor (RLR) signaling pathway. In the present study, a new TRAF family member (CgTRAF2) was identified in the Pacific oyster, Crassostrea gigas. Comparison and phylogenetic analysis revealed that CgTRAF2 could be a new member of the invertebrate TRAF2 family. Quantitative real-time PCR revealed that CgTRAF2 mRNA was highly expressed in the digestive gland, gills, and hemocytes, and it was significantly up-regulated after Vibrio alginolyticus and ostreid herpesvirus 1 (OsHV-1) challenge. The CgTRAF2 mRNA expression profile in different developmental stages of oyster larvae suggested that CgTRAF2 could function in early larval development. CgTRAF2 mRNA expression pattern, after the silence of CgMAVS (Mitochondrial Antiviral Signaling) -like, indicated that CgTRAF2 might function downstream of CgMAVS-like. Moreover, the subcellular localization analysis revealed that CgTRAF2 was localized in cytoplasm, and it may play predominately important roles in signal transduction. Collectively, these results demonstrated that CgTRAF2 might play important roles in the innate immunity and larval development of the Pacific oyster.

  11. Vascular endothelial growth factor promotes macrophage apoptosis through stimulation of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT).

    PubMed

    Petreaca, Melissa L; Yao, Min; Ware, Carl; Martins-Green, Manuela M

    2008-01-01

    Resolution of inflammation is critical for normal wound healing. Inflammation is prolonged and fails to resolve properly in chronic wounds. We used in vivo and in vitro approaches to show that vascular endothelial growth factor (VEGF) induces macrophage apoptosis and to delineate mechanisms involved in this process. VEGF inhibition during wound healing leads to an increased number of macrophages remaining in wounds, suggesting the involvement of VEGF in removal of these cells from the wound. If this effect has physiological relevance, it likely occurs via apoptosis. We show that VEGF increases apoptosis of macrophages in vitro using Annexin V-FITC staining and caspase activation. Microarray analysis, reverse transcription-polymerase chain reaction, and immunoblotting showed that VEGF increases the expression of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT) in macrophages. We also show that in macrophages LIGHT promotes apoptosis through the lymphotoxin beta receptor. Moreover, inhibition of LIGHT prevents VEGF-induced death, suggesting that LIGHT mediates VEGF-induced macrophage apoptosis. Taken together, our results identify a novel role for VEGF and for LIGHT in macrophage apoptosis during wound healing, an event critical in the resolution of inflammation. This finding may lead to the development of new strategies to improve resolution of inflammation in problematic wounds. PMID:19128255

  12. Epidermal Platelet-activating Factor Receptor Activation and Ultraviolet B Radiation Result in Synergistic Tumor Necrosis Factor-alpha Production

    PubMed Central

    Wolverton, Jay E.; Al-Hassani, Mohammed; Yao, Yongxue; Zhang, Qiwei; Travers, Jeffrey B.

    2010-01-01

    Ultraviolet B radiation (UVB) is a potent stimulator of epidermal cytokine production which has been implicated in photoaggravated dermatoses. In addition to cytokines such as tumor necrosis factor-α (TNF-α), UVB generates bioactive lipids including platelet-activating factor (PAF). Our previous studies have demonstrated that UVB-mediated production of keratinocyte TNF-α is in part due to PAF. The current studies use a human PAF-receptor (PAF-R) negative epithelial cell line transduced with PAF-Rs and PAF–R-deficient mice to demonstrate that activation of the epidermal PAF-R along with UVB irradiation results in a synergistic production of TNF-α. It should be noted that PAF-R effects are mimicked by the protein kinase C (PKC) agonist phorbol myristic acetate, and are inhibited by pharmacological antagonists of the PKC gamma isoenzyme. These studies suggest that concomitant PAF-R activation and UVB irradiation results in a synergistic production of the cytokine TNF-α which is mediated in part via PKC. These studies provide a novel potential mechanism for photosensitivity responses. PMID:19769579

  13. High-volume hemofiltration reduces the expression of myocardial tumor necrosis factor-alpha in septic shock pigs.

    PubMed

    Li, Chunmei; Zhang, Ping; Cheng, Xiuju; Chen, Jianghua

    2013-02-01

    Increasing evidence indicates that the expression of tumor necrosis factor-α (TNF-α) in myocardium correlates with the severity of cardiac dysfunction in septic shock. The aim of this study was to investigate the impact of high-volume hemofiltration (HVHF) on the expression of TNF-α in myocardium in septic shock pigs. Sixteen male Landrace pigs weighing 31 ± 5 kg were randomly assigned to control group (n = 4), septic shock group (n = 6), and HVHF group (septic shock + HVHF, n = 6). All animals were anesthetized and mechanically ventilated. After baseline examinations, septic shock group and HVHF group underwent induction of peritonitis. One hour later, the animals in HVHF group received treatment with HVHF and the treatment was continued for 12 h. As the control of HVHF group, the animals in septic shock group received the same support but hemofiltration. Twelve hours after HVHF therapy, all the animals were sacrificed. TNF-α and nitric oxide (NO) levels in both circulation and myocardium were measured. Compared with those of septic shock animals, the levels of cardiac output, stroke volume, and mean arterial pressure were better maintained in HVHF group. The expression of TNF-α in myocardium in HVHF group was lower than that in septic shock group (44.17 ± 18.70 vs. 92.50 ± 33.89 pg/mg protein, P = 0.015). The difference of TNF-α in circulation between HVHF group and septic shock group was no significance at different time. However, circulating NO in HVHF group was lower than that in septic shock group. These results suggest that HVHF improves hemodynamics and heart dysfunction in septic shock pigs, which may be attributed to reduction of TNF-α in myocardium but not in circulation.

  14. Wormwood (Artemisia absinthium) suppresses tumour necrosis factor alpha and accelerates healing in patients with Crohn's disease - A controlled clinical trial.

    PubMed

    Krebs, Simone; Omer, Talib N; Omer, Bilal

    2010-04-01

    Suppression of tumour necrosis factor alpha (TNF-alpha) and other interleukins by wormwood (Artemisia absinthium) extracts were reported recently in in vitro studies. The aim of the present study was to find out if this effect can be also be observed in Crohn's Disease (CD) patients where TNF-alpha appears to play an important role. In a controlled trial, 10 randomly selected patients suffering from CD were given in addition to their basic CD therapy 3x750mg dried powdered wormwood for 6 weeks. Ten patients, also randomly selected who met the inclusion criteria served as control group. Minimum score of 200 on Crohn's Disease Activity Index (CDAI) was required at baseline for inclusion in each group. Patients who received infliximab or similar were excluded from the trial. TNF-alpha level in serum were measured at baseline, and after three and six weeks. During this period all concomitant CD medications was maintained at the baseline dose levels. Average serum TNF-alpha level fell from 24.5+/-3.5pg/ml at baseline to 8.0+/-2.5pg/ml after six weeks. The corresponding levels in the control group were 25.7+/-4.6 (week 0), and 21.1+/-3.2 (week 6). On the clinical side, CDAI scores fell from 275+/-15 to below 175+/-12 in wormwood group with remission of symptoms in eight patients (CDAI score below 170 or reduction by 70 points), compared to only two in the placebo group (CDAI of placebo group 282+/-11 at baseline and 230+/-14 on week 6). IBDQ also reflected accelerated clinical response with wormwood. Of clinical significance were the findings that wormwood also improved mood of the CD patients, as reflected in Hamilton's Depression Scale. These findings provide a base to test wormwood in clinical conditions thought to be mediated by increased production of pro-inflammatory cytokines such as TNF-alpha.

  15. 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.

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

    PubMed

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

    2004-01-16

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

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

    PubMed

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

    2016-01-01

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

  18. Streptococcal Histone Induces Murine Macrophages To Produce Interleukin-1 and Tumor Necrosis Factor Alpha

    PubMed Central

    Zhang, Liping; Ignatowski, Tracey A.; Spengler, Robert N.; Noble, Bernice; Stinson, Murray W.

    1999-01-01

    The histone-like protein (HlpA) is highly conserved among streptococci. After lysis of streptococci in infected tissues, HlpA can enter the bloodstream and bind to proteoglycans in the glomerular capillaries of kidneys, where it can react with antibodies or stimulate host cell receptors. Deposits of streptococcal antigens in tissues have been associated with localized acute inflammation. In this study, we measured the ability of purified HlpA (5 to 100 μg/ml), from Streptococcus mitis, to induce the production of proinflammatory cytokines by cultured, murine peritoneal macrophages. The release of tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) was time and concentration dependent and was not diminished by the presence of polymyxin B. Exposure of macrophages to a mixture of HlpA and lipoteichoic acid resulted in a synergistic response in the production of both TNF-α and IL-1. Stimulation with a mixture of HlpA and heparin resulted in reduced cytokine production (50% less IL-1 and 76% less TNF-α) compared to that by cells incubated with HlpA alone. The inclusion of antibodies specific to HlpA in macrophage cultures during stimulation with HlpA did not affect the quantity of TNF-α or IL-1 produced. These observations suggest that streptococcal histone may contribute to tissue injury at infection sites by promoting monocytes/macrophages to synthesize and release cytokines that initiate and exacerbate inflammation. Streptococcus pyogenes, which can infect tissues in enormous numbers, may release sufficient amounts of HlpA to reach the kidneys and cause acute poststreptococcal glomerulonephritis. PMID:10569765

  19. Tumor Necrosis Factor α and Interleukin 1β Enhance the Cortisone/Cortisol Shuttle

    PubMed Central

    Escher, Geneviève; Galli, Ivo; Vishwanath, Bannikuppe S.; Frey, Brigitte M.; Frey, Felix J.

    1997-01-01

    Endogenously released or exogenously administered glucocorticosteroids are relevant hormones for controlling inflammation. Only 11β-hydroxy glucocorticosteroids, but not 11-keto glucocorticosteroids, activate glucocorticoid receptors. Since we found that glomerular mesangial cells (GMC) express 11β-hydroxysteroid dehydrogenase 1 (11β-OHSD1), which interconverts 11-keto glucocorticosteroids into 11β-hydroxy glucocorticosteroids (cortisone/cortisol shuttle), we explored whether 11β-OHSD1 determines the antiinflammatory effect of glucocorticosteroids. GMC exposed to interleukin (IL)-1β or tumor necrosis factor α (TNF-α) release group II phospholipase A2 (PLA2), a key enzyme producing inflammatory mediators. 11β-hydroxy glucocorticosteroids inhibited cytokine-induced transcription and release of PLA2 through a glucocorticoid receptor–dependent mechanism. This inhibition was enhanced by inhibiting 11β-OHSD1. Interestingly, 11-keto glucocorticosteroids decreased cytokine-induced PLA2 release as well, a finding abrogated by inhibiting 11β-OHSD1. Stimulating GMC with IL-1β or TNF-α increased expression and reductase activity of 11β-OHSD1. Similarly, this IL-1β– and TNF-α–induced formation of active 11β-hydroxy glucocorticosteroids from inert 11-keto glucocorticosteroids by the 11β-OHSD1 was shown in the Kiki cell line that expresses the stably transfected bacterial β-galactosidase gene under the control of a glucocorticosteroids response element. Thus, we conclude that 11β-OHSD1 controls access of 11β-hydroxy glucocorticosteroids and 11-keto glucocorticosteroids to glucocorticoid receptors and thus determines the anti-inflammatory effect of glucocorticosteroids. IL-1β and TNF-α upregulate specifically the reductase activity of 11β-OHSD1 and counterbalance by that mechanism their own proinflammatory effect. PMID:9221748

  20. Role of tumor necrosis factor-alpha in zebrafish retinal neurogenesis and myelination

    PubMed Central

    Lei, Xu-Dan; Sun, Yan; Cai, Shi-Jiao; Fang, Yang-Wu; Cui, Jian-Lin; Li, Yu-Hao

    2016-01-01

    AIM To investigate the role of tumor necrosis factor-alpha (TNF-α) in zebrafish retinal development and myelination. METHODS Morpholino oligonucleotides (MO), which are complementary to the translation start site of the wild-type embryonic zebrafish TNF-α mRNA sequence, were synthesized and injected into one- to four-cell embryos. The translation blocking specificity was verified by Western blotting using an anti-TNF-α antibody, whole-mount in situ hybridization using a hepatocyte-specific mRNA probe ceruloplasmin (cp), and co-injection of TNF-α MO and TNF-α mRNA. An atonal homolog 7 (atoh7) mRNA probe was used to detect neurogenesis onset. The retinal neurodifferentiation was analyzed by immunohistochemistry using antibodies Zn12, Zpr1, and Zpr3 to label ganglion cells, cones, and rods, respectively. Myelin basic protein (mbp) was used as a marker to track and observe the myelination using whole-mount in situ hybridization. RESULTS Targeted knockdown of TNF-α resulted in specific suppression of TNF-α expression and a severely underdeveloped liver. The co-injection of TNF-α MO and mRNA rescued the liver development. Retinal neurogenesis in TNF-α morphants was initiated on time. The retina was fully laminated, while ganglion cells, cones, and rods were well differentiated at 72 hours post-fertilization (hpf). mbp was expressed in Schwann cells in the lateral line nerves and cranial nerves from 3 days post-fertilization (dpf) as well as in oligodendrocytes linearly along the hindbrain bundles and the spinal cord from 4 dpf, which closely resembled its endogenous profile. CONCLUSION TNF-α is not an essential regulator for retinal neurogenesis and optic myelination. PMID:27366683

  1. Somatostatin and macrophage function: modulation of hydrogen peroxide, nitric oxide and tumor necrosis factor release.

    PubMed

    Chao, T C; Cheng, H P; Walter, R J

    1995-07-21

    Recent studies have shown that somatostatin modulates lymphocyte function, but the effects of somatostatin on macrophage function are not clearly defined. In the present study, peritoneal macrophages (Mluminal diameter) obtained from male rats were treated in vitro with somatostatin or octreotide and their effects on the release of hydrogen peroxide (H2O2), nitrite, and tumor necrosis factor (TNF) determined. Macrophages treated with somatostatin (10(-9) M to 10(-7) M) or octreotide (10(-8) M and 10(-7) M) released significantly greater amounts of PMA-stimulated H2O2 than did the untreated controls. In addition, 10(-9) M of somatostatin significantly enhanced PMA-stimulated H2O2 release by LPS-treated Mluminal diameter. Octreotide had no effect on H2O2 release by LPS-treated Mluminal diameter. At concentrations of 10(-14) M, 10(-13) M, or greater than 10(-8) M, somatostatin or octreotide suppressed nitrite release by Mluminal diameter. Somatostatin or octreotide did not affect nitrite release by LPS-treated Mluminal diameter. On the other hand, Mluminal diameter treated with 10(-11) M of somatostatin or octreotide released greater amounts of TNF than did the untreated controls. In contrast, TNF release by Mluminal diameter treated with 10(-9) M to 10(-5) M of somatostatin or 10(-7) M to 10(-5) M of octreotide was less than that of the controls. Anti-TNF antibody (1:1000) caused a reduction in the release of H2O2 and nitrite. These findings demonstrate that somatostatin and octreotide modulate the release of H2O2, nitric oxide, and TNF by Mluminal diameter depending on the concentration of hormones used.

  2. Role of interleukin 1 and tumor necrosis factor on energy metabolism in rabbits

    SciTech Connect

    Tredget, E.E.; Yu, Y.M.; Zhong, S.; Burini, R.; Okusawa, S.; Gelfand, J.A.; Dinarello, C.A.; Young, V.R.; Burke, J.F.

    1988-12-01

    A study of the combined effects of intravenous infusion of the recombinant cytokines beta-interleukin 1 (IL-1) and alpha-tumor necrosis factor (TNF) on energy substrate metabolism in awake, conditioned, adult rabbits was performed. After a 2-h basal or control period, 48-h fasted rabbits were administered TNF and IL-1 as a bolus (5 micrograms/kg) followed by a continuous intravenous infusion (25 ng.kg-1.min-1) for 3 h. Significant increases in plasma lactate (P less than 0.01), glucose (P less than 0.01), and triglycerides (P less than 0.05) occurred during the combined infusion of IL-1 and TNF, whereas neither cytokine alone had no effect. There was a 33% increase in the rate of glucose appearance (P less than 0.05), but glucose clearance was not altered compared with the control period. Glucose oxidation increased during the combined cytokine infusion period and glucose recycling increased by 600% (P less than 0.002). Lactic acidosis and decreased oxygen consumption, as a result of the cytokine infusions, indicated development of anaerobic glycolytic metabolism. A reduction in the activity state of hepatic mitochondrial pyruvate dehydrogenase (65 vs. 82% in control animals, P less than 0.05) was consistent with the observed increase in anaerobic glycolysis. Thus the combined infusion of IL-1 and TNF in rabbits produces metabolic manifestations seen in severe injury and sepsis in human patients and, as such, may account for the profound alterations of energy metabolism seen in these conditions.

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

    SciTech Connect

    Mulcahy, B.; Waldron-Lynch, F.; Adams, C.; O`Gara, F.

    1996-09-01

    The major histocompatibility complex class H1 tumor necrosis factor-tymphotoxin (TNF-LT) region (6p21.3) was investigated as a possible susceptibility locus for rheumatoid arthritis (RA). Inheritance of five TNF microsatellite markers was determined in 50 multiplex families. Overall, 47 different haplotypes were observed. One of these, the TNF a6, b5, c1, d3, e3 (H1) haplotype, was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P < .005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3 % not transmitted to affected offspring (P = .0003). The TNF a6 and TNF c1 alleles were individually associated with RA (P = .0005 and .0008, respectively), as were the HLA-DRB1 {open_quotes}shared epitope{close_quotes} (SE) (P = .0001) and HLA-DRB1*0401 (P = .0018). Both univariate and bivariate conditional logistic regression analysis showed significant effects of TNF c1 and SE in increasing risk to RA (P < .001). Stratification by the presence of SE indicated an independent effect of the TNFc1 allele (P = .0003) and the HLA A1, BS, DR3 extended haplotype (always TNFa2, b3, c1, d1, e3) (P = .0027) in SE heterozygotes, while the H1 haplotype was associated with RA in SE homozygotes (P = .0018). The TNF-LT region appears to influence susceptibility to RA, distinct from HLA-DR. 50 refs., 1 fig., 1 tab.

  4. The cardiodepressant and vasodepressant effects of tumour necrosis factor in rat isolated atrial and aortic tissues.

    PubMed Central

    Foulkes, R.; Shaw, S.

    1992-01-01

    1. The ability of recombinant human tumour necrosis factor-alpha (rec huTNF) to elicit cardiodepressor and vasodepressor effects in rat isolated tissues was investigated. 2. rec huTNF (3 x 10(-11)-3 x 10(-8) M) administered directly to the organ bath, caused a concentration-dependent relaxation of the isoprenaline-induced inotropic response in electrically stimulated rat left atria. This occurred within 20 min of administration. In contrast, rec huTNF was without effect on the chronotropic response to isoprenaline in isolated spontaneously beating atria. 3. rec huTNF (1 microgram kg-1) was also given systemically to rats and the atria studied in vitro. Only 60 min of rec huTNF pretreatment was sufficient to cause a marked attenuation of the isoprenaline-induced inotropic response. This effect was not further augmented when rats were pretreated with rec huTNF for 24 h. 4. In isolated aortic rings taken from rats 60 min after rec huTNF (1 microgram kg-1, i.v.) administration, there was no effect seen on the constriction induced by phenylephrine in either endothelium-intact or denuded tissues. In addition, any responses to L-arginine or NG-nitro-L-arginine methyl ester (L-NAME) administration were unaffected by rec huTNF pretreatment. 5. In aortic rings taken from rats 24 h after rec huTNF administration, the phenylephrine-induced constriction was significantly attenuated in tissues with an intact endothelium. Furthermore, the relaxation to subsequent L-arginine administration was greater in these tissues than in those saline-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1382789

  5. Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension.

    PubMed

    Zhang, Jiandong; Patel, Mehul B; Griffiths, Robert; Mao, Alice; Song, Young-soo; Karlovich, Norah S; Sparks, Matthew A; Jin, Huixia; Wu, Min; Lin, Eugene E; Crowley, Steven D

    2014-12-01

    Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease. In this regard, we recently identified a role for proinflammatory Th1 T-lymphocyte responses in hypertensive kidney injury. Because Th1 cells generate interferon-γ and tumor necrosis factor-α (TNF-α), we hypothesized that interferon-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system. Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking interferon-γ or TNF-α to our model of hypertensive chronic kidney disease. Interferon deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (knockout) mice had blunted hypertensive responses and reduced end-organ damage in our model. As angiotensin II-infused TNF knockout mice had exaggerated endothelial nitric oxide synthase expression in the kidney and enhanced nitric oxide bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF knockout kidneys into wild-type recipients before the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to angiotensin II and augmented renal endothelial nitric oxide synthase expression, confirming a role for kidney-derived TNF-α to promote angiotensin II-induced blood pressure elevation by limiting renal nitric oxide generation.

  6. Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence

    SciTech Connect

    Zheng, H.; Crowley, J.J.; Chan, J.C.; Hoffmann, H.; Hatherill, J.R.; Ishizaka, A.; Raffin, T.A. )

    1990-11-01

    Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents that attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.

  7. Targeted lipid-coated nanoparticles: delivery of tumor necrosis factor-functionalized particles to tumor cells.

    PubMed

    Messerschmidt, Sylvia K E; Musyanovych, Anna; Altvater, Martin; Scheurich, Peter; Pfizenmaier, Klaus; Landfester, Katharina; Kontermann, Roland E

    2009-07-01

    Polymeric nanoparticles displaying tumor necrosis factor on their surface (TNF nanocytes) are useful carrier systems capable of mimicking the bioactivity of membrane-bound TNF. Thus, TNF nanocytes are potent activators of TNF receptor 1 and 2 leading to a striking enhancement of apoptosis. However, in vivo applications are hampered by potential systemic toxicity. Here, using TNF nanocytes as a model system, we developed a procedure to generate targeted lipid-coated particles (TLP) in which TNF activity is shielded. The TLPs generated here are composed of an inner single-chain TNF (scTNF)-functionalized, polymeric nanoparticle core surrounded by a lipid coat endowed with polyethylene glycol (PEG) for sterical stabilization and a single-chain Fv (scFv) fragment for targeting. Using a scFv directed against the tumor stroma marker fibroblast activation protein (FAP) we show that TLP and scTNF-TLP specifically bind to FAP-expressing, but not to FAP-negative cells. Lipid coating strongly reduced nonspecific binding of particles and scTNF-mediated cytotoxicity towards FAP-negative cells. In contrast, an increased cytotoxicity of TLP was observed for FAP-positive cells. Thus, through liposome encapsulation, nanoparticles carrying bioactive molecules, which are subject to nonselective uptake and activity towards various cells and tissues, can be converted into target cell-specific composite particles exhibiting a selective activity towards antigen-positive target cells. Besides safe and targeted delivery of death ligands such as TNF, TLP should be suitable for various diagnostic and therapeutic applications, which benefit from a targeted delivery of reagents embedded into the particle core or displayed on the core particle surface.

  8. Soluble malarial antigens are toxic and induce the production of tumour necrosis factor in vivo.

    PubMed Central

    Bate, C A; Taverne, J; Playfair, J H

    1989-01-01

    Heat-stable soluble products of rodent malarial parasites induce activated peritoneal macrophages to secrete tumour necrosis factor (TNF) in vitro. Since heat-stable parasite antigens are known to be present in the circulation of patients with malaria and it has been suggested that much of the pathology of malaria is due to TNF, we investigated the ability of such antigens to induce the production of TNF in vivo and to be toxic to mice. Injection of antigens obtained from Plasmodium yoelii or from P. berghei into mice which had previously received the macrophage-activating agent Propionibacterium acnes induced the release of TNF into the serum in amounts equivalent to the maximum release induced by bacterial lipopolysaccharide (LPS). Specific antiserum blocked the ability to the boiled soluble antigens, but not of LPS, to induce release of TNF. Similarly, vaccination specifically inhibited the release of TNF into the serum in response to subsequent stimulation with the antigens, but not with LPS. Mice made hypersensitive to the lethal action of TNF by pretreatment with D-galactosamine were killed in a dose-related fashion by administration of antigen preparations; addition of specific antiserum or prior vaccination with the antigens protected such mice, but not those given LPS, from death. We conclude that, in malaria, soluble antigens derived from the parasites may act like a toxin by stimulating the production of TNF, an important mediator of endotoxic shock, and that immunization with such antigens may diminish TNF secretion and consequently many of the clinical manifestations of the disease. PMID:2654012

  9. Tumor necrosis factor regulates NMDA receptor-mediated airway smooth muscle contractile function and airway responsiveness.

    PubMed

    Anaparti, Vidyanand; Pascoe, Christopher D; Jha, Aruni; Mahood, Thomas H; Ilarraza, Ramses; Unruh, Helmut; Moqbel, Redwan; Halayko, Andrew J

    2016-08-01

    We have shown that N-methyl-d-aspartate receptors (NMDA-Rs) are receptor-operated calcium entry channels in human airway smooth muscle (HASM) during contraction. Tumor necrosis factor (TNF) augments smooth muscle contractility by influencing pathways that regulate intracellular calcium flux and can alter NMDA-R expression and activity in cortical neurons and glial cells. We hypothesized that NMDA-R-mediated Ca(2+) and contractile responses of ASM can be altered by inflammatory mediators, including TNF. In cultured HASM cells, we assessed TNF (10 ng/ml, 48 h) effect on NMDA-R subunit abundance by quantitative PCR, confocal imaging, and immunoblotting. We observed dose- and time-dependent changes in NMDA-R composition: increased obligatory NR1 subunit expression and altered regulatory NR2 and inhibitory NR3 subunits. Measuring intracellular Ca(2+) flux in Fura-2-loaded HASM cultures, we observed that TNF exposure enhanced cytosolic Ca(2+) mobilization and changed the temporal pattern of Ca(2+) flux in individual myocytes induced by NMDA, an NMDA-R selective analog of glutamate. We measured airway responses to NMDA in murine thin-cut lung slices (TCLS) from allergen-naive animals and observed significant airway contraction. However, NMDA acted as a bronchodilator in TCLS from house dust mice-challenged mice and in allergen-naive TCLS subjected to TNF exposure. All contractile or bronchodilator responses were blocked by a selective NMDA-R antagonist, (2R)-amino-5-phosphonopentanoate, and bronchodilator responses were prevented by N(G)-nitro-l-arginine methyl ester (nitric oxide synthase inhibitor) or indomethacin (cyclooxygenase inhibitor). Collectively, we show that TNF augments NMDA-R-mediated Ca(2+) mobilization in HASM cells, whereas in multicellular TCLSs allergic inflammation and TNF exposure leads to NMDA-R-mediated bronchodilation. These findings reveal the unique contribution of ionotrophic NMDA-R to airway hyperreactivity.

  10. Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α.

    PubMed

    Shealy, David J; Cai, Ann; Staquet, Kim; Baker, Audrey; Lacy, Eilyn R; Johns, Laura; Vafa, Omid; Gunn, George; Tam, Susan; Sague, Sarah; Wang, Dana; Brigham-Burke, Mike; Dalmonte, Paul; Emmell, Eva; Pikounis, Bill; Bugelski, Peter J; Zhou, Honghui; Scallon, Bernard J; Giles-Komar, Jill

    2010-01-01

    We prepared and characterized golimumab (CNTO148), a human IgG1 tumor necrosis factor alpha (TNFα) antagonist monoclonal antibody chosen for clinical development based on its molecular properties. Golimumab was compared with infliximab, adalimumab and etanercept for affinity and in vitro TNFα neutralization. The affinity of golimumab for soluble human TNFα, as determined by surface plasmon resonance, was similar to that of etanercept (18 pM versus 11 pM), greater than that of infliximab (44 pM) and significantly greater than that of adalimumab (127 pM, p=0.018).  The concentration of golimumab necessary to neutralize TNFα-induced E-selectin expression on human endothelial cells by 50% was significantly less than those for infliximab (3.2 fold; p=0.017) and adalimumab (3.3-fold; p=0.008) and comparable to that for etanercept. The conformational stability of golimumab was greater than that of infliximab (primary melting temperature [Tm] 74.8 °C vs. 69.5 °C) as assessed by differential scanning calorimetry.  In addition, golimumab showed minimal aggregation over the intended shelf life when formulated as a high concentration liquid product (100 mg/mL) for subcutaneous administration.  In vivo, golimumab at doses of 1 and 10 mg/kg significantly delayed disease progression in a mouse model of human TNFα-induced arthritis when compared with untreated mice, while infliximab was effective only at 10 mg/kg. Golimumab also significantly reduced histological scores for arthritis severity and cartilage damage, as well as serum levels of pro-inflammatory cytokines and chemokines associated with arthritis. Thus, we have demonstrated that golimumab is a highly stable human monoclonal antibody with high affinity and capacity to neutralize human TNFα in vitro and in vivo.

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

    PubMed Central

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

    2016-01-01

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

  12. Tumor necrosis factor alpha signaling in the development of experimental murine pre-hepatic portal hypertension

    PubMed Central

    Theodorakis, Nicholas G; Wang, Yining N; Wu, Jianmin; Maluccio, Mary A; Skill, Nicholas J

    2010-01-01

    The cytokine tumor necrosis factor alpha (TNFa) has previously been identified in the development of portal hypertension (PHT) by facilitating portal venous and systemic hyperemia. TNFa is reported to contribute to hyperemia via endothelial nitric oxide synthase (eNOS) induction and nitric oxide (NO) production. This study examines this hypothesis by utilizing TNFa receptor knockout mice and a murine model of pre-hepatic PHT. Plasma TNFa and NOx and tissue TNFa mRNA levels were determined in wild-type mice 0-7d post induction of pre-hepatic PHT by partial portal vein ligation (PVL). TNFa receptor knockout mice also received PVL or sham surgery and splenic pulp pressure, abdominal aortic flow and portal-systemic shunting were recorded 7d following. Portal pressure and systemic hyperemia developed rapidly following PVL. Plasma NOx was increased temporarily 2-3 days following PVL and returned to baseline by day 7. Circulating TNFa was below detectable limits of the ELISA used, as such no increase was observed. Hepatic and vascular TNFa mRNA levels were transiently changed after PVL otherwise there was no significant change. TNFa receptor targeted gene deletion did not ameliorate plasma NOx following PVL and had no effect on the development of PHT. TNFa receptor signaling plays no detectable role in the development of systemic hyperemia in the murine model of pre-hepatic PHT. Consequently, increased TNFa observed in intra-hepatic inflammatory models (CCl4) and in patients is probably related to inflammation associated with intra-hepatic pathology. Alternatively, TNFa may be signaling via a TNFa receptor independent mechanism. PMID:21383890

  13. Wnt3a regulates tumor necrosis factor-α-stimulated interleukin-6 release in osteoblasts.

    PubMed

    Natsume, Hideo; Tokuda, Haruhiko; Adachi, Seiji; Matsushima-Nishiwaki, Rie; Kato, Kenji; Minamitani, Chiho; Otsuka, Takanobu; Kozawa, Osamu

    2011-01-01

    It is recognized that Wnt pathways regulate bone metabolism. We have previously shown that tumor necrosis factor-α (TNF-α) stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3-kinase)/Akt in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of Wnt3a on TNF-α-stimulated IL-6 synthesis in these cells. Wnt3a, which alone did not affect the IL-6 levels, significantly suppressed the TNF-α-stimulated IL-6 release. Lithium Chloride (LiCl), which is an inhibitor of GSK3β, markedly reduced the TNF-α-stimulated IL-6 release, similar to the results with Wnt3a. The suppression by Wnt3a or LiCl was also observed in the intracellular protein levels of IL-6 elicited by TNF-α. Wnt3a failed to affect the TNF-α-induced phosphorylation of p44/p42 MAP kinase, Akt, IκB or NFκB. Either Wnt3a or LiCl failed to reduce, rather increased the IL-6 mRNA expression stimulated by TNF-α. Lactacystin, a proteasome inhibitor, and bafilomycin A1, a lysosomal protease inhibitor, significantly restored the suppressive effect of Wnt3a on TNF-α-stimulated IL-6 release. Taken together, our results strongly suggest that Wnt3a regulates IL-6 release stimulated by TNF-α at post-transcriptional level in osteoblasts.

  14. Structural changes of tumor necrosis factor alpha associated with membrane insertion and channel formation.

    PubMed Central

    Baldwin, R L; Stolowitz, M L; Hood, L; Wisnieski, B J

    1996-01-01

    Low pH enhances tumor necrosis factor alpha (TNF)-induced cytolysis of cancer cells and TNF-membrane interactions that include binding, insertion, and ion-channel formation. We have also found that TNF increases Na+ influx in cells. Here, we examined the structural features of the TNF-membrane interaction pathway that lead to channel formation. Fluorometric studies link TNF's acid-enhanced membrane interactions to rapid but reversible acquisition of hydrophobic surface properties. Intramembranous photolabeling shows that (i) protonation of TNF promotes membrane insertion, (ii) the physical state of the target bilayer affects the kinetics and efficiency of TNF insertion, and (iii) binding and insertion of TNF are two distinct events. Acidification relaxes the trimeric structure of soluble TNF so that the cryptic carboxyl termini, centrally located at the base of the trimer cone, become susceptible to carboxypeptidase Y. After membrane insertion, TNF exhibits a trimeric configuration in which the carboxyl termini are no longer exposed; however, the proximal salt-bridged Lys-11 residues as well as regional surface amino acids (Glu-23, Arg-32, and Arg-44) are notably more accessible to proteases. The sequenced cleavage products bear the membrane-restricted photoreactive probe, proof that surface-cleaved TNF has an intramembranous disposition. In summary, the trimer's structural plasticity is a major determinant of its channel-forming ability. Channel formation occurs when cracked or partially splayed trimers bind and penetrate the bilayer. Reannealing leads to a slightly relaxed trimeric structure. The directionality of bilayer penetration conforms with x-ray data showing that receptor binding to the monomer interfaces of TNF poises the tip of the trimeric cone directly above the target cell membrane. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8577707

  15. Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity.

    PubMed Central

    Corral, L. G.; Muller, G. W.; Moreira, A. L.; Chen, Y.; Wu, M.; Stirling, D.; Kaplan, G.

    1996-01-01

    BACKGROUND: Tumor necrosis factor alpha (TNF alpha) is thought to mediate both protective and detrimental manifestations of the inflammatory response. Recently, thalidomide (alpha-N-phthalimidoglutarimide) was shown to partially inhibit monocyte TNF alpha production (by 50-70%) both in vivo and in vitro. More efficient inhibition of TNF alpha may, however, be necessary to rescue the host from more acute and extensive toxicities of TNF alpha-mediated inflammation. MATERIALS AND METHODS: Three structural analogues of thalidomide were selected for study based on increased activity against TNF alpha production. The parent drug and the analogs were tested in vitro in human peripheral blood mononuclear cell cultures for their effects on lipopolysaccharide (LPS) induced cytokine protein and mRNA production using ELISAs and Northern blot hybridization. The in vitro effects of the drugs were then confirmed in vivo in a mouse model of LPS induced lethality. RESULTS: The new compounds (two esters and one amide) showed increased inhibition of TNF alpha production by LPS-stimulated human monocytes, relative to the parent drug thalidomide. The analogs and the parent drug enhanced the production of interleukin 10 (IL-10), but had little effect on IL-6 and IL-1 beta protein and mRNA production. When tested in vivo, the amide analog protected 80% of LPS-treated mice against death from endotoxin induced shock. CONCLUSIONS: Analogs of thalidomide designed to better inhibit TNF alpha production in vitro have correspondingly greater efficacy in vivo. These finding may have therapeutic implication for the treatment of human diseases characterized by acute and extensive TNF alpha production such as tuberculous meningitis or toxic shock. Images FIG. 3 FIG. 4 PMID:8827720

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

    PubMed Central

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

    2015-01-01

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

  17. Isolated guinea pig gastric chief cells express tumour necrosis factor receptors coupled with the sphingomyelin pathway.

    PubMed

    Fiorucci, S; Santucci, L; Migliorati, G; Riccardi, C; Amorosi, A; Mancini, A; Roberti, R; Morelli, A

    1996-02-01

    The tumour necrosis factor alpha (TNF), has been implicated in the pathogenesis of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy and Helicobacter pylori induced gastritis. Both conditions are characterised by high plasma pepsinogen concentrations, which are thought to reflect an increased rate of enzyme release by the pepsinogen secreting (chief) cells. The mechanisms responsible for this cell dysfunction are unknown. This study investigates whether chief cells express TNF receptors and, if so, whether their activation results in cell death. Immunohistochemical studies conducted with monoclonal antibodies (mAbs) directed against two TNF receptor associated proteins of 55 kDa (TNF-R1) and 75 kDa (TNF-R2) showed that TNF binding sites were expressed in approximately 100% gastric chief cells. Western blot analysis of whole chief cell lysates probed with the TNF-R1 and TNF-R2 mAbs gave two distinct bands of 55 and 75 kDa in the immunoprecipitate. Incubating chief cells with TNF caused concentration and time dependent cell death, which was prevented by pretreating the cells with anti-TNF receptor mAbs. Exposing the cells to TNF reduced sphingomyelin content by 25%. Sphingomyelinase (10(-6) to 10(-2) IU/ml) mimicked the effect of TNF in that it provoked a concentration and time dependent reduction in chief cell viability and increased pepsinogen release. In conclusion, gastric chief cells express two TNF receptors partially linked to the sphingomyelin pathway. TNF induced chief cell dysfunction might be responsible for the high plasma pepsinogen concentrations seen in patients with NSAID gastropathy or H pylori induced gastritis.

  18. Regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor-α genetic variations

    PubMed Central

    LIU, YANGZHOU; HAN, NING; LI, QINCHUAN; LI, ZENGCHUN

    2016-01-01

    The present study aimed to investigate the regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor (TNF)-α genetic variations. The GSE5760 expression profile data, which was downloaded from the Gene Expression Omnibus database, contained 30 wild-type (WT) and 28 mutation (MUT) samples. Differentially expressed genes (DEGs) between the two types of samples were identified using the Student's t-test, and the corresponding microRNAs (miRNAs) were screened using WebGestalt software. An integrated miRNA-DEG network was constructed using the Cytoscape software, based on the interactions between the DEGs, as identified using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and the correlation between miRNAs and their target genes. Furthermore, Gene Ontology and pathway enrichment analyses were conducted for the DEGs using the Database for Annotation, Visualization and Integrated Discovery and the KEGG Orthology Based Annotation System, respectively. A total of 390 DEGS between the WT and MUT samples, along with 11 -associated miRNAs, were identified. The integrated miRNA-DEG network consisted of 38 DEGs and 11 miRNAs. Within this network, COPS2 was found to be associated with transcriptional functions, while FUS was found to be involved in mRNA metabolic processes. Other DEGs, including FBXW7 and CUL3, were enriched in the ubiquitin-mediated proteolysis pathway. In addition, miR-15 was predicted to target COPS2 and CUL3. The results of the present study suggested that COPS2, FUS, FBXW7 and CUL3 may be associated with sepsis in patients with TNF-α genetic variations. In the progression of sepsis, FBXW7 and CUL3 may participate in the ubiquitin-mediated proteolysis pathway, whereas COPS2 may regulate the phosphorylation and ubiquitination of the FUS protein. Furthermore, COPS2 and CUL3 may be novel targets of miR-15. PMID:27347057

  19. Tumor necrosis factor: receptor binding and expression of receptors in cultured mouse hepatocytes.

    PubMed

    Adamson, G M; Billings, R E

    1994-04-01

    Recombinant murine tumor necrosis factor (TNF-alpha) was labeled with 125I and used to determine the binding characteristics, internalization and intracellular degradation in cultured mouse hepatocytes. [125I]TNF-alpha bound specifically to hepatocytes and Scatchard analysis of the data indicated binding to both a low-affinity (Kd = 20 nM) high capacity (51225 sites/cell) component and high-affinity component (Kd = 4 pM), with low capacity (290 sites/cell). The extent of TNF-alpha binding to hepatocytes correlated closely with its biological activity in hepatocytes, as indexed by depletion of intracellular ATP. At concentrations lower than 0.06 nM there was minimal binding and no effect on cellular ATP, whereas maximal binding at concentrations greater than 45 nM caused 80% depletion (in comparison to controls) of hepatocyte ATP. Incubation at 37 degrees C resulted in rapid uptake, internalization and degradation of [125I]TNF-alpha. This was followed by release of degraded material from hepatocytes. Examination, by reverse transcriptase/polymerase chain reaction technology, of hepatocyte RNA extracted after the 4-hr adherence period revealed that mouse hepatocytes expressed mRNA for both TNF-alpha receptor 1 and TNF-alpha receptor 2, and that the relative abundance of TNF-alpha receptor 1 was approximately 7-fold greater than that for TNF-alpha receptor 2. Because it has been shown that these receptors have different affinities for TNF-alpha, this may explain the high- and low-affinity binding sites present on cultured mouse hepatocytes.

  20. Effect of Tumour Necrosis Factor-Alpha on Estrogen Metabolic Pathways in Breast Cancer Cells

    PubMed Central

    Kamel, Marwa; Shouman, Samia; El-Merzebany, Mahmoud; Kilic, Gokhan; Veenstra, Timothy; Saeed, Muhammad; Wagih, Mohamed; Diaz-Arrastia, Concepcion; Patel, Deepa; Salama, Salama

    2012-01-01

    Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been linked to breast cancer development. Estrogen metabolic pathway is also involved in breast carcinogenesis and DNA adducts formation. In this study we investigated the effect of TNF-α on the estrogen metabolic pathway in MCF-7, a breast cancer cell line. Capillary liquid chromatography/mass spectrometry (LC/MS) and High performance liquid chromatography (HPLC) were used for analysis of estrogen metabolites and estrogen-DNA adducts levels respectively. Reporter gene assay, Real time reverse transcription polymerase chain reaction (real time RT-PCR) and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes. TNF-α significantly increased the total EM and decreased the estrone (E1) / 17-β estradiol (E2) ratio. Moreover, it altered the expression of genes and enzymes involved in E2 activation and deactivation pathways e.g. Cytochrome P-450 1A1 (CYP1A1), Cytochrome P-450 1B1 (CYP1B1), Catechol-O-methyl transferase (COMT) and Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1 (NQO1). In addition, there were increased levels of some catechol estrogens e.g. 4-hydroxy-estrone (4-OHE1) and 2-hydroxyestradiol (2-OHE2) with decreased levels of methylated catechols e.g. 2-methoxy estradiol (2-MeOE2). DNA adducts especially 4-OHE1-[2]-1-N3 Adenine was significantly increased. TNF-α directs the estrogen metabolism into more hormonally active and carcinogenic products in MCF-7. This may implicate a new possible explanation for inflammation associated breast cancer. PMID:22866165

  1. Immunolocalization of tumor necrosis factor alpha in turbot (Scophthalmus maximus, L.) tissues.

    PubMed

    Ronza, Paolo; Losada, Ana Paula; Villamarín, Antonio; Bermúdez, Roberto; Quiroga, María Isabel

    2015-08-01

    Tumor necrosis factor alpha (TNFα) is a cytokine involved in a broad spectrum of cellular and organismal responses. Its main function, as a potent pro-inflammatory mediator, has been demonstrated in numerous teleost species and there are many reports on the modulation of TNFα gene expression under pathological conditions. Nevertheless, there is still scarce knowledge about the tissue distribution and type of cells that express this cytokine in fish species, which would help to further investigate its biological activities. These studies are hampered by the lack of molecular markers for teleost that hinder the development of morphological techniques, like immunohistochemistry. The aim of this work was to develop an immunohistochemical technique for the detection of TNFα in paraffin-embedded organs from healthy turbot (Scophthalmus maximus), an economically-important marine fish species. A commercial anti-human TNFα antibody, whose specificity was confirmed by western blot analysis, was used. Immunoreactive cells were observed in higher numbers in the lymphohematopoietic organs, kidney, spleen and thymus, although TNFα-positive cells were also present in the digestive tract, liver, heart, gills and skin. Similarly to non-fish species, monocytes/macrophages appeared to be the main producers of this cytokine; nevertheless, the presence of immunoreactive rodlet cells in different tissues was also reported. The nature and distribution of the labeled cells appeared to be related with a strategic localization for defense response to antigenic challenge. The relative abundance of TNFα-positive cells in the lymphohematopoietic organs also suggests that this cytokine may have a broader role in the normal physiology of those organs. The immunohistochemical technique allowed the in-situ characterization of TNFα expression, representing a valid tool to investigate the immune response of turbot.

  2. Development of a mouse-feline chimeric antibody against feline tumor necrosis factor-alpha

    PubMed Central

    DOKI, Tomoyoshi; TAKANO, Tomomi; HOHDATSU, Tsutomu

    2016-01-01

    Feline infectious peritonitis (FIP) is a fatal inflammatory disease caused by FIP virus infection. Feline tumor necrosis factor (fTNF)-alpha is closely involved in the aggravation of FIP pathology. We previously described the preparation of neutralizing mouse anti-fTNF-alpha monoclonal antibody (mAb 2–4) and clarified its role in the clinical condition of cats with FIP using in vitro systems. However, administration of mouse mAb 2–4 to cat may lead to a production of feline anti-mouse antibodies. In the present study, we prepared a mouse-feline chimeric mAb (chimeric mAb 2–4) by fusing the variable region of mouse mAb 2–4 to the constant region of feline antibody. The chimeric mAb 2–4 was confirmed to have fTNF-alpha neutralization activity. Purified mouse mAb 2–4 and chimeric mAb 2–4 were repeatedly administered to cats, and the changes in the ability to induce feline anti-mouse antibody response were investigated. In the serum of cats treated with mouse mAb 2–4, feline anti-mouse antibody production was induced, and the fTNF-alpha neutralization effect of mouse mAb 2–4 was reduced. In contrast, in cats treated with chimeric mAb 2–4, the feline anti-mouse antibody response was decreased compared to that of mouse mAb 2–4-treated cats. PMID:27264736

  3. Effect of anti-tumor necrosis factor alpha antibodies on histopathology of primary Salmonella infections.

    PubMed

    Mastroeni, P; Skepper, J N; Hormaeche, C E

    1995-09-01

    We reported that administration of anti-tumor necrosis factor alpha (anti-TNF-alpha) antibodies exacerbates the course of a Salmonella infection in both susceptible and resistant mice by preventing the suppression of bacterial growth in the reticuloendothelial system. In the present study, we evaluated the effect of in vivo neutralization of TNF-alpha on the histopathology of primary Salmonella infections. We show that in primary infections, the suppression of bacterial growth in the reticuloendothelial system coincides with granuloma formation in the spleen and liver. Administration of anti-TNF-alpha globulins on day -1 of salmonellosis affected neither the histological picture nor the course of the infection in the early stages of the disease (days 1 to 3), with splenic and hepatic lesions consisting mainly of polymorphonuclear leukocytes (PMNs); conversely, later in infection (days 3 to 7), the treatment inhibited the formation of granulomas. When the anti-TNF-alpha treatment was started well after the suppression of bacterial growth in the reticuloendothelial system and the formation of granulomatous lesions in the spleen and liver, a prompt relapse of the infection and regression of already established granulomas were seen. In anti-TNF-alpha-treated mice, salmonellae were found inside macrophages and PMNs and extracellularly in the necrotic tissue of the spleen, while in the liver the organisms were seen mainly in inflammatory mononuclear cells, resident Kupffer cells, and hepatocytes and occasionally in the extracellular compartment within necrotic lesions. The bacteria appeared most often in clusters, being morphologically intact when in the extracellular space or within hepatocytes, while undergoing various degrees of degeneration when inside phagocytes. The results suggest that TNF-alpha is required for granuloma formation in salmonellosis and that its neutralization does not completely abrogate the bactericidal activity of macrophages and PMNs

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

    PubMed Central

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

    2016-01-01

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

  5. Increased serum concentrations of tumour necrosis factor in beta thalassaemia: effect of bone marrow transplantation.

    PubMed Central

    Meliconi, R; Uguccioni, M; Lalli, E; Nesci, S; Delfini, C; Paradisi, O; Lucarelli, G; Gasbarrini, G; Facchini, A

    1992-01-01

    AIMS: Serum concentrations of tumour necrosis factor-alpha (TNF) were determined in beta thalassemic patients before and after bone marrow transplantation (BMT) to evaluate whether changes in TNF concentrations after BMT were related to immune mediated complications. METHODS: Serum TNF concentrations were determined by enzyme linked immunoassay (EIA) in paired samples from 71 patients with beta thalassemia before and after BMT. Serial samples from 13 patients were also studied for up to six months after BMT. Forty one normal healthy children matched for sex and age were studied as controls. RESULTS: beta thalassemic patients had high serum TNF concentrations before transplantation compared with controls. These were not related to sex, age, duration of disease, number of blood transfusions, transferrin concentrations or splenectomy. DQw1 positive patients showed significantly lower TNF concentrations than non-DQw1 cases. Patients with severe liver fibrosis had significantly higher TNF concentrations. No correlation was found between TNF values and BMT outcome before transplantation but TNF alpha values fell significantly after BMT. The decrease persisted only in patients with successful engraftment. In serial samples studied for up to six months after BMT, TNF values decreased but in four out of five patients with graft rejection and in all five with acute graft versus host disease (GVHD) sharp increases occurred at the time of clinical symptoms. No correlation was found between the degree of GVHD and serum TNF-alpha concentrations nor between TNF-alpha concentrations after BMT and the presence of bacterial, viral, and fungal infections. CONCLUSIONS: About 50% of beta thalassemic patients have increased serum TNF, and the changes after BMT are related to the occurrence of immune mediate complications. The persistence of low TNF concentrations after successful engraftment may be due to the preparative regimen and the lack of adverse immune reactions. PMID:1740519

  6. Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists

    PubMed Central

    Askling, J; Fored, C; Baecklund, E; Brandt, L; Backlin, C; Ekbom, A; Sundstrom, C; Bertilsson, L; Coster, L; Geborek, P; Jacobsson, L; Lindblad, S; Lysholm, J; Rantapaa-Dahlqvis..., S; Saxne, T; Klareskog, L; Feltelius, N

    2005-01-01

    Background: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear. Objective: To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA. Methods: A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53 067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed. Results: Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas. Conclusion: Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk. PMID:15843454

  7. Targeting Mycobacterium tuberculosis Tumor Necrosis Factor Alpha-Downregulating Genes for the Development of Antituberculous Vaccines

    PubMed Central

    Olsen, Aaron; Chen, Yong; Ji, Qingzhou; Zhu, Guofeng; De Silva, Aruna Dharshan; Vilchèze, Catherine; Weisbrod, Torin; Li, Weimin; Xu, Jiayong; Larsen, Michelle; Zhang, Jinghang; Porcelli, Steven A.; Jacobs, William R.

    2016-01-01

    ABSTRACT Tumor necrosis factor alpha (TNF) plays a critical role in the control of Mycobacterium tuberculosis, in part by augmenting T cell responses through promoting macrophage phagolysosomal fusion (thereby optimizing CD4+ T cell immunity by enhancing antigen presentation) and apoptosis (a process that can lead to cross-priming of CD8+ T cells). M. tuberculosis can evade antituberculosis (anti-TB) immunity by inhibiting host cell TNF production via expression of specific mycobacterial components. We hypothesized that M. tuberculosis mutants with an increased capacity to induce host cell TNF production (TNF-enhancing mutants) and thus with enhanced immunogenicity can be useful for vaccine development. To identify mycobacterial genes that regulate host cell TNF production, we used a TNF reporter macrophage clone to screen an H37Rv M. tuberculosis cosmid library constructed in M. smegmatis. The screen has identified a set of TNF-downregulating mycobacterial genes that, when deleted in H37Rv, generate TNF-enhancing mutants. Analysis of mutants disrupted for a subset of TNF-downregulating genes, annotated to code for triacylglycerol synthases and fatty acyl-coenzyme A (acyl-CoA) synthetase, enzymes that concern lipid biosynthesis and metabolism, has revealed that these strains can promote macrophage phagolysosomal fusion and apoptosis better than wild-type (WT) bacilli. Immunization of mice with the TNF-enhancing M. tuberculosis mutants elicits CD4+ and CD8+ T cell responses that are superior to those engendered by WT H37Rv. The results suggest that TNF-upregulating M. tuberculosis genes can be targeted to enhance the immunogenicity of mycobacterial strains that can serve as the substrates for the development of novel anti-TB vaccines. PMID:27247233

  8. The role of tumor necrosis factor in increased airspace epithelial permeability in acute lung inflammation.

    PubMed

    Li, X Y; Donaldson, K; Brown, D; MacNee, W

    1995-08-01

    Increased airspace epithelial permeability is an early event in lung inflammation and injury. In this study, we have developed a rat model to study the mechanisms of the epithelial permeability to 125iodine-labeled bovine serum albumin (125I-BSA), instilled intratracheally during acute lung inflammation. Epithelial permeability was measured as the percentage of instilled 125I-BSA appearing in the blood. The increase in epithelial permeability induced by intratracheal instillation of heat-killed Corynebacterium parvum produced a peak influx of neutrophils into the bronchoalveolar space at 16 h, which occurred after the peak increase in epithelial permeability (8 h). The increased epithelial permeability induced by C. parvum did not appear to be protease- or oxidant-mediated. Depletion of peripheral blood neutrophils was achieved by an intravenous injection of anti-neutrophil polyclonal antibody. The consequent profound reduction in neutrophil and macrophage influx into the airspaces 8 h after instillation of C. parvum reduced the epithelial permeability to control values. Bronchoalveolar lavage (BAL) leukocytes from rats 8 h, but not 16 h, after treatment with C. parvum caused a modest increase in epithelial permeability when re-instilled intratracheally into control rat lungs. Separation of the leukocytes before re-instillation indicated that macrophages rather than neutrophils were predominantly responsible for the increased epithelial permeability. The presence of dramatically increased levels of tumor necrosis factor (TNF) in BAL 8 h in contrast to a slight increase in BAL 16 h after C. parvum, the release of TNF from 8 h macrophages, the increased epithelial permeability induced by TNF in epithelial monolayers in vitro, and the inhibition of C. parvum-induced epithelial permeability by TNF antibody support the premise that TNF is a major player in the increased epithelial permeability that occurs during C. parvum-induced acute alveolitis. PMID:7626286

  9. Trypanosoma cruzi Infection in Tumor Necrosis Factor Receptor p55-Deficient Mice

    PubMed Central

    Castaños-Velez, Esmeralda; Maerlan, Stephanie; Osorio, Lyda M.; Åberg, Frederik; Biberfeld, Peter; Örn, Anders; Rottenberg, Martín E.

    1998-01-01

    Tumor necrosis factor receptor p55 (TNFRp55) mediates host resistance to several pathogens by allowing microbicidal activities of phagocytes. In the studies reported here, TNFRp55−/− mice infected with the intracellular parasite Trypanosoma cruzi showed clearly higher parasitemia and cumulative mortality than wild-type (WT) controls did. However, gamma interferon (IFN-γ)-activated macrophages from TNFRp55−/− mice produced control levels of nitric oxide and killed the parasite efficiently in vitro. Trypanocidal mechanisms of nonphagocytic cells (myocardial fibroblasts) from both TNFRp55−/− and WT mice were also activated by IFN-γ in a dose-dependent way. However, IFN-γ-activated TNFRp55−/− nonphagocytes showed less effective killing of T. cruzi than WT control nonphagocytes, even when interleukin 1β (IL-1β) was added as a costimulator. In vivo, T. cruzi-infected TNFRp55−/− mice and WT mice released similar levels of NO and showed similar levels of IFN-γ mRNA and inducible nitric oxide synthase mRNA in their tissues. Instead, increased susceptibility to T. cruzi of TNFRp55−/− mice was associated with reduced levels of parasite-specific immunoglobulin G (IgG) (but not IgM) antibodies during infection, which is probably linked to abnormal B-cell differentiation in secondary lymphoid tissues of the mutant mice. Surprisingly, T. cruzi-infected TNFRp55−/− mice showed increased inflammatory and necrotic lesions in several tissues, especially in skeletal muscles, indicating that TNFRp55 plays an important role in controlling the inflammatory process. Accordingly, levels of Mn2+ superoxide dismutase mRNA, a TNF-induced enzyme which protects the cell from the toxic effects of superoxide, were lower in mutant than in WT infected mice. PMID:9596773

  10. The -308 bp TNF gene polymorphism influences tumor necrosis factor expression in leprosy patients in Bahia State, Brazil.

    PubMed

    Oliveira, Joyce Moura; Rêgo, Jamile Leão; de Lima Santana, Nadja; Braz, Marcos; Jamieson, Sarra E; Vieira, Thaillamar Silva; Magalhães, Thaís Lamêgo; Machado, Paulo Roberto Lima; Blackwell, Jenefer M; Castellucci, Léa C

    2016-04-01

    Leprosy or Hansen's disease is a debilitating chronic granulomatous disease caused by Mycobacterium leprae, with high incidence and prevalence in Brazil. The -308 bp G/A single nucleotide polymorphism (SNP rs1800629) in the tumor necrosis factor (TNF) gene promoter is a proposed risk factor for leprosy. In Brazil, Northern India, Egypt and Nepal, the common G allele was associated with leprosy. In Eastern India, Thailand and Malawi the minor A allele was the risk factor. Allele A was previously associated with high TNF. We genotyped rs1800629 in 326 leprosy cases from Bahia State, Brazil, including 72 paucibacillary (PB) and 47 multibacillary (MB) without reactions, and 69 reversal reaction (RR) and 78 erythema nodosum leprosum (ENL) with reactions. Logistic regression was used to compare patient groups with 331 healthy controls. Relative TNF mRNA was determined in peripheral blood leukocytes by QRTPCR, and serum TNF levels measured by ELISA. We found that TNF mRNA expression was higher (P=0.03) in leprosy patients compared to endemic controls, but did not differ significantly between clinical subgroups. Carriage of the minor A allele was associated (P=0.003) with low TNF mRNA across leprosy patients. Nevertheless, we found no evidence for either allele at this SNP as a risk factor for leprosy per se (OR=1.12, 95% CI 0.79-1.60, P=0.52), PB (OR=0.99, 95% CI 0.54-1.81, P=0.97), MB (OR=0.86, 95% CI 0.40-1.83, P=0.70), RR (OR=1.37, 95% CI 0.79-2.38, P=0.27) or ENL (OR=0.76, 95% CI 0.40-1.45, P=0.42) when compared to endemic controls. Further studies are required to determine whether the influence of the minor A allele on TNF mRNA levels determines response to treatment, particularly in the context of ENL reaction treatment with anti-TNF therapies and RR reactions where treatment with prednisolone is known to reduce TNF levels. Our findings contribute to understanding TNF as an important determinant of leprosy immunopathology in Brazil. PMID:26829382

  11. Increased expression of vascular endothelial growth factor attenuates contusion necrosis without influencing contusion edema after traumatic brain injury in rats.

    PubMed

    Tado, Masahiro; Mori, Tatsuro; Fukushima, Masamichi; Oshima, Hideki; Maeda, Takeshi; Yoshino, Atsuo; Aizawa, Shin; Katayama, Yoichi

    2014-04-01

    To clarify the role of vascular endothelial growth factor (VEGF) in the formation of contusion edema and necrosis after traumatic brain injury, we examined the time course of changes in the VEGF expression (enzyme-linked immunosorbent assay), cerebrovascular permeability (extravasation of Evans blue), and water content (dry-wet weight method) of the contused brain tissue in a cortical impact injury model using rats. In addition, we tested the effects of administration of bevacizumab (VEGF monoclonal antibody) on changes in the cerebrovascular permeability and water content of the contused brain tissue, as well as the neurological deficits (rota rod test) and volume of contusion necrosis. Increased VEGF expression was maximal at 72 h after injury (p<0.003). Increases in cerebrovascular permeability and water content, however, became maximal within 24 h (p<0.001) after injury (p<0.01), respectively. Administration of bevacizumab did not influence these changes in cerebrovascular permeability and water content, but led to a significant rise in the neurological deficits at 72 h-14 days (p<0.05 or 0.01) and the volume of contusion necrosis at 21 days (p<0.001) after injury. These findings suggest that increased expression of VEGF after injury does not contribute to the formation of contusion edema, but attenuates the formation of contusion necrosis. This is probably because of an increased angiogenesis and improved microcirculation in the areas surrounding the core of contusion. PMID:24294928

  12. Active tuberculosis in a psoriasis patient treated with tumor necrosis factor inhibitors despite an initial negative tuberculin skin test and no known risk factors.

    PubMed

    Gilbert, Kathleen E Gilbert E; Manalo, Iviesan F; Wu, Jashin J

    2016-01-01

    Tumor necrosis factor (TNF) inhibitors are becoming more common in the treatment of moderate-to-severe chronic plaque psoriasis. These medications have a low incidence of serious adverse events and are generally considered safe; however, they do make patients more susceptible to tuberculosis (TB) infection both through latent reactivation and primary infection. We describe a case of a patient who had an initial negative tuberculin skin test (TST), began TNF inhibitor therapy, and then 11 years later was diagnosed with active TB. After the initial screening, the patient did not have any subsequent screenings for TB and no apparent change to his TB risk status. TB is still common in many areas of the United States and travel is not necessary to be exposed. Patients on TNF inhibitors that develop active TB have increased morbidity and mortality than those who are not. It is necessary that dermatologists limit the risk of TB to patients by screening them before initiation and annually when they are on the TNF inhibitor. PMID:27617949

  13. Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice

    PubMed Central

    Khuman, Jugta; Meehan, William P; Zhu, Xiaoxia; Qiu, Jianhua; Hoffmann, Ulrike; Zhang, Jimmy; Giovannone, Eric; Lo, Eng H; Whalen, Michael J

    2011-01-01

    Tumor necrosis factor alpha (TNFα) and Fas receptor contribute to cell death and cognitive dysfunction after focal traumatic brain injury (TBI). We examined the role of TNFα/Fas in postinjury functional outcome independent of cell death in a novel closed head injury (CHI) model produced with weight drop and free rotational head movement in the anterior–posterior plane. The CHI produced no cerebral edema or blood–brain barrier damage at 24 to 48 hours, no detectable cell death, occasional axonal injury (24 hours), and no brain atrophy or hippocampal cell loss (day 60). Microglia and astrocytes were activated (48 to 72 hours). Tumor necrosis factor-α mRNA, Fas mRNA, and TNFα protein were increased in the brain at 3 to 6 hours after injury (P<0.001 versus sham injured). In wild-type (WT) mice, CHI produced hidden platform (P=0.009) and probe deficits (P=0.001) in the Morris water maze versus sham. Surprisingly, injured TNFα/Fas knockout (KO) mice performed worse in hidden platform trials (P=0.036) but better in probe trials than did WT mice (P=0.0001). Administration of recombinant TNFα to injured TNFα/Fas KO mice reduced probe trial performance to that of WT. Thus, TNFα/Fas influence cognitive deficits independent of cell death after CHI. Therapies targeting TNFα/Fas together may be inappropriate for patients with concussive TBI. PMID:20940727

  14. Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice.

    PubMed

    Khuman, Jugta; Meehan, William P; Zhu, Xiaoxia; Qiu, Jianhua; Hoffmann, Ulrike; Zhang, Jimmy; Giovannone, Eric; Lo, Eng H; Whalen, Michael J

    2011-02-01

    Tumor necrosis factor alpha (TNFα) and Fas receptor contribute to cell death and cognitive dysfunction after focal traumatic brain injury (TBI). We examined the role of TNFα/Fas in postinjury functional outcome independent of cell death in a novel closed head injury (CHI) model produced with weight drop and free rotational head movement in the anterior-posterior plane. The CHI produced no cerebral edema or blood-brain barrier damage at 24 to 48 hours, no detectable cell death, occasional axonal injury (24 hours), and no brain atrophy or hippocampal cell loss (day 60). Microglia and astrocytes were activated (48 to 72 hours). Tumor necrosis factor-α mRNA, Fas mRNA, and TNFα protein were increased in the brain at 3 to 6 hours after injury (P<0.001 versus sham injured). In wild-type (WT) mice, CHI produced hidden platform (P=0.009) and probe deficits (P=0.001) in the Morris water maze versus sham. Surprisingly, injured TNFα/Fas knockout (KO) mice performed worse in hidden platform trials (P=0.036) but better in probe trials than did WT mice (P=0.0001). Administration of recombinant TNFα to injured TNFα/Fas KO mice reduced probe trial performance to that of WT. Thus, TNFα/Fas influence cognitive deficits independent of cell death after CHI. Therapies targeting TNFα/Fas together may be inappropriate for patients with concussive TBI. PMID:20940727

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

    SciTech Connect

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

    2010-11-16

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

  16. Regulation of human lung fibroblast glycosaminoglycan production by recombinant interferons, tumor necrosis factor, and lymphotoxin.

    PubMed Central

    Elias, J A; Krol, R C; Freundlich, B; Sampson, P M

    1988-01-01

    Mononuclear cells may be important regulators of fibroblast glycosaminoglycan (GAG) biosynthesis. However, the soluble factors mediating these effects, the importance of intercytokine interactions in this regulation and the mechanisms of these alterations remain poorly understood. We analyzed the effect of recombinant (r) tumor necrosis factor (TNF), lymphotoxin (LT), and gamma, alpha, and beta 1 interferons (INF-gamma, -alpha and -beta 1), alone and in combination, on GAG production by normal human lung fibroblasts. rTNF, rLT, and rINF-gamma each stimulated fibroblast GAG production. In addition, rIFN-gamma synergized with rTNF and rLT to further augment GAG biosynthesis. In contrast, IFN-alpha A, -alpha D, and -beta 1 neither stimulated fibroblast GAG production nor interacted with rTNF or rLT to regulate GAG biosynthesis. The effects of the stimulatory cytokines and cytokine combinations were dose dependent and were abrogated by the respective monoclonal antibodies. In addition, these cytokines did not cause an alteration in the distribution of GAG between the fibroblast cell layer and supernatant. However, the stimulation was at least partially specific for particular GAG moieties with hyaluronic acid biosynthesis being markedly augmented without a comparable increase in the production of sulfated GAGs. Fibroblast prostaglandin production did not mediate these alterations since indomethacin did not decrease the stimulatory effects of the cytokines. In contrast, protein and mRNA synthesis appeared to play a role since the stimulatory effects of the cytokines were abrogated by cyclohexamide and actinomycin D, respectively. In addition, the cytokines and cytokine combinations increased cellular hyaluronate synthetase activity in proportion to their effects on hyaluronic acid suggesting that induction of this enzyme(s) is important in this stimulatory process. These studies demonstrate that IFN-gamma, TNF, and LT are important stimulators of fibroblast GAG

  17. Association of tumor necrosis factor-α and -β gene polymorphisms in inflammatory bowel disease

    PubMed Central

    Al-Meghaiseeb, Ebtissam Saleh; Al-Robayan, Abdulrahman A; Al-Otaibi, Mulfi Mubarak; Arfin, Misbahul; Al-Asmari, Abdulrahman K

    2016-01-01

    Inflammatory bowel disease (IBD) is a complex, multifactorial, chronic inflammatory disorder of the gastrointestinal tract in which immune dysregulation caused by genetic and/or environmental factors plays an important role. The aim of this case–control study was to evaluate the association of tumor necrosis factor-alpha (TNF-α) (308) and -β (+252) polymorphisms with susceptibility of IBD. A total of 379 Saudi subjects including 179 IBD patients (ulcerative colitis (UC) =84 and Crohn’s disease (CD) =95) and 200 age- and sex-matched healthy controls were recruited. TNF-α and TNF-β genes were amplified using an amplification refractory mutation systems polymerase chain reaction methodology to detect TNF-α (−308) and -β (+252) polymorphisms. The frequency of the GA genotype of TNF-α (−308G/A) was higher, and the frequencies of the GG and AA genotypes were significantly lower in IBD patients compared with those in controls, indicating that genotype GA-positive individuals are susceptible to IBD and that the GG and AA genotypes exert a protective effect. The frequency of allele A of TNF-α (−308G/A) was significantly higher and that of allele G was lower in IBD patients compared with those in controls, indicating an association of allele A with IBD risk in Saudi patients. On stratification of IBD patients into UC and CD, an almost similar pattern was noticed in both the groups. The results of TNF-β (+252A/G) polymorphisms showed a significant increase in the frequency of the GG genotype in IBD patients, suggesting a positive association of GG genotype with IBD risk. On stratification of IBD patients into UC and CD, the genotype GG of TNF-β was associated with susceptibility risk to UC but not CD. The frequencies of alleles and genotypes of both TNF-α and-β polymorphisms are not affected by sex or type of IBD (familial or sporadic). TNF-α (−308G/A) and TNF-β (+252A/G) polymorphisms are associated with risk of developing IBD in Saudi population

  18. Inflammatory cytokine tumor necrosis factor α suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor-2α.

    PubMed

    Nagaya, Yoshiaki; Aoyama, Mineyoshi; Tamura, Tetsuya; Kakita, Hiroki; Kato, Shin; Hida, Hideki; Saitoh, Shinji; Asai, Kiyofumi

    2014-12-01

    Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood-brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor α (TNFα) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFα in vivo. In cultured astrocytes exposed to hypoxic conditions for 6 and 12 h, TNFα suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration-dependent manner. TNFα inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2α rather than HIF-1α. The effects of TNFα in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2α, which is regulated by the nuclear factor (NF)-κB signaling pathway. TNFα treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFα signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response. PMID:25283246

  19. Discrepancy between tissue factor activity and tissue factor expression in endotoxin-induced monocytes is associated with apoptosis and necrosis.

    PubMed

    Henriksson, Carola E; Klingenberg, Olav; Ovstebø, Reidun; Joø, Gun-Britt; Westvik, Ase-Brit; Kierulf, Peter

    2005-12-01

    Tissue factor (TF), the main initiator of blood coagulation, contributes to the manifestation of disseminated intravascular coagulation following septic shock in meningococcal infection. Since a direct relationship between disease severity and lipopolysaccharide (LPS) concentration in the circulation has been shown, we hypothesized that the procoagulant and cytotoxic effects of endotoxin also in vitro were related to its concentration. In vitro studies, however, have frequently used much higher LPS concentrations than those observed in clinical samples. Using elutriation-purified human monocytes, we observed that LPS up to 1000 ng/ml exerted a concentration-dependent increase in TF activity (tenase activity, fibrin formation in plasma). Although there was a dose-dependent increase in TF activity, there was not a concomitant increase in TF expression at LPS concentrations above 1 ng/ml (flow cytometry, Western blotting, TF mRNA). Flow cytometry revealed that this discrepancy between TF activity and TF expression at endotoxin concentrations above 1 ng/ml, coincided with an LPS dose-dependent increase in cell surface phosphatidylserine (PS), considered to promote coagulation. The increased PS expression was associated with an increased number of 7-AAD-positive cells indicating cell death. We conclude that enhancement of monocyte procoagulant activity in vitro by high concentrations of LPS may result from increased PS exposure due to apoptosis and necrosis. Therefore, the LPS concentrations used to examine monocyte procoagulant activity in vitro, should be carefully chosen.

  20. Staphylococcus aureus protein A binding to osteoblast tumour necrosis factor receptor 1 results in activation of nuclear factor kappa B and release of interleukin-6 in bone infection.

    PubMed

    Claro, Tânia; Widaa, Amro; McDonnell, Cormac; Foster, Timothy J; O'Brien, Fergal J; Kerrigan, Steven W

    2013-01-01

    Staphylococcus aureus is the major pathogen among the staphylococci and the most common cause of bone infections. These infections are mainly characterized by bone destruction and inflammation, and are often debilitating and very difficult to treat. Previously we demonstrated that S. aureus protein A (SpA) can bind to osteoblasts, which results in inhibition of osteoblast proliferation and mineralization, apoptosis, and activation of osteoclasts. In this study we used small interfering RNA (siRNA) to demonstrate that osteoblast tumour necrosis factor receptor-1 (TNFR-1) is responsible for the recognition of and binding to SpA. TNFR-1 binding to SpA results in the activation of nuclear factor kappa B (NFκB). In turn, NFκB translocates to the nucleus of the osteoblast, which leads to release of interleukin 6 (IL-6). Silencing TNFR-1 in osteoblasts or disruption of the spa gene in S. aureus prevented both NFκB activation and IL-6 release. As well as playing a key role in proinflammatory reactions, IL-6 is also an important osteotropic factor. Release of IL-6 from osteoblasts results in the activation of the bone-resorbing cells, the osteoclasts. Consistent with our results described above, both silencing TNFR-1 in osteoblasts and disruption of spa in S. aureus prevented osteoclast activation. These studies are the first to demonstrate the importance of the TNFR-1-SpA interaction in bone infection, and may help explain the mechanism through which osteoclasts become overactivated, leading to bone destruction. Anti-inflammatory drug therapy could be used either alone or in conjunction with antibiotics to treat osteomyelitis or for prophylaxis in high-risk patients.

  1. Correlation of C-reactive protein haplotypes with serum C-reactive protein level and response to anti-tumor necrosis factor therapy in UK rheumatoid arthritis patients: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort

    PubMed Central

    2012-01-01

    Introduction In many European countries, restrictions exist around the prescription of anti-tumor necrosis factor (anti-TNF) treatments for rheumatoid arthritis (RA). Eligibility and response to treatment is assessed by using the disease activity score 28 (DAS28) algorithm, which incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Although DAS28-CRP provides a more reliable measure of disease activity, functional variants exist within the CRP gene that affect basal CRP production. Therefore, we aimed to determine the relation between functional genetic variants at the CRP gene locus and levels of serum CRP in RA patients, and whether these variants, alone or in combination, are correlated with DAS28-CRP and change in DAS28-CRP after anti-TNF treatment. Methods DNA samples from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) were genotyped for rs1205, rs1800947, and rs3091244 by using either TaqMan or the Sequenom MassARRAY iPLEX system. Estimated haplotypes were constructed for each sample by using the expectation maximization algorithm implemented in the haplo.stats package within the R statistical program. CRP values were log transformed, and the association between single nucleotide polymorphisms (SNPs), haplotypes of SNPs and baseline CRP, baseline DAS28-CRP, and change in DAS28-CRP were evaluated by using linear regression in STATA v.10. Results Baseline CRP measurements were available for 599 samples with 442 also having data 6 months after treatment with an anti-TNF. For these 442 samples, the study had > 80% power to detect a clinically meaningful difference of 0.6 DAS28 Units for an allele frequency of 5%. Estimated haplotype frequencies corresponded with previous frequencies reported in the literature. Overall, no significant association was observed between any of the markers investigated and baseline CRP levels. Further, CRP haplotypes did not correlate

  2. Identification and characterization of tumor necrosis factor receptor (TNFR)-associated factor 3 from humphead snapper, Lutjanus sanguineus.

    PubMed

    Cai, Jia; Xia, Hongli; Huang, Yucong; Tang, Jufen; Jian, Jichang; Wu, Zaohe; Lu, Yishan

    2015-10-01

    Tumor necrosis factor receptor (TNFR)-associated factor 3(TRAF3) is a key regulator in TNFR and Toll-like receptor (TLRs)/RIG-I-like receptors (RLRs) signal pathway. Here, a TRAF3 gene (Ls-TRAF3, GenBank Accession No: KJ789921) is cloned from humphead snapper (Lutjanus sanguineus). The Ls-TRAF3 cDNA contains an open reading frame of 1788 bp, which encodes a polypeptide of 595 amino acids. The deduced amino acid of Ls-TRAF3 possesses a RING finger, two TRAF-type zinc fingers, a coiled-coil and a MATH domain. Ls-TRAF3 protein shares high identities with other known TRAF3 proteins. In healthy fish, Ls-TRAF3 transcripts were broadly expressed in all examined tissues with highest expression levels in spleen, liver and head kidney. Quantitative real-time PCR (qRT-PCR) analysis revealed that Ls-TRAF3 could be induced by bacteria or viral PAMP poly I:C stimulation in vivo. Here, we also showed Ls-TRAF3 that, positively regulated IRF3 and Mx upon poly I:C stimuli, whereas prevented production of proinflammatory cytokine IL-6 after LPS injection. Moreover, over-expression of wide type (WT) Ls-TRAF3 and truncated forms, including ΔZinc finger 1, ΔZinc finger 2 and Δcoiled-coil suppressed NF-κB activity significantly, whereas the inhibitory effect of NF-κB was partially impaired when the RING finger or MATH domain deletion, suggesting the latter was more important for downstream signal transduction. Taken together, these results implicated that Ls-TRAF3 might play regulatory roles in immune response to pathogen invasion.

  3. 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

  4. Inhibitory effect of tetrahydroswertianolin on tumor necrosis factor-alpha-dependent hepatic apoptosis in mice.

    PubMed

    Hase, K; Xiong, Q; Basnet, P; Namba, T; Kadota, S

    1999-06-15

    We investigated the effect of tetrahydroswertianolin (THS), a hepatoprotective agent from Swertia japonica, on tumor necrosis factor-alpha (TNF-alpha)-dependent hepatic apoptosis induced by D-galactosamine (D-GalN) (700 mg/kg, i.p.) and lipopolysaccharide (LPS) (10 microg/kg, i.p.) in mice. Apoptotic symptoms were observed at the initial stage of liver damage. By 5 hr after intoxication, hepatic DNA fragmentation had risen to 2123%, with the value in untreated mice set at 100%, without a significant elevation of serum alanine transaminase (ALT) activity. There was a parallel increase in hepatocytes undergoing chromatin condensation and apoptotic body formation. By 8 hr after intoxication, serum ALT activity had risen to 3707 U/L. Pretreatment with THS (50 mg/kg, p.o.) at 18 and 2 hr before intoxication significantly reduced DNA fragmentation to 821% of that in untreated mice and prevented the emergence of chromatin condensation and apoptotic body formation. A significant and dose-dependent reduction in serum ALT activity at 8 hr also was observed with THS pretreatment. These effects of THS were different from those observed from pretreatment with glycyrrhizin (GCR), which is a clinically used hepatoprotective agent with membrane-stabilizing activity. GCR pretreatment (100 mg/kg, p.o.) did not inhibit hepatic DNA fragmentation (1588% of untreated mice), although this compound significantly protected against serum ALT elevation (1463 U/L). These data suggest that an inhibitory effect on the progression of hepatic apoptosis prior to liver injury may be involved in the hepatoprotective mechanisms of THS, whereas it appears that GCR affects the processes after apoptosis. In a separate experiment, we found that the concentration of serum TNF-alpha rose to 2016 pg/mL at 1 hr after intoxication of mice with D-GalN and LPS, but this increase was suppressed by THS pretreatment (10, 50, or 200 mg/kg, p.o.) to 716, 454, or 406 pg/mL, respectively. Further study with a reverse

  5. Nitric oxide and tumour necrosis factor alpha in the process of pseudoexfoliation glaucoma

    PubMed Central

    Sarenac Vulovic, Tatjana S.; Pavlovic, Sladjana M.; Jakovljevic, Vladimir LJ.; Janicijevic, Katarina B.; Zdravkovic, Nemanja S.

    2016-01-01

    AIM To establish the role of nitric oxide (NO), ascorbic acid and tumour necrosis factor-α (TNF-α) in the pathogenesis of pseudoexfoliation glaucoma (XFG). METHODS Our study included 120 patients who were referred for cataract surgery. All patients were divided into four groups according to clinical findings: XFG, early and late pseudoexfoliation syndrome (XFS), and cataract (without pseudoexfoliation). Serum and aqueous humour levels of the ascorbic acid, NO and TNF-α were measured. The concentrations of the ascorbic acid and NO were measured by an appropriate spectrophotometric method. Enzyme-linked immunosorbent assay (ELISA) was used to determine TNF-α level. RESULTS Aqueous humour concentration of ascorbic acid was significantly lower in patients with late XFS (0.61±0.11 mmol/L) and XFG (0.48±0.15 mmol/L) compared to patients with early XFS (0.9±0.15 mmol/L) and cataract (1.16±0.22 mmol/L), while there was no difference in serum concentration in all examined groups. Aqueous humour concentration of NO was significantly higher in patients with XFG (77.7±11.4 µmol/L) compared to patients with early XFS (50.27±9.34 µmol/L) and cataract (49.77±7.1 µmol/L), while serum concentration was increased in the early stage of XFS (73.26±8.29 µmol/L). Aqueous humour level of proinflammatory cytokine TNF-α was increased in patients with XFS (early 460.04±18.32 pg/mL; late 502.42±53.23 pg/mL) and XFG (510.34±43.07 pg/mL), while there was no difference in serum level in all examined groups of patients. CONCLUSION Reduced ascorbic acid and elevated NO and inflammation related cytokine TNF-α level in aqueous humour of the patients with developed XFG suggest that oxidative stress induces local inflammation. PMID:27588268

  6. Tumor necrosis factor alpha has a protective role in a murine model of systemic candidiasis.

    PubMed Central

    Louie, A; Baltch, A L; Smith, R P; Franke, M A; Ritz, W J; Singh, J K; Gordon, M A

    1994-01-01

    The role of tumor necrosis factor alpha (TNF-alpha) in host defense against systemic Candida albicans infection was evaluated in a murine model of systemic candidiasis in which uniform death occurred between 5 and 6 days after infection. TNF-alpha was first detected at 16 h postinfection and progressively increased thereafter. Peak levels (700 to 900 pg/ml) were measured in mice near death. Administration of 0.5 to 1.0 mg of polyclonal immunoglobulin G (IgG) TNF-alpha antibody (TNF-alpha Ab) to mice 2 h preinfection neutralized serum TNF-alpha for up to 30 h. However, this regimen shortened survival from a mean of 5.5 days for IgG controls to 3.4 days (P = 1.9 x 10(-12)). Semiquantitative cultures of spleen, lung, liver, and kidney conducted at 1, 2, and 3 days postinfection found colony counts of spleen and kidney to be significantly higher for TNF-alpha Ab recipients but only for the first 48 h. Administration of 1.5 and 1.0 mg of TNF-alpha Ab at 2 h before and 48 h after fungal injection, respectively, shortened the mean survival from 4.9 to 2.3 days (P = 5.2 x 10(-8)). This regimen neutralized serum TNF-alpha throughout infection. With this regimen, colony counts of all organs were significantly higher in TNF-alpha Ab recipients at 1, 2, and 3 days postinfection. Histopathologic studies showed an increase in the number and size of C. albicans foci in tissues. Peripheral leukocyte counts and inflammatory response in tissue were similar for TNF-alpha Ab and IgG sham recipients. In vitro, incubation of C. albicans with four to eight times the peak serum levels of TNF-alpha for up to 24 h did not inhibit the rate of germ tube or pseudohypha formation. Thus, TNF-alpha that was produced during infection with C. albicans augmented host resistance against this organism and prolonged survival. The protective effect of TNF-alpha was not mediated by increased leukocytes in blood or tissues nor by a direct anticandidal effect of TNF-alpha. This study suggests that the

  7. Tumor necrosis factor-alpha-induced changes in insulin-producing beta-cells.

    PubMed

    Parkash, Jai; Chaudhry, Muhammad A; Rhoten, William B

    2005-10-01

    The migration of macrophages and lymphocytes that produce cytokines such as tumor necrosis factor-alpha (TNF-alpha) causes beta-cell death, leading to type 1 diabetes. Similarly, in type 2 diabetes, the adipocyte-derived cytokines including TNF-alpha are elevated in the circulation, causing inflammation and insulin resistance. Thus, the studies described in this article using TNF-alpha are relevant to furthering our understanding of the pathogenesis of diabetes mellitus. We used RINr1046-38 (RIN) insulin-producing beta-cells, which constitutively express calbindin-D(28k), to characterize the effect of TNF-alpha on apoptosis, replication, insulin release, and gene and protein expression. Western blots of TNF-alpha-treated RIN cells revealed a decrease in calbindin-D(28k). By ELISA, TNF-alpha-treated beta-cells had 47% less calbindin-D(28k) than controls. In association with the decline in calbindin-D(28k), TNF-alpha treatment of RIN cells led to a 73% greater increase in changes in intracellular calcium concentration (Delta[Ca(2+)](i)) in TNF-alpha-treated cells as compared to that in control RIN cells upon treatment with 50 mM KCl; caused a greater increase in the [Ca(2+)](i) following the addition of 5.5 microM ionomycin; increased by more than threefold the apoptotic rate, expressed as the percentage of TUNEL-positive nuclei to total nuclei; decreased the rate of cell replication by 36%; and increased and decreased selectively the expression of specific genes as determined by microarray analysis. The subcellular localizations of Bcl-2, an antiapoptotic protein, and Bax, a proapoptotic protein, within RIN cells were altered with TNF-alpha treatment such that the two were colocalized with mitochondria in the perinuclear region. We conclude that the proapoptotic action of TNF-alpha on beta-cells is manifested via decreased expression of calbindin-D(28k) and is mediated at least in part by [Ca(2+)](i). PMID:16114068

  8. Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists

    PubMed Central

    Hamdi, Haïfa; Mariette, Xavier; Godot, Véronique; Weldingh, Karin; Hamid, Abdul Monem; Prejean, Maria-Victoria; Baron, Gabriel; Lemann, Marc; Puechal, Xavier; Breban, Maxime; Berenbaum, Francis; Delchier, Jean-Charles; Flipo, René-Marc; Dautzenberg, Bertrand; Salmon, Dominique; Humbert, Marc; Emilie, Dominique

    2006-01-01

    Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-α treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-γ. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-α treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-γ-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-γ release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-γ upon challenge with mycobacterial antigens. Added in vitro, they inhibit the

  9. [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.

  10. Transforming growth factor-beta suppresses tumor necrosis factor alpha-induced matrix metalloproteinase-9 expression in monocytes.

    PubMed

    Vaday, G G; Schor, H; Rahat, M A; Lahat, N; Lider, O

    2001-04-01

    The inflammatory response is marked by the release of several cytokines with multiple roles in regulating leukocyte activities, including the secretion of matrix metalloproteinases (MMPs). Although the effects of individual cytokines on monocyte MMP expression have been studied extensively, few studies have examined the influence of combinations of cytokines, which are likely present at inflammatory sites. Herein, we report our investigation of the combinatorial effects of tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta on MMP-9 synthesis. We found that TGF-beta suppressed TNF-alpha-induced MMP-9 secretion by MonoMac-6 monocytic cells in a dose-dependent manner, with a maximal effect of TGF-beta observed at 1 ng/ml. Such suppression was likely regulated at the pretranslational level, because steady-state mRNA levels of TNF-alpha-induced MMP-9 were reduced by TGF-beta, and pulse-chase radiolabeling also showed a decrease in new MMP-9 protein synthesis. The suppressive effects of TGF-beta were time dependent, because short exposures to TNF-alpha before TGF-beta or simultaneous exposure to both cytokines efficiently reduced MMP-9 secretion. Expression of the tissue inhibitor of metalloproteinases (TIMP)-1 and TNF-alpha receptors was unaffected by either cytokine individually or in combination. Affinity binding with radiolabeled TGF-beta demonstrated that levels of TGF-beta receptors were not increased after preincubation with TGF-beta. Suppression of TNFalpha-induced MMP-9 secretion by TGF-beta correlated with a reduction in prostaglandin E2 (PGE2) secretion. Furthermore, the effect of TGF-beta or indomethacin on blockage of TNF-alpha-stimulated MMP-9 production was reversed by the addition of either exogenous PGE2 or the cyclic AMP (cAMP) analogue Bt2cAMP. Thus, we concluded that TGF-beta acts as a potent suppressor of TNF-alpha-induced monocyte MMP-9 synthesis via a PGE2- and cAMP-dependent mechanism. These results suggest that various

  11. Mycobacterial lipoarabinomannan induces nitric oxide and tumor necrosis factor alpha production in a macrophage cell line: down regulation by taurine chloramine.

    PubMed Central

    Schuller-Levis, G B; Levis, W R; Ammazzalorso, M; Nosrati, A; Park, E

    1994-01-01

    Avirulent mycobacterium H37Ra lipoarabinomannan (LAM) elicited nitric oxide (NO) and tumor necrosis factor alpha in a dose-dependent manner in a murine macrophage cell line, RAW 264.7 cells. H37Ra LAM and recombinant gamma interferon were highly synergistic for NO production. The production of NO and the release of tumor necrosis factor alpha stimulated by H37Ra LAM plus recombinant gamma interferon in RAW 264.7 cells are inhibited by taurine chloramine. PMID:7927739

  12. Proliferative and antiproliferative effects of interferon-gamma and tumor necrosis factor-alpha on cell lines derived from cervical and ovarian malignancies

    SciTech Connect

    Mutch, D.G.; Massad, L.S.; Kao, M.S.; Collins, J.L. )

    1990-12-01

    Four human cell lines derived from cervical carcinomas (ME-180, SiHa, HT-3, and MS751) and three human cell lines derived from ovarian carcinomas (SK-OV-3, Caov-3, and NIH:OVCAR-3) were analyzed in vitro to determine the effect of recombinant interferon-gamma and recombinant human tumor necrosis factor-alpha on cell growth and survival. The effects of interferon-gamma, tumor necrosis factor-alpha, and both interferon-gamma and tumor necrosis factor-alpha on cell growth were measured after 24 and 72 hours of incubation by the incorporation of chromium 51. The results of this analysis showed that all seven cell lines were resistant to the antiproliferative action of tumor necrosis factor-alpha, that the growth of most cell lines was inhibited by interferon-gamma by 72 hours of incubation, and that after 72 hours of incubation all cell lines demonstrated a synergistic antiproliferative response to the combination of interferon-gamma and tumor necrosis factor-alpha. However, the effects of these cytokines on cell growth were found to differ among cell lines and varied with the concentration and the duration of incubation. The growth of one cell line (Caov-3) was stimulated by both tumor necrosis factor-alpha and interferon-gamma. These results suggest that the clinical effects of these cytokines on the growth of gynecologic cancers may be more complex than previously supposed.

  13. [Phalanges necrosis--a rare manifestation of "hand-foot" syndrome induced by gemcitabine used in the second--line therapy for progressive ovarian cancer. A case report].

    PubMed

    Gołka, Karolina Agnieszka; Kobierski, Juliusz; Milczek, Tomasz; Emerich, Janusz

    2009-04-01

    "Hand-foot" syndrome is a well-documented, dermatologic reaction after several chemotherapeutic agents with wild spectrum of symptoms. To the best of our knowledge, palmar-plantar erythrodysesthesia syndrome--presented as irreversible cytotoxic side effect induced by gemcitabine alone--has not been reported so far. We present a case of a patient with a history of peripheral sensory neuropathy who developed a painless finger necrosis caused by gemcitabine used in the second-line therapy for progressive ovary cancer.

  14. A therapy inactivating the tumor angiogenic factors.

    PubMed

    Morales-Rodrigo, Cristian

    2013-02-01

    This paper is devoted to a nonlinear system of partial differential equations modeling the effect of an anti-angiogenic therapy based on an agent that binds to the tumor angiogenic factors. The main feature of the model under consideration is a nonlinear flux production of tumor angiogenic factors at the boundary of the tumor. It is proved the global existence for the nonlinear system and the effect in the large time behavior of the system for high doses of the therapeutic agent.

  15. Fundamental study on photodynamic therapy for atrial fibrillation: effect of photosensitization reaction parameters on myocardial necrosis in vitro

    NASA Astrophysics Data System (ADS)

    Ogawa, Emiyu; Ito, Arisa; Arai, Tsunenori

    2012-03-01

    We studied necrotic cell death effect on myocardial cells with photosensitizer existed outside the cells varying photosensitization reaction parameters widely in vitro. We have developed non-thermal ablator with the application of photosensitization reaction for atrial fibrillation. Since laser irradiation is applied shortly after photosensitizer injection, the photosensitization reaction is induced outside the cells. The interaction for the myocardial cells by the photosensitization reaction is not well understood yet on various photosensitization reaction parameters. Rat myocardial cells were cultured in 96 well plates for 7 days. The photosensitization reaction was applied with talaporfin sodium (NPe6) and the semiconductor laser of 663nm wavelength. The average drug light interval was set 8 mins. The photosensitizer concentration and radiant exposure were varied from 5 to 40 μg/ml and 1.2 to 60 J/cm2, respectively. The well bottom was irradiated by the red laser with irradiance of 293 mW/cm2. The photosensitizer fluorescence was monitored during the photosensitization reaction. Alive cell rate was measured by WST assay after 2 hours from the irradiation. In the case of the photosensitizer concentration of 10 μg/ml, the myocardial cells were almost alive even thought 60 J/cm2 in the radiant exposure was applied. In the 15 μg/ml case, the alive cell rate was almost linear relation to the photosensitizer concentration and radiant exposure. We obtained that the threshold for myocardial cell necrosis on the photosensitizer concentration was around 15 μg/ml with 20 J/cm2 in the radiant exposure. This threshold on the photosensitizer concentration was similar to the reported threshold for cancer therapy.

  16. Tumor Necrosis Factor Related Apoptosis Inducing Ligand (Trail) in endothelial response to biomechanical and biochemical stresses in arteries.

    PubMed

    D'Auria, F; Centurione, L; Centurione, M A; Angelini, A; Di Pietro, R

    2015-11-01

    Shear stress is determined by three physical components described in a famous triad: blood flow, blood viscosity and vessel geometry. Through the direct action on endothelium, shear stress is able to radically interfere with endothelial properties and the physiology of the vascular wall. Endothelial cells (ECs) have also to sustain biochemical stresses represented by chemokines, growth factors, cytokines, complement, hormones, nitric oxide (NO), oxygen and reactive oxygen species (ROS). Many growth factors, cytokines, chemokines, hormones, and chemical substances, like NO, act and regulate endothelium functions and homeostasis. Among these cytokines Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) has been assigned a regulatory role in ECs physiology and physiopathology. Thus, the aim of this review is to provide a general overview of the endothelial response pathways after different types of biomechanical and biochemical stress in in vitro models and to analyze the crucial role of TRAIL under pathological conditions of the cardiocirculatory system like atherosclerosis, coronary artery disease, and diabetes.

  17. Stem cell therapy for the treatment of early stage avascular necrosis of the femoral head: a systematic review

    PubMed Central

    2014-01-01

    Background Avascular necrosis (AVN) of the femoral head (FH) is believed to be caused by a multitude of etiologic factors and is associated with significant morbidity in younger populations. Eventually, the disease progresses and results in FH collapse. Thus, a focus on early disease management aimed at joint preservation by preventing or delaying progression is key. The use of stem cells (SC) for the treatment of AVN of the FH has been proposed. We undertook a systematic review of the medical literature examining the use of SC for the treatment of early stage (precollapse) AVN of the FH, in both pre-clinical and clinical studies. Methods Data collected included: Pre-clinical studies – model of AVN, variety and dosage of SC, histologic and imaging analyses. Clinical studies – study design, classification and etiology of AVN, SC dosage and treatment protocol, incidence of disease progression, patient reported outcomes, volume of necrotic lesion and hip survivorship. Results In pre-clinical studies, the use of SC uniformly demonstrated improvements in osteogenesis and angiogenesis, yet source of implanted SC was variable. In clinical studies, groups treated with SC showed significant improvements in patient reported outcomes; however hip survivorship was not affected. Discrepancies regarding dose of SC, AVN etiology and disease severity were present. Conclusions Routine use of this treatment method will first require further research into dose and quality optimization as well as confirmed improvements in hip survivorship. PMID:24886648

  18. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder.

    PubMed

    Haapakoski, Rita; Mathieu, Julia; Ebmeier, Klaus P; Alenius, Harri; Kivimäki, Mika

    2015-10-01

    Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and PsychInfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d=0.54, p<0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d=0.47, p<0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-α levels and major depression (d=0.40, p=0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1β levels and major depression (d=-0.05, p=0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-α, interleukin-1β and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression.

  19. Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model.

    PubMed Central

    Costelli, P; Carbó, N; Tessitore, L; Bagby, G J; Lopez-Soriano, F J; Argilés, J M; Baccino, F M

    1993-01-01

    Rats bearing the Yoshida AH-130 ascites hepatoma showed enhanced fractional rates of protein degradation in gastrocnemius muscle, heart, and liver, while fractional synthesis rates were similar to those in non-tumor bearing rats. This hypercatabolic pattern was associated with marked perturbations of the hormonal homeostasis and presence of tumor necrosis factor in the circulation. The daily administration of a goat anti-murine TNF IgG to tumor-bearing rats decreased protein degradation rates in skeletal muscle, heart, and liver as compared with tumor-bearing rats receiving a nonimmune goat IgG. The anti-TNF treatment was also effective in attenuating early perturbations in insulin and corticosterone homeostasis. Although these results suggest that tumor necrosis factor plays a significant role in mediating the changes in protein turnover and hormone levels elicited by tumor growth, the inability of such treatment to prevent a reduction in body weight implies that other mediators or tumor-related events were also involved. PMID:8254032

  20. Magnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn's disease treated with anti-tumor necrosis factor antibodies.

    PubMed

    Eder, Piotr; Michalak, Michal; Katulska, Katarzyna; Lykowska-Szuber, Liliana; Krela-Kazmierczak, Iwona; Stawczyk-Eder, Kamila; Klimczak, Katarzyna; Szymczak, Aleksandra; Linke, Krzysztof

    2015-01-01

    The aim of the study was to assess the role of magnetic resonance enterography (MRE) in predicting one-year efficacy of anti-tumor necrosis factor antibodies--infliximab (IFX), adalimumab (ADA) in Crohn's disease (CD) patients primarily responding to therapy. We performed retrospective analysis among 61 CD patients who had undergone a successful IFX/ADA induction therapy and were treated with maintenance doses. All patients underwent MRE at week 0. We assessed which MRE features were predictive for steroid-free remission at week 52, and which were associated with a secondary loss of response. 44 patients were in steroid-free remission at week 52, 17--were secondary non-responders. The ROC curve showed that bowel thickening with contrast enhancement analyzed together at week 0 were associated with steroid-free remission at week 52 (p = 0.01; AUC 0.67). Bowel stenosis with or without prestenotic dilatation [OR 5.8 (95% CI 1.4-25) and 2.4 (95% CI 1.2 - 5) respectively; p = 0.01] and the presence of intra-abdominal fistulas [OR 1.4 (95% CI 1.1-2); p=0.004] were related to secondary non-response. A high baseline inflammatory activity detected by MRE predicts one-year response in CD after IFX/ADA. In case of bowel stenosis, intra-abdominal fistulas, other therapeutic options should be considered.

  1. Adalimumab treatment leads to reduction of tissue tumor necrosis factor-alpha correlated with venous leg ulcer improvement: a pilot study.

    PubMed

    Fox, Joshua D; Baquerizo-Nole, Katherine L; Keegan, Brian R; Macquhae, Flor; Escandon, Julia; Espinosa, Aliette; Perez, Carmen; Romanelli, Paolo; Kirsner, Robert S

    2016-10-01

    Venous leg ulcers (VLUs) have higher tumor necrosis factor-α (TNF-α) levels compared with normal skin. Refractory VLUs of long duration have higher TNF-α levels compared with VLUs of shorter duration. As up to 75% of VLUs fail to heal with standard care, we sought to evaluate the role of anti-TNF-α therapy for patients with refractory VLUs. Evaluable data were obtained in four of five subjects with recalcitrant VLUs treated with 80 mg of subcutaneous adalimumab at week 0 and with 40 mg at week 2 along with compression therapy and were followed-up for 6 weeks. Wound biopsies taken at weeks 0 and 4 were stained with anti-TNF-α antibodies. Average 4-week percent wound size reduction was 20.5% ± 6.4%. Two patients had wound size reduction more than 25%, and their percent wound size reduction correlated to percent TNF-α staining score reductions (P = 0.02, R(2) = 0.999). VLU TNF-α level decrease 4 weeks post-adalimumab treatment correlated with wound healing.

  2. Tumour necrosis factor-α plus interleukin-10 low producer phenotype predicts acute kidney injury and death in intensive care unit patients

    PubMed Central

    Dalboni, M A; Quinto, B M R; Grabulosa, C C; Narciso, R; Monte, J C; Durão, M; Rizzo, L; Cendoroglo, M; Santos, O P; Batista, M C

    2013-01-01

    Genetic polymorphism studies of cytokines may provide an insight into the understanding of acute kidney injury (AKI) and death in intensive care unit (ICU) patients. The aim of this study was to investigate whether the genetic polymorphisms of −308 G < A tumour necrosis factor (TNF)-α, −174 G > C interleukin (IL)-6 and −1082 G > A IL-10 may predispose ICU patients to the development of AKI and/or death. In a prospective nested case–control study, 303 ICU patients and 244 healthy individuals were evaluated. The study group included ICU patients who developed AKI (n = 139) and 164 ICU patients without AKI. The GG genotype of TNF-α (low producer phenotype) was significantly lower in the with AKI than without AKI groups and healthy individuals (55 versus 62 versus 73%, respectively; P = 0·01). When genotypes were stratified into four categories of TNF-α/IL-10 combinations, it was observed that low TNF-α plus low IL-10 producer phenotypes were more prevalent in patients with AKI, renal replacement therapy and death (P < 0·05). In logistic regression analysis, low TNF-α producer plus low IL-10 producer phenotypes remained as independent risk factors for AKI and/or death [odds ratio (OR) = 2·37, 95% confidence interval (CI): 1·16–4·84; P = 0·02] and for renal replacement therapy (RRT) and/or death (OR = 3·82, 95% CI: 1·19–12·23; P = 0·02). In this study, the combination of low TNF-α plus low IL-10 producer phenotypes was an independent risk factor to AKI and/or death and RRT and/or death in critically ill patients. Our results should be validated in a larger prospective study with long-term follow-up to emphasize the combination of these genotypes as potential risk factors to AKI in critically ill patients. PMID:23607333

  3. Prolactin increases tumor necrosis factor alpha expression in peripheral CD14 monocytes of patients with rheumatoid arthritis.

    PubMed

    Tang, Chun; Li, Yun; Lin, Xiaojun; Ye, Jinghua; Li, Weinian; He, Zhixiang; Li, Fangfei; Cai, Xiaoyan

    2014-07-01

    Tumor necrosis factor (TNF)-α is one of the major proinflammatory mediators of rheumatic arthritis (RA); the regulatory factors for TNF-α release is not fully understood. This study aims to investigate the role of prolactin receptor (PRLR) activation in regulating the expression and release of TNF-α from CD14(+) monocytes. The results showed that the expression of PRLR was detectable in CD14(+) monocytes of healthy subjects, which was markedly increased in RA patients. Exposure to PRL in the culture increased the expression and release of TNF-α from CD14(+) monocytes, which was abolished by the PRLR gene silencing or blocking the mitogen activated protein (MAPK) pathway. We conclude that exposure to PRL increases TNF-α release from CD14(+) monocytes of RA patients, which can be abolished by PRLR gene silencing or treating with MAPK inhibitor.

  4. Late Consequential Surgical Bed Soft Tissue Necrosis in Advanced Oropharyngeal Squamous Cell Carcinomas Treated With Transoral Robotic Surgery and Postoperative Radiation Therapy

    SciTech Connect

    Lukens, J. Nicholas; Lin, Alexander; Gamerman, Victoria; Mitra, Nandita; Grover, Surbhi; McMenamin, Erin M.; Weinstein, Gregory S.; O'Malley, Bert W.; Cohen, Roger B.; Orisamolu, Abimbola; Ahn, Peter H.; Quon, Harry

    2014-08-01

    Purpose: A subset of patients with oropharyngeal squamous cell carcinoma (OP-SCC) managed with transoral robotic surgery (TORS) and postoperative radiation therapy (PORT) developed soft tissue necrosis (STN) in the surgical bed months after completion of PORT. We investigated the frequency and risk factors. Materials and Methods: This retrospective analysis included 170 consecutive OP-SCC patients treated with TORS and PORT between 2006 and 2012, with >6 months' of follow-up. STN was defined as ulceration of the surgical bed >6 weeks after completion of PORT, requiring opioids, biopsy, or hyperbaric oxygen therapy. Results: A total of 47 of 170 patients (28%) had a diagnosis of STN. Tonsillar patients were more susceptible than base-of-tongue (BOT) patients, 39% (41 of 104) versus 9% (6 of 66), respectively. For patients with STN, median tumor size was 3.0 cm (range 1.0-5.6 cm), and depth of resection was 2.2 cm (range 1.0-5.1 cm). Median radiation dose and dose of fraction to the surgical bed were 6600 cGy and 220 cGy, respectively. Thirty-one patients (66%) received concurrent chemotherapy. Median time to STN was 2.5 months after PORT. All patients had resolution of STN after a median of 3.7 months. Multivariate analysis identified tonsillar primary (odds ratio [OR] 4.73, P=.01), depth of resection (OR 3.12, P=.001), total radiation dose to the resection bed (OR 1.51 per Gy, P<.01), and grade 3 acute mucositis (OR 3.47, P=.02) as risk factors for STN. Beginning May 2011, after implementing aggressive avoidance of delivering >2 Gy/day to the resection bed mucosa, only 8% (2 of 26 patients) experienced STN (all grade 2). Conclusions: A subset of OP-SCC patients treated with TORS and PORT are at risk for developing late consequential surgical bed STN. Risk factors include tonsillar location, depth of resection, radiation dose to the surgical bed, and severe mucositis. STN risk is significantly decreased with carefully avoiding a radiation dosage of >2 Gy/day to the

  5. Interleukin-1, tumor necrosis factor-alpha, and transforming growth factor-beta 1 and integrative meniscal repair: influences on meniscal cell proliferation and migration

    PubMed Central

    2011-01-01

    Introduction Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are up-regulated in injured and osteoarthritic knee joints. IL-1 and TNF-α inhibit integrative meniscal repair; however, the mechanisms by which this inhibition occurs are not fully understood. Transforming growth factor-β1 (TGF-β1) increases meniscal cell proliferation and accumulation, and enhances integrative meniscal repair. An improved understanding of the mechanisms modulating meniscal cell proliferation and migration will help to improve approaches for enhancing intrinsic or tissue-engineered repair of the meniscus. The goal of this study was to examine the hypothesis that IL-1 and TNF-α suppress, while TGF-β1 enhances, cellular proliferation and migration in cell and tissue models of meniscal repair. Methods A micro-wound assay was used to assess meniscal cell migration and proliferation in response to the following treatments for 0, 24, or 48 hours: 0 to 10 ng/mL IL-1, TNF-α, or TGF-β1, in the presence or absence of 10% serum. Proliferated and total cells were fluorescently labeled and imaged using confocal laser scanning microscopy and the number of proliferated, migrated, and total cells was determined in the micro-wound and edges of each image. Meniscal cell proliferation was also assessed throughout meniscal repair model explants treated with 0 or 10 ng/mL IL-1, TNF-α, or TGF-β1 for 14 days. At the end of the culture period, biomechanical testing and histological analyses were also performed. Statistical differences were assessed using an ANOVA and Newman-Keuls post hoc test. Results IL-1 and TNF-α decreased cell proliferation in both cell and tissue models of meniscal repair. In the presence of serum, TGF-β1 increased outer zone cell proliferation in the micro-wound and in the cross section of meniscal repair model explants. Both IL-1 and TNF-α decreased the integrative shear strength of repair and extracellular matrix deposition in the meniscal repair model system

  6. Phytochemicals of Aristolochia tagala and Curcuma caesia exert anticancer effect by tumor necrosis factor-α-mediated decrease in nuclear factor kappaB binding activity

    PubMed Central

    Hadem, Khetbadei Lysinia Hynniewta; Sharan, Rajeshwar Nath; Kma, Lakhan

    2015-01-01

    Rationale: The active compounds or metabolites of herbal plants exert a definite physiological action on the human body and thus are widely used in human therapy for various diseases including cancer. Previous studies by our group have reported the anticarcinogenic properties of the two herbal plants extracts (HPE) of Aristolochia tagala (AT) Cham. and Curcuma caesia (CC) Roxb. in diethylnitrosamine-induced mouse liver cancer in vivo. The anticarcinogenic properties of these extracts may be due to the active compounds present in them. Objectives: Our objective was to analyze the phytochemical constituents present in AT and CC, to assay their antioxidant properties and to determine their role in a possible intervention on tumor progression. Materials and Methods: Qualitative and quantitative analysis of constituent with anticancer properties present in the crude methanol extract of the two plants CC and AT was carried out following standard methods. Separation of the phytochemical compounds was done by open column chromatography. The extracts were eluted out with gradients of chloroform-methanol solvents. Ultraviolet-visible spectra of individual fractions were recorded, and the fractions were combined based on their λmax. The free radical scavenging activity of crude extracts and fractions obtained was also determined; the radical scavenging activity was expressed as IC50. High-performance thin layer chromatography (HPTLC) analysis of fractionated compounds was carried out to identify partially the phytochemical compounds. The anti-inflammatory and anticancer activity of AT and CC extracts was studied in DEN induced BALB/c mice by analyzing the tumor necrosis factor-α (TNF-α) levels in serum and the nuclear factor kappaB (NF-κB) binding activity in nuclear extracts of the liver. Results: It was observed that both AT and CC contained compounds such as phenolics, tannins, flavonoids, terpenoids, etc., and both extracts exhibited antioxidant capacity. HPTLC

  7. Randomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System

    SciTech Connect

    Levin, Victor A.; Bidaut, Luc; Hou, Ping; Kumar, Ashok J.; Wefel, Jeffrey S.; Bekele, B. Nebiyou; Prabhu, Sujit; Loghin, Monica; Gilbert, Mark R.; Jackson, Edward F.

    2011-04-01

    Purpose: To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain. Methods and Materials: A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression. Results: The volumes of necrosis estimated on T{sub 2}-weighted fluid-attenuated inversion recovery and T{sub 1}-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T{sub 2}-weighted fluid-attenuated inversion recovery and T{sub 1}-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients-and none of the placebo-treated patients-showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses. Conclusion: The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with

  8. Ubiquitination of Tumor Necrosis Factor Receptor-associated Factor 4 (TRAF4) by Smad Ubiquitination Regulatory Factor 1 (Smurf1) Regulates Motility of Breast Epithelial and Cancer Cells*

    PubMed Central

    Wang, Xiangchun; Jin, Chaoyang; Tang, Yi; Tang, Liu-Ya; Zhang, Ying E.

    2013-01-01

    Smad ubiquitin regulatory factors (Smurfs) are HECT-domain ubiquitin E3 ligases that regulate diverse cellular processes, including normal and tumor cell migration. However, the underlying mechanism of the Smurfs' role in cell migration is not fully understood. Here we show that Smurf1 induces ubiquitination of tumor necrosis factor receptor-associated factor 4 (TRAF4) at K190. Using the K190R mutant of TRAF4, we demonstrate that Smurf1-induced ubiquitination is required for proper localization of TRAF4 to tight junctions in confluent epithelial cells. We further show that TRAF4 is essential for the migration of both normal mammary epithelial and breast cancer cells. The ability of TRAF4 to promote cell migration is also dependent on Smurf1-mediated ubiquitination, which is associated with Rac1 activation by TRAF4. These results reveal a new regulatory circuit for cell migration, consisting of Smurf1-mediated ubiquitination of TRAF4 and Rac1 activation. PMID:23760265

  9. Interleukin-8 is a major neutrophil chemotactic factor derived from cultured human gingival fibroblasts stimulated with interleukin-1 beta or tumor necrosis factor alpha.

    PubMed Central

    Takashiba, S; Takigawa, M; Takahashi, K; Myokai, F; Nishimura, F; Chihara, T; Kurihara, H; Nomura, Y; Murayama, Y

    1992-01-01

    Inflammatory mediators produced by cells in the gingiva have been implicated in the initiation and progression of periodontal disease, a common infectious disease. In this study, we examined the biological activity of neutrophil chemotactic factors and the kinetics of expression of interleukin-8 (IL-8) mRNA derived from normal gingival fibroblasts in response to inflammatory mediators in an in vitro model. Gingival fibroblasts stimulated by either recombinant human interleukin-1 beta or recombinant human tumor necrosis factor alpha produced neutrophil chemotactic factors after 4 h, whereas expression of cell-derived IL-8 mRNA was detected within 1 h after stimulation. Furthermore, in a neutralization assay, rabbit anti-recombinant human IL-8 antiserum inhibited neutrophil chemotactic activity to basal levels. These results provide evidence that gingival fibroblasts synthesize potent chemotactic factors such as IL-8 in the presence of the inflammatory mediators interleukin-1 beta and tumor necrosis factor alpha. The activity of these factors may contribute to neutrophil-mediated processes in the pathogenesis of periodontal disease. Images PMID:1452358

  10. A therapy inactivating the tumor angiogenic factors.

    PubMed

    Morales-Rodrigo, Cristian

    2013-02-01

    This paper is devoted to a nonlinear system of partial differential equations modeling the effect of an anti-angiogenic therapy based on an agent that binds to the tumor angiogenic factors. The main feature of the model under consideration is a nonlinear flux production of tumor angiogenic factors at the boundary of the tumor. It is proved the global existence for the nonlinear system and the effect in the large time behavior of the system for high doses of the therapeutic agent. PMID:23311368

  11. Tumor necrosis factor and immune interferon synergistically increase transcription of HLA class I heavy- and light-chain genes in vascular endothelium

    SciTech Connect

    Johnson, D.R.; Pober, J.S. )

    1990-07-01

    Tumor necrosis factor and immune interferon synergistically increase cell-surface expression of class I major histocompatibility complex molecules in cultured human endothelial cells. The authors report that tumor necrosis factor and interferon {gamma} each independently increase mRNA levels and together cause a greater-than-additive (i.e., synergistic) increase in steady-state mRNA levels and transcriptional rates of the class I heavy- and light-chain genes. HLA heavy-chain mRNA is equally stable in cytokine-treated and -untreated endothelial cells. Interferon {gamma} does not increase tumor necrosis factor receptor number or affinity on human endothelial cells. They conclude that the synergistic increase in class I major histocompatibility complex cell-surface expression results principally from the synergistic increase in transcriptional rates. They propose that this increase is caused by the cooperative binding of independently activated transcription factors to the promoter/enhancer sequences of class I genes.

  12. An overview of economic evaluations for drugs used in rheumatoid arthritis : focus on tumour necrosis factor-alpha antagonists.

    PubMed

    Bansback, Nick J; Regier, Dean A; Ara, Roberta; Brennan, Alan; Shojania, Kamran; Esdaile, John M; Anis, Aslam H; Marra, Carlo A

    2005-01-01

    Rheumatoid arthritis (RA) is a chronic, progressive, inflammatory disease that affects approximately 0.5-1% of the adult population. The introduction of new disease-modifying antirheumatic drugs (DMARDs) such as leflunomide, anakinra and the tumour necrosis factor (TNF)-alpha antagonists (infliximab, etanercept and adalimumab) have transformed the management of RA. In particular, the last class of agents has generated substantial controversy. Costing between 16,000 US dollars and 20,000 US dollars per patient-year (2001 values), the potential greater efficacy of treatment with TNFalpha antagonists comes at much higher drug costs, making these agents natural candidates for cost-effectiveness analyses (CEAs).A MEDLINE search (until 31 January 2004) identified six original CEAs evaluating TNFalpha antagonists in RA. The aim of a CEA is to facilitate the allocation of scarce health resources and to inform policy decisions. However, to enhance the reliability and relevance of these analyses to policy makers, there must be similarity between the methodologies used. Recently, the OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) group produced a document to define such a reference case; the OMERACT document was used as a foundation to structure comparisons and highlight discrepancies. The methodologies employed in each analysis differed; in particular, disparate time horizons, comparators, quantities of drug and treatment sequences prohibit the comparison of cost effectiveness between studies. Outcomes also differed between the analyses. Most reported health-related quality of life (HR-QOL) in quality-adjusted life-years (QALYs). The QALYs metric was based on preference scores that were typically derived from linear regressions using the Health Assessment Questionnaire (HAQ). However, models also used American College of Rheumatology (ACR) criteria, as well as the disease activity score (DAS). Common to all studies was the lack of data from long

  13. Elevated CO2 selectively inhibits interleukin-6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage

    PubMed Central

    Wang, Naizhen; Gates, Khalilah L.; Trejo, Humberto; Favoreto, Silvio; Schleimer, Robert P.; Sznajder, Jacob I.; Beitel, Greg J.; Sporn, Peter H. S.

    2010-01-01

    Elevated blood and tissue CO2, or hypercapnia, is common in severe lung disease. Patients with hypercapnia often develop lung infections and have an increased risk of death following pneumonia. To explore whether hypercapnia interferes with host defense, we studied the effects of elevated PCO2 on macrophage innate immune responses. In differentiated human THP-1 macrophages and human and mouse alveolar macrophages stimulated with lipopolysaccharide (LPS) and other Toll-like receptor ligands, hypercapnia inhibited expression of tumor necrosis factor and interleukin (IL)-6, nuclear factor (NF)-κB-dependent cytokines critical for antimicrobial host defense. Inhibition of IL-6 expression by hypercapnia was concentration dependent, rapid, reversible, and independent of extracellular and intracellular acidosis. In contrast, hypercapnia did not down-regulate IL-10 or interferon-β, which do not require NF-κB. Notably, hypercapnia did not affect LPS-induced degradation of IκBα, nuclear translocation of RelA/p65, or activation of mitogen-activated protein kinases, but it did block IL-6 promoter-driven luciferase activity in mouse RAW 264.7 macrophages. Elevated PCO2 also decreased phagocytosis of opsonized polystyrene beads and heat-killed bacteria in THP-1 and human alveolar macrophages. By interfering with essential innate immune functions in the macrophage, hypercapnia may cause a previously unrecognized defect in resistance to pulmonary infection in patients with advanced lung disease.—Wang, N., Gates, K. L., Trejo, H., Favoreto, Jr., S., Schleimer, R. P., Sznajder, J. I., Beitel, G. J., Sporn, P. H. S. Elevated CO2 selectively inhibits interleukin-6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage. PMID:20181940

  14. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis.

    PubMed Central

    Yoshida, S; Ono, M; Shono, T; Izumi, H; Ishibashi, T; Suzuki, H; Kuwano, M

    1997-01-01

    Tumor necrosis factor alpha (TNF-alpha) is a macrophage/monocyte-derived polypeptide which modulates the expression of various genes in vascular endothelial cells and induces angiogenesis. However, the underlying mechanism by which TNF-alpha mediates angiogenesis is not completely understood. In this study, we assessed whether TNF-alpha-induced angiogenesis is mediated through TNF-alpha itself or indirectly through other TNF-alpha-induced angiogenesis-promoting factors. Cellular mRNA levels of interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors were increased after the treatment of human microvascular endothelial cells with TNF-alpha (100 U/ml). TNF-alpha-dependent tubular morphogenesis in vascular endothelial cells was inhibited by the administration of anti-IL-8, anti-VEGF, and anti-bFGF antibodies, and coadministration of all three antibodies almost completely abrogated tubular formation. Moreover, treatment with Sp1, NF-kappaB, and c-Jun antisense oligonucleotides inhibited TNF-alpha-dependent tubular morphogenesis by microvascular endothelial cells. Administration of a NF-kappaB antisense oligonucleotide almost completely inhibited TNF-alpha-dependent IL-8 production and partially abrogated TNF-alpha-dependent VEGF production, and an Sp1 antisense sequence partially inhibited TNF-alpha-dependent production of VEGF. A c-Jun antisense oligonucleotide significantly inhibited TNF-alpha-dependent bFGF production but did not affect the production of IL-8 and VEGF. Administration of an anti-IL-8 or anti-VEGF antibody also blocked TNF-alpha-induced neovascularization in the rabbit cornea in vivo. Thus, angiogenesis by TNF-alpha appears to be modulated through various angiogenic factors, both in vitro and in vivo, and this pathway is controlled through paracrine and/or autocrine mechanisms. PMID:9199336

  15. Tumor necrosis factor alpha promotes the expression of immunosuppressive proteins and enhances the cell growth in a human bone marrow-derived stem cell culture

    SciTech Connect

    Miettinen, Johanna A.; Pietilae, Mika; Salonen, Riikka J.; Ohlmeier, Steffen; Ylitalo, Kari; Huikuri, Heikki V.; Lehenkari, Petri

    2011-04-01

    Mesenchymal stem cells (MSCs) are widely used in experimental treatments for various conditions that involve normal tissue regeneration via inflammatory repair. It is known that MSCs can secrete multiple soluble factors and suppress inflammation. Even though the effect of MSCs on inflammation has been extensively studied, the effect of inflammation on MSCs is poorly understood. One of the major cytokines released at the site of inflammation is tumor necrosis factor alpha (TNF-{alpha}) which is known to induce MSC invasion and proliferation. Therefore, we wanted to test the effects of TNF-{alpha} exposure on MSCs derived from human bone marrow. We found, as expected, that cell proliferation was significantly enhanced during TNF-{alpha} exposure. However, according to the cell surface marker analysis, the intensity of several antigens in the minimum criteria panel for MSCs proposed by International Society of Cellular Therapy (ISCT) was decreased dramatically, and in certain cases, the criteria for MSCs were not fulfilled. In addition, TNF-{alpha} exposure resulted in a significant but transient increase in human leukocyte antigen and CD54 expression. Additional proteomic analysis by two-dimensional difference gel electrophoresis and mass spectrometry revealed three proteins whose expression levels decreased and 8 proteins whose expression levels increased significantly during TNF-{alpha} exposure. The majority of these proteins could be linked to immunosuppressive and signalling pathways. These results strongly support reactive and immunosuppressive activation of MSCs during TNF-{alpha} exposure, which might influence MSC differentiation stage and capacity.

  16. Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype

    PubMed Central

    Jin, Ping; Zhao, Yuanlong; Liu, Hui; Chen, Jinguo; Ren, Jiaqiang; Jin, Jianjian; Bedognetti, Davide; Liu, Shutong; Wang, Ena; Marincola, Francesco; Stroncek, David

    2016-01-01

    Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-α and IFN-γ stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-γ and TNF-α was synergistic and induced a transcriptome most similar to that found in MSCs stimulated with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-γ and TNF-α polarized uniformly to this phenotype. The combination of IFN-γ and TNF-α results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-γ and TNF-α released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment. PMID:27211104

  17. Effects of Tumour Necrosis Factor Antagonists on Insulin Sensitivity/Resistance in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

    PubMed Central

    2015-01-01

    Objective Beyond the joints, TNFi (tumour necrosis factor inhibitor) therapy may confer systemic benefits in rheumatoid arthritis (RA). Several studies have investigated the role of TNFi on insulin resistance/sensitivity (IR/IS). This question is of general interest given the emerging evidence linking inflammation and insulin resistance. The main aim of this review was to summarise the published data and to determine the effects of TNFi on IR/IS. Methods We searched the PubMed and ISI Web of Knowledge databases for studies which examined the effects of TNFi on IR/IS. The studies were assessed independently by two reviewers according to a pre-specified protocol. The data on Homeostatic Model Assessment for Insulin resistance (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI) were pooled and reported as standard difference in means (SDM) with 95% confidence interval (CI) using a random-effects model. Results A total of eight studies with 260 subjects met the selection criteria. The duration of the studies was from 8 weeks to 12 months. There was statistically significant reduction in HOMA index in six out of eight studies and four reported significant increment in QUICKI. The pooled analysis revealed significant reduction in HOMA [SDM-0.148, 95%CI[-0.278 to -0.017], p=0.026] and increment in QUICKI [SDM 0.312, 95%CI[0.019 to 0.606], p=0.037] with TNFi. Conclusion There is emerging evidence to support that TNFi therapy improves IS and reduces IR in RA. Further, well conducted trials are needed to determine if such effects translate to lower incidence of diabetes in RA or other autoimmune conditions on biologic therapy. PMID:26110878

  18. 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

  19. Anti-tumour necrosis factor treatment increases circulating T helper type 17 cells similarly in different types of inflammatory arthritis

    PubMed Central

    Hull, D N; Williams, R O; Pathan, E; Alzabin, S; Abraham, S; Taylor, P C

    2015-01-01

    We investigated changes in circulating T helper type 17 (Th17) cells following anti-tumour necrosis factor (TNF) in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients. Peripheral blood mononuclear cells (PBMC) were isolated from 25 RA, 15 AS and eight PsA patients at baseline 4 and 12 weeks after treatment, and Th17 cell frequencies were analysed using interleukin (IL)-17 enzyme-linked immunospot (ELISPOT) and flow cytometry. A significant increase in IL-17-producing cells was observed by ELISPOT in RA and AS patients at 12 weeks. Flow cytometry confirmed significant increases in CD4+IL-17+ cells at 12 weeks in RA and AS and 4 weeks in PsA patients. Anti-TNF treatment increases circulating Th17 cells in three different diseases. PMID:25766640

  20. 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.

  1. Increased liver apoptosis and tumor necrosis factor expression in Atlantic bluefin tuna (Thunnus thynnus) reared in the northern Adriatic Sea.

    PubMed

    Corriero, Aldo; Zupa, Rosa; Pousis, Chrysovalentinos; Santamaria, Nicoletta; Bello, Giambattista; Jirillo, Emilio; Carrassi, Michele; De Giorgi, Carla; Passantino, Letizia

    2013-06-15

    The Atlantic bluefin tuna Thunnus thynnus (ABFT) is intensely fished in the Mediterranean Sea to supply a prosperous capture-based mariculture industry. Liver apoptotic structures and tumor necrosis factor (TNF) gene expression were determined in: wild ABFT caught in the eastern Atlantic; juvenile ABFT reared in the central Adriatic Sea; juvenile ABFT reared in the northern Adriatic Sea; adult ABFT reared in the western Mediterranean. The highest density of liver apoptotic structures was found in the juveniles from the northern Adriatic. Two partial TNF cDNAs (TNF1 and TNF2) were cloned and sequenced. TNF1 gene expression was higher in juveniles than in adults. The highest expression of TNF2 was found in the juveniles from the northern Adriatic. These findings might be related to the juvenile exposure to environmental pollutants.

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

    PubMed Central

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

    2014-01-01

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

  3. Synergistic effects of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha: central monoamine, corticosterone, and behavioral variations.

    PubMed

    Brebner, K; Hayley, S; Zacharko, R; Merali, Z; Anisman, H

    2000-06-01

    The proinflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) influence neuroendocrine activity, promote central neurotransmitter alterations, and induce a constellation of symptoms collectively referred to as sickness behaviors. These cytokines may also elicit anxiety and anhedonia, and have been associated with psychological disturbances in humans. In the present investigation, systemic IL-1beta and TNF-alpha dose-dependently and synergistically disrupted consumption of a highly palatable food source (chocolate milk), possibly reflecting anorexia or anhedonia engendered by the treatments. As well, these cytokines synergistically increased plasma corticosterone levels. Although IL-1beta and TNF-alpha provoked variations of amine turnover in the hypothalamus, locus coeruleus, and central amygdala, synergistic effects were not evident in this respect. Nevertheless, in view of the central amine variations induced by the cytokines, it is suggested that immune activation may come to influence complex behavioral processes, as well as affective state. PMID:10788757

  4. Association study of the interleukin-1 gene complex and tumor necrosis factor alpha gene with suicide attempts.

    PubMed

    Sáiz, Pilar A; García-Portilla, Paz; Paredes, Begoña; Arango, Celso; Morales, Blanca; Alvarez, Victoria; Coto, Eliécer; Bascarán, María-Teresa; Bousoño, Manuel; Bobes, Julio

    2008-06-01

    To investigate the association between four functional polymorphisms in interleukin-1 (IL-1) [IL-1 alpha -889 C/T, IL-1 beta +3953 C/T, IL-1RA (86 bp)n] and tumor necrosis factor alpha (TNFalpha) (-308A/G) genes and suicide attempts. Distribution of the aforesaid polymorphisms was analyzed in 193 suicide attempters compared with 420 unrelated healthy controls from Asturias (Northern Spain). Genotypes were determined using standard methods. No significant differences were found in genotype or in allelic distribution of IL-1 alpha, IL-1 beta, IL-1RA, or TNFalpha gene polymorphisms. No relationship was found between genotypes and the impulsivity of the suicide attempt. Estimated IL-1 haplotype frequencies were similar in both groups (likelihood ratio test=13.26, df=14, P=0.506). Our data do not suggest that genetically determined changes in the IL-1 or TNFalpha genes confer increased susceptibility to suicidal behavior.

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

    PubMed

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

    2013-06-01

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

  6. Lysosomal serine protease CLN2 regulates tumor necrosis factor-alpha-mediated apoptosis in a Bid-dependent manner.

    PubMed

    Autefage, Hélène; Albinet, Virginie; Garcia, Virginie; Berges, Hortense; Nicolau, Marie-Laure; Therville, Nicole; Altié, Marie-Françoise; Caillaud, Catherine; Levade, Thierry; Andrieu-Abadie, Nathalie

    2009-04-24

    Apoptosis is a highly organized, energy-dependent program by which multicellular organisms eliminate damaged, superfluous, and potentially harmful cells. Although caspases are the most prominent group of proteases involved in the apoptotic process, the role of lysosomes has only recently been unmasked. This study investigated the role of the lysosomal serine protease CLN2 in apoptosis. We report that cells isolated from patients affected with late infantile neuronal ceroid lipofuscinosis (LINCL) having a deficient activity of CLN2 are resistant to the toxic effect of death ligands such as tumor necrosis factor (TNF), CD95 ligand, or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not to receptor-independent stress agents. CLN2-deficient cells exhibited a defect in TNF-induced Bid cleavage, release of cytochrome c, and caspase-9 and -3 activation. Moreover, extracts from CLN2-overexpressing cells or a CLN2 recombinant protein were able to catalyze the in vitro cleavage of Bid. Noteworthy, correction of the lysosomal enzyme defect of LINCL fibroblasts using a medium enriched in CLN2 protein enabled restoration of TNF-induced Bid and caspase-3 processing and toxicity. Conversely, transfection of CLN2-corrected cells with small interfering RNA targeting Bid abrogated TNF-induced cell death. Altogether, our study demonstrates that genetic deletion of the lysosomal serine protease CLN2 and the subsequent loss of its catalytic function confer resistance to TNF in non-neuronal somatic cells, indicating that CLN2 plays a yet unsuspected role in TNF-induced cell death. PMID:19246452

  7. Tumor necrosis factor α-induced protein-3 protects zinc transporter 8 against proinflammatory cytokine-induced downregulation

    PubMed Central

    Cheng, Liqing; Zhang, Dongmei; Chen, Bing

    2016-01-01

    Zinc transporter 8 (ZnT8) is exclusively expressed in the pancreatic islet and is essential for insulin crystallization, hexamerization and secretion. Tumor necrosis factor α-induced protein-3 (TNFAIP3) is a zinc finger protein that serves a major role in the negative feedback regulation of NF-κB signaling in response to multiple stimuli, and is a central regulator of immunopathology. Although the role of TNFAIP3 in diabetes has been extensively studied, its effect on ZnT8 has not been fully elucidated. The present study aimed to verify whether proinflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), are able to affect ZnT8 expression in islet cells. In addition, the study aimed to determine the effect of TNFAIP3 overexpression on cytokine-altered ZnT8 activity, considering its effect on NF-κB signaling. Cell-based studies using NIT-1 cells overexpressing TNFAIP3 were used to assess the effect of cytokines on ZnT8 and NF-κB activation, as well as the effect of TNFAIP3 on ZnT8 expression. Western blot analysis and immunofluorescence staining were employed to determine the protein expression and NF-κB activation, respectively. The results indicated that cytokine stimulation led to TNFAIP3 upregulation, ZnT8 downregulation and NF-κB activation. Furthermore, TNFAIP3 overexpression protected ZnT8 from cytokine-induced downregulation. In conclusion, the current results suggest that inflammation or TNFAIP3 dysfunction may be involved in the pathogenesis of diabetes via ZnT8 expression, besides from islet cell apoptosis. In addition, restricting inflammation and enhancing TNFAIP3 expression may exert a positive effect in diabetes prevention, treatment and pancreatic cell transplantation. PMID:27588072

  8. Tumor necrosis factor alpha induces the expression of transforming growth factor alpha and the epidermal growth factor receptor in human pancreatic cancer cells.

    PubMed Central

    Schmiegel, W; Roeder, C; Schmielau, J; Rodeck, U; Kalthoff, H

    1993-01-01

    Recombinant human tumor necrosis factor (TNF)-alpha increased the expression of epidermal growth factor receptor (EGFR) mRNA and protein in all of six human pancreatic carcinoma cell lines tested. In addition, TNF-alpha increased the expression of an EGFR ligand, transforming growth factor (TGF)-alpha, at the mRNA and protein level in all cell lines. Increased expression of EGFR protein was associated with elevated steady-state EGFR mRNA levels. Nuclear run-on analysis showed that increase in EGFR mRNA was due to an increased rate of transcription. Induction of EGFR mRNA expression by TNF-alpha was abrogated by cycloheximide but occurred independently of TNF-alpha-induced production of TGF-alpha protein. Protein kinase A or Gi-type guanine nucleotide-binding proteins were not involved in this process as assessed by using appropriate stimulators and inhibitors of these signal transduction pathways. By contrast, staurosporine, an inhibitor of protein kinase C, partially inhibited, and 4-bromophenacyl bromide, a phospholipase inhibitor, completely inhibited TNF-alpha-dependent EGFR mRNA expression. The phospholipase C-specific inhibitor tricyclodecan-9-yl xanthogenate did not alter TNF-alpha-dependent EGFR mRNA expression, suggesting that phospholipase A2 is involved in the modulation of EGFR expression by TNF-alpha. The simultaneous induction of a ligand/receptor system by TNF-alpha suggests that this cytokine modulates autocrine growth-regulatory pathways in pancreatic cancer cells. Images PMID:8430098

  9. Regulation of arterial-venous differences in tumor necrosis factor responsiveness of endothelial cells by anatomic context.

    PubMed

    Liu, Meng; Kluger, Martin S; D'Alessio, Alessio; García-Cardeña, Guillermo; Pober, Jordan S

    2008-04-01

    We analyzed tumor necrosis factor (TNF) responses of human umbilical artery and vein endothelial cells (HUAECs and HUVECs) in organ and cell culture. In organ culture, TNF induced expression of E-selectin, VCAM-1, and ICAM-1 on HUVECs but only ICAM-1 on HUAECs. Activation of nuclear factor-kappaB, c-jun, and ATF2 by TNF was comparable in HUAECs and HUVECs, whereas binding of transcription factors and p300 co-activator to the E-selectin enhancer was lower in HUAECs compared to HUVECs. In cell culture, HUAECs rapidly acquired inducible E-selectin and VCAM-1 whereas ICAM-1 inducibility decreased. Culture of HUVECs rapidly decreased TNF responses of all three genes. By 72 hours in cell culture, TNF-treated HUVECs and HUAECs showed comparable adhesion molecule induction and transcription factor binding to the E-selectin enhancer. Freshly isolated HUAECs expressed higher levels of Kruppel-like factor 2 (KLF2) than HUVECs, consistent with greater KLF2 induction by arterial levels of shear stress in vitro. KLF2 expression decreased rapidly in both cell types during culture. Transduction of HUVECs with KLF2 reduced TNF-mediated induction of E-selectin and VCAM-1 while increasing ICAM-1 induction and reduced transcription factor/co-activator binding to the E-selectin enhancer. In conclusion, the differential responses of HUAECs and HUVECs to TNF in organ culture correlate with transcription factor/co-activator binding to DNA and converge during cell culture. Flow-induced expression of KLF2 contributes to the in situ responses of HUAECs but not of HUVECs. PMID:18292233

  10. Thrombospondin-4, tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14: novel extracellular matrix modulating factors in cardiac remodelling.

    PubMed

    Mustonen, Erja; Ruskoaho, Heikki; Rysä, Jaana

    2012-12-01

    Cardiac remodelling is defined as changes in the size, shape, and function of the heart, which are most commonly caused by hypertension-induced left ventricular hypertrophy and myocardial infarction. Both neurohumoral and inflammatory factors have critical roles in the regulation of cardiac remodelling. A characteristic feature of cardiac remodelling is modification of the extracellular matrix (ECM), often manifested by fibrosis, a process that has vital consequences for the structure and function of the myocardium. In addition to established modulators of the ECM, the matricellular protein thrombospondin-4 (TSP-4) as well as the tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 has been recently shown to modulate cardiac ECM. TSP-4 null mice develop pronounced cardiac hypertrophy and fibrosis with defects in collagen maturation in response to pressure overload. TWEAK and Fn14 belong to the tumour necrosis factor superfamily of proinflammatory cytokines. Recently it was shown that elevated levels of circulating TWEAK via Fn14 critically affect the cardiac ECM, characterized by increasing fibrosis and cardiomyocyte hypertrophy in mice. Here we review the literature concerning the role of matricellular proteins and inflammation in cardiac ECM remodelling, with a special focus on TSP-4, TWEAK, and its receptor Fn14.

  11. [Tuberculosis in rheumatic patients treated with tumour necrosis factor alpha antagonists: the Portuguese experience].

    PubMed

    Fonseca, João Eurico; Canhão, Helena; Silva, Cândida; Miguel, Cláudia; Mediavilla, Maria Jesus; Teixeira, Ana; Castelão, Walter; Nero, Patrícia; Bernardes, Miguel; Bernardo, Alexandra; Mariz, Eva; Godinho, Fátima; Santos, Maria José; Bogas, Mónica; Oliveira, Margarida; Saavedra, Maria João; Barcelos, Anabela; Cruz, Margarida; Santos, Rui André; Maurício, Luís; Rodrigues, Mário; Figueiredo, Guilherme; Quintal, Alberto; Patto, José Vaz; Malcata, Armando; da Silva, José Canas; Araújo, Domingos; Ventura, Francisco; Branco, Jaime; Queiroz, Mário Viana

    2006-01-01

    In Portugal, 13 cases of tuberculosis (TB) were reported, in the period between 1999 and 2005, in 960 patients exposed to anti-TNFalpha treatment (1.35%), 8 females and 5 males. Mean age was 46.7 +/- 13.8 years. 9 patients had rheumatoid arthritis (RA), in 639 exposed patients (1.4%), 3 had ankylosing spondylitis (AS), in 200 exposed patients (1.5%) and 1 had psoriatic arthritis (PA), in 101 exposed patients (1%). The anti-TNFa used was in 8 cases infliximab (in 456 patients exposed, 1.5%), in 4 adalimumab (in 171 patients exposed, 2.3%) and in 1 etanercept (in 333 exposed, 0.3%). Treatment with a biological agent was started 11.1 +/- 8.7 months (min 3 and max 50) before TB onset. Tuberculin skin test (TST) was performed in 9 out of the 13 patients (the other 4 had started biological therapy before 2002). In 3 cases the TST response was 0 mm, in 3 less than 10 mm, in one was 14 mm and in two 20 mm. In the 3 cases with a TST response superior to 10 mm, isoniazid treatment 300 mg/d was prescribed, during 9 months. The time between first symptoms and TB diagnosis was 2.6 +/- 2.9 months. TB involvement was pulmonary in 6 patients, lymph node disease in 2, peritoneal and pulmonary in 2, osteoarticular in one case, lymph node disease and splenic in another and miliar TB in the last case. One death was reported; all of the other cases had a good outcome after anti-TB treatment. In two cases (one treated with adalimumab and the other with infliximab), paradoxical response to treatment occurred. None of the patients has restarted biological therapy after TB treatment.

  12. Dichotomy between RIP1- and RIP3-Mediated Necroptosis in Tumor Necrosis Factor-α–Induced Shock

    PubMed Central

    Linkermann, Andreas; Bräsen, Jan H; De Zen, Federica; Weinlich, Ricardo; Schwendener, Reto A; Green, Douglas R; Kunzendorf, Ulrich; Krautwald, Stefan

    2012-01-01

    Tumor necrosis factor receptor (TNFR) signaling may result in survival, apoptosis or programmed necrosis. The latter is called necroptosis if the receptor-interacting protein 1 (RIP1) inhibitor necrostatin-1 (Nec-1) or genetic knockout of RIP3 prevents it. In the lethal mouse model of TNFα-mediated shock, addition of the pan-caspase inhibitor zVAD-fmk (zVAD) accelerates time to death. Here, we demonstrate that RIP3-deficient mice are protected markedly from TNFα-mediated shock in the presence and absence of caspase inhibition. We further show that the fusion protein TAT-crmA, previously demonstrated to inhibit apoptosis, also prevents necroptosis in L929, HT29 and FADD-deficient Jurkat cells. In contrast to RIP3-deficient mice, blocking necroptosis by Nec-1 or TAT-crmA did not protect from TNFα/zVAD-mediated shock, but further accelerated time to death. Even in the absence of caspase inhibition, Nec-1 application led to similar kinetics. Depletion of macrophages, natural killer (NK) cells, granulocytes or genetic deficiency for T lymphocytes did not influence this model. Because RIP3-deficient mice are known to be protected from cerulein-induced pancreatitis (CIP), we applied Nec-1 and TAT-crmA in this model and demonstrated the deterioration of pancreatic damage upon addition of these substances. These data highlight the importance of separating genetic RIP3 deficiency from RIP1 inhibition by Nec-1 application in vivo and challenge the current definition of necroptosis. PMID:22371307

  13. Dichotomy between RIP1- and RIP3-mediated necroptosis in tumor necrosis factor-α-induced shock.

    PubMed

    Linkermann, Andreas; Bräsen, Jan H; De Zen, Federica; Weinlich, Ricardo; Schwendener, Reto A; Green, Douglas R; Kunzendorf, Ulrich; Krautwald, Stefan

    2012-01-01

    Tumor necrosis factor receptor (TNFR) signaling may result in survival, apoptosis or programmed necrosis. The latter is called necroptosis if the receptor-interacting protein 1 (RIP1) inhibitor necrostatin-1 (Nec-1) or genetic knockout of RIP3 prevents it. In the lethal mouse model of TNFα-mediated shock, addition of the pan-caspase inhibitor zVAD-fmk (zVAD) accelerates time to death. Here, we demonstrate that RIP3-deficient mice are protected markedly from TNFα-mediated shock in the presence and absence of caspase inhibition. We further show that the fusion protein TAT-crmA, previously demonstrated to inhibit apoptosis, also prevents necroptosis in L929, HT29 and FADD-deficient Jurkat cells. In contrast to RIP3-deficient mice, blocking necroptosis by Nec-1 or TAT-crmA did not protect from TNFα/zVAD-mediated shock, but further accelerated time to death. Even in the absence of caspase inhibition, Nec-1 application led to similar kinetics. Depletion of macrophages, natural killer (NK) cells, granulocytes or genetic deficiency for T lymphocytes did not influence this model. Because RIP3-deficient mice are known to be protected from cerulein-induced pancreatitis (CIP), we applied Nec-1 and TAT-crmA in this model and demonstrated the deterioration of pancreatic damage upon addition of these substances. These data highlight the importance of separating genetic RIP3 deficiency from RIP1 inhibition by Nec-1 application in vivo and challenge the current definition of necroptosis. PMID:22371307

  14. Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits.

    PubMed Central

    Mathison, J C; Wolfson, E; Ulevitch, R J

    1988-01-01

    Macrophages are induced by LPS to release a number of products that determine the host response during gram negative sepsis. To examine the role of one such substance, tumor necrosis factor (TNF), in mediating LPS-induced injury, we employed a rabbit model of endotoxic shock to (a) determine the kinetics and extent of release of TNF into plasma after injection of LPS, and (b) to evaluate the protective effect of in vivo neutralization of LPS-induced TNF by prior infusion of anti-TNF antibody. TNF was maximally induced 45-100 min after injection of 10 micrograms i.v. parent Salmonella minnesota Re595 LPS or 250 micrograms Re595 LPS-HDL complexes. Maximal induction of TNF by LPS was associated with development of hypotension, focal hepatic necrosis, intravascular fibrin deposition and lethality. Based on (a) the peak levels of TNF observed in serum, 2.5 X 10(3) U/ml, (b) the specific activity of purified rabbit macrophage-derived TNF, 1 X 10(8) U/mg, and (c) the biphasic disappearance of intravenously injected purified TNF (t1/2 = 0.5 min, 11 min) we constructed a kinetic model showing that at least 130 micrograms of TNF (1.3 X 10(7) U) was released into plasma 30-200 min postinjection of LPS. Prior infusion of anti-TNF antibody (30-45 min before LPS injection) resulted in neutralization of the LPS-induced serum TNF activity and provided significant protection from the development of hypotension, fibrin deposition, and lethality. Thus, these results provide further evidence that TNF plays a central role mediating the pathophysiologic changes that occur during gram negative endotoxic shock. Images PMID:3384955

  15. Role of interferon gamma and tumor necrosis factor-related apoptosis-inducing ligand receptor 1 single nucleotide polymorphism in natural clearance and treatment response of HCV infection.

    PubMed

    Azam, Sikandar; Manzoor, Sobia; Imran, Muhammad; Ashraf, Javed; Ashraf, Sarah; Resham, Saleha; Ghani, Eijaz

    2015-05-01

    Hepatitis C virus (HCV) pathogenesis and treatment outcomes are multifactorial phenomena involving both viral and host factors. This study was designed to determine the role of tumor necrosis factor-related apoptosis-inducing ligand receptor 1(TRAIL-R1) and interferon gamma (IFN-γ) genetic mutations in susceptibility and response to interferon-based therapy of hepatitis C virus (HCV) infection. The detection of TRAIL-R1 rs4242392 and IFN-γ rs2069707 single nucleotide polymorphisms was completed in 118 chronic HCV patients and 96 healthy controls by allele-specific polymerase chain reaction and restriction fragment length polymorphisms polymerase chain reaction. Patients were further categorized into sustained virological responder (SVR) and nonresponder (NR) groups on the basis of their response to interferon-based therapy for HCV infection. Real-time PCR was used for HCV quantification. HCV genotyping was performed by Ohno's method. The results demonstrated that the distribution of the TRAIL-R1 rs4242392TT genotype was significantly higher in the SVR group (78%) compared to the NR group (36%). It showed that chronic HCV patients possessing the TRAIL-R1 rs4242392TT genotype are better responders to interferon-based therapy (p<0.05). The prevalence of the TRAIL-R1 rs4242392TT genotype in healthy controls and chronic HCV patients was 56% and 65% respectively. It indicated that there is the TRAIL-R1 rs4242392 genetic variation plays no role in the spontaneous clearance of HCV infection (p>0.05). The distribution of IFN-γ rs2069707 was the opposite to TRAIL-R1 rs4242392 prevalence, that is, there was high distribution of the IFN-γ rs2069707GG genotype in patients and healthy controls (p<0.05), while the prevalence of IFN-γ rs2069707GG in SVR and NR groups was comparable (p>0.05). In conclusion, genetic variation of TRAIL-R1 rs4242392 is linked with response to interferon-based therapy for HCV infection, and genetic variation IFN-γ rs2069707 is associated with

  16. Identification of a novel cyclosporin-sensitive element in the human tumor necrosis factor alpha gene promoter

    PubMed Central

    1993-01-01

    Tumor necrosis factor alpha (TNF-alpha), a cytokine with pleiotropic biological effects, is produced by a variety of cell types in response to induction by diverse stimuli. In this paper, TNF-alpha mRNA is shown to be highly induced in a murine T cell clone by stimulation with T cell receptor (TCR) ligands or by calcium ionophores alone. Induction is rapid, does not require de novo protein synthesis, and is completely blocked by the immunosuppressant cyclosporin A (CsA). We have identified a human TNF-alpha promoter element, kappa 3, which plays a key role in the calcium-mediated inducibility and CsA sensitivity of the gene. In electrophoretic mobility shift assays, an oligonucleotide containing kappa 3 forms two DNA protein complexes with proteins that are present in extracts from unstimulated T cells. These complexes appear in nuclear extracts only after T cell stimulation. Induction of the inducible nuclear complexes is rapid, independent of protein synthesis, and blocked by CsA, and thus, exactly parallels the induction of TNF-alpha mRNA by TCR ligands or by calcium ionophore. Our studies indicate that the kappa 3 binding factor resembles the preexisting component of nuclear factor of activated T cells. Thus, the TNF-alpha gene is an immediate early gene in activated T cells and provides a new model system in which to study CsA-sensitive gene induction in activated T cells. PMID:8376940

  17. RAC1 regulate tumor necrosis factor-α-mediated impaired osteogenic differentiation of dental pulp stem cells.

    PubMed

    Feng, Guijuan; Shen, Qijie; Lian, Min; Gu, Zhifeng; Xing, Jing; Lu, Xiaohui; Huang, Dan; Li, Liren; Huang, Shen; Wang, Yi; Zhang, Jinlong; Shi, Jiahai; Zhang, Dongmei; Feng, Xingmei

    2015-09-01

    Human dental pulp contains a rapidly proliferative subpopulation of precursor cells termed dental pulp stem cells (DPSCs) that show self-renewal and multilineage differentiation, including neurogenic, chondrogenic, osteogenic and adipogenic. We previously reported that tomuor necrosis factor-α (TNF-α) (10 ng/mL) triggered osteogenic differentiation of human DPSCs via the nuclear factor-κB (NF-κB) signaling pathway. While previous studies showed that cells treated with TNF-α at higher concentrations showed decreased osteogenic differentiation capability. In this study we analyze the function of TNF-α (100 ng/mL) on osteogenic differentiation of human DPSCs for the first time and identify the underlying molecule mechanisms. Our data revealed that TNF-α with higher concentration significantly reduced mineralization and the expression of bone morphogenetic protein 2 (BMP2), alkaline phosphatase (ALP) and runt-related transcription factor 2 (RUNX2). Further, we revealed that TNF-α could suppress the osteogenic differentiation of DPSCs via increasing the expression of RAC1, which could activate the Wnt/β-catenin signaling pathway and liberate β-catenin to translocate into the nucleus. Genetic silencing of RAC1 expression using siRNA restored osteogenic differentiation of DPSCs. Our findings may provide a potential approach to bone regeneration in inflammatory microenvironments.

  18. Plasma Tumor Necrosis Factor-alpha (TNF-α) Levels Correlate with Disease Severity in Spastic Diplegia, Triplegia, and Quadriplegia in Children with Cerebral Palsy.

    PubMed

    Wu, Jianxian; Li, Xueming

    2015-12-11

    BACKGROUND Inflammatory responses in utero and in neonates have been involved in the development of white matter lesions. This study aimed to investigate the role of tumor necrosis factor-alpha (TNF-α) in spastic cerebral palsy. MATERIAL AND METHODS Plasma TNF-α was measured by ELISA in 54 children with spastic cerebral palsy and 28 aged-matched controls. Both groups were split into age subgroups (1-3 vs. 4-12). Gross motor function and activities of daily living were assessed on enrollment and after 6 months of rehabilitation. RESULTS TNF-α was higher in patients with cerebral palsy than in controls in young (P<0.001) and older subjects (P<0.001). TNF-α levels were comparable in both control subgroups (P=0.819). Younger patients with cerebral palsy had significantly higher TNF-α levels compared with older ones (P<0.001). Pre-rehabilitation TNF-α levels correlated with improvements in activities of daily living after rehabilitation (P<0.001). CONCLUSIONS Children with cerebral palsy showed higher plasma levels of TNF-α than controls. In addition, pre-treatment TNF-α levels were correlated with the improvements after rehabilitation therapy.

  19. Human tumor necrosis factor receptor (p55) and interleukin 10 gene transfer in the mouse reduces mortality to lethal endotoxemia and also attenuates local inflammatory responses

    PubMed Central

    1995-01-01

    Anticytokine therapies have been promulgated in gram-negative sepsis as a means of preventing or neutralizing excessive production of proinflammatory cytokines. However, systemic administration of cytokine inhibitors is an inefficient means of targeting excessive production in individual tissue compartments. In the present study, human gene transfer was used to deliver to organs of the reticuloendothelial system antagonists that either inhibit tumor necrosis factor-alpha (TNF- alpha) synthesis or block its interactions with cellular receptors. Mice were treated intraperitoneally with cationic liposomes containing 200 micrograms of either a pCMV (cytomegalovirus)/p55 expression plasmid that contains the extracellular domain and transmembrane region of the human p55 TNF receptor, or a pcD-SR-alpha/hIL-10 expression plasmid containing the DNA for human interleukin 10. 48 h later, mice were challenged with lipopolysaccharide (LPS) and D-galactosamine. Pretreatment of mice with p55 or IL-10 cDNA-liposome complexes improved survival (p < 0.01) to LPS-D-galactosamine. In additional studies, intratracheal administration of IL-10 DNA-liposome complexes 48 h before an intratracheal LPS challenge reduced pulmonary TNF-alpha levels by 62% and decreased neutrophil infiltration in the lung by 55% as measured by myeloperoxidase activity (both p < 0.05). Gene transfer with cytokine inhibitors is a promising option for the treatment of both the systemic and local sequelae of septic shock. PMID:7760015

  20. Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity.

    PubMed

    Yuan, Z; Syrkin, G; Adem, A; Geha, R; Pastoriza, J; Vrikshajanani, C; Smith, T; Quinn, T J; Alemu, G; Cho, H; Barrett, C J; Arap, W; Pasqualini, R; Libutti, S K

    2013-01-01

    In the current study, we examined whether the combination of tumor vasculature-targeted gene therapy with adeno-associated virus bacteriophage-tumor necrosis factor-α (AAVP-TNF-α) and/or the orally administered LCL161, an antagonist of inhibitors of apoptosis proteins (IAPs), enhanced antitumor efficacy without systemic toxicity. M21 human melanoma xenografts were grown subcutaneously in nude mice. Mice were treated according to one of four treatment regimens: AAVP-TNF-α alone (AAVP-TNF-α plus sodium acetate-acetic acid (NaAc) buffer) via tail vein injection; LCL161 alone (phosphate-buffered saline (PBS) plus LCL161) via oral gavage; AAVP-TNF-α plus LCL161; and PBS plus NaAc Buffer as a control group. Tumor volume, survival and toxicity were analyzed. AAVP trafficking and TNF-α production in vivo were detected on days 7 and 21 by real-time PCR, enzyme-linked immunosorbent assay and immunofluorescence. The levels of apoptosis and activation of caspases were assessed on days 7 and 21 by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) and immunofluorescence assays. Our results showed that the combination of AAVP-TNF-α and LCL161 significantly inhibited tumor growth and prolonged survival in mice with melanoma xenografts. The combination of AAVP-TNF-α and LCL161 was also significantly more effective than either agent alone, showing a synergistic effect without systemic toxicity.

  1. Plasma levels of tumor necrosis factor-alpha (TNF-α), TNF-α soluble receptor type 1 (sTNFR I) and IL-22 in human leishmaniasis.

    PubMed

    Nateghi Rostami, M; Seyyedan Jasbi, E; Khamesipour, A; Miramin Mohammadi, A

    2015-09-01

    The role of pro-inammatory cytokine tumor necrosis factor-alpha (TNF-α) in human leishmaniasis is not fully understood. We analyzed the alterations in the plasma levels of TNF- α, soluble TNF receptor type 1 (sTNFR I), IL-17 and IL-22 in the volunteers with leishmaniasis. Blood samples were collected from patients with active cutaneous leishmaniasis (CL), the same CL patients after standard antimonial therapy as healed CL, active visceral leishmaniasis (VL) and healed VL volunteers. Levels of the cytokines were titrated on plasma samples by sandwich ELISA method. The mean level of TNF-α was significantly higher in active CL patients than healthy controls (P<0.001) and significantly reduced after treatment in the same volunteers (P<0.001). The mean level of sTNFR I was significantly higher in active CL patients than healthy controls (P<0.05). The mean level of IL-22 in plasma of the AVL patients was significantly higher than that of healthy control group (P<0.05). There is a negative correlation between the levels of TNF-α and sTNFR I and healing of CL. Measurement of cytokines in plasma samples is more feasible than cell culture in evaluation of immune response in human leishmaniasis.

  2. Plasma Tumor Necrosis Factor-alpha (TNF-α) Levels Correlate with Disease Severity in Spastic Diplegia, Triplegia, and Quadriplegia in Children with Cerebral Palsy

    PubMed Central

    Wu, Jianxian; Li, Xueming

    2015-01-01

    Background Inflammatory responses in utero and in neonates have been involved in the development of white matter lesions. This study aimed to investigate the role of tumor necrosis factor-alpha (TNF-α) in spastic cerebral palsy. Material/Methods Plasma TNF-α was measured by ELISA in 54 children with spastic cerebral palsy and 28 aged-matched controls. Both groups were split into age subgroups (1–3 vs. 4–12). Gross motor function and activities of daily living were assessed on enrollment and after 6 months of rehabilitation. Results TNF-α was higher in patients with cerebral palsy than in controls in young (P<0.001) and older subjects (P<0.001). TNF-α levels were comparable in both control subgroups (P=0.819). Younger patients with cerebral palsy had significantly higher TNF-α levels compared with older ones (P<0.001). Pre-rehabilitation TNF-α levels correlated with improvements in activities of daily living after rehabilitation (P<0.001). Conclusions Children with cerebral palsy showed higher plasma levels of TNF-α than controls. In addition, pre-treatment TNF-α levels were correlated with the improvements after rehabilitation therapy. PMID:26656070

  3. 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.

  4. Propanil inhibits tumor necrosis factor-alpha production by reducing nuclear levels of the transcription factor nuclear factor-kappab in the macrophage cell line ic-21.

    PubMed

    Frost, L L; Neeley, Y X; Schafer, R; Gibson, L F; Barnett, J B

    2001-05-01

    Tumor necrosis factor-alpha (TNF-alpha) is an essential proinflammatory cytokine whose production is normally stimulated by bacterial cell wall components, such as lipopolysaccharide (LPS), during an infection. Macrophages stimulated with LPS in vitro produce several cytokines, including TNF-alpha. LPS-stimulated primary mouse macrophages produced less TNF-alpha protein and message after treatment with the herbicide propanil (Xie et al., Toxicol. Appl. Pharmacol. 145, 184-191, 1997). Nuclear factor-kappaB (NF-kappaB) tightly regulates TNF-alpha transcription. Therefore, as a step toward understanding the mechanism of the effect of propanil on TNF-alpha transcription, IC-21 cells were transfected with a TNF-alpha promoter-luciferase construct, and the effect of propanil on luciferase activity was measured. Cells transfected with promoter constructs containing a kappaB site showed decreased luciferase activity relative to controls after propanil treatment. These observations implicated NF-kappaB binding as an intracellular target of propanil. Further studies demonstrated a marked reduction in the nuclear levels of the stimulatory p65 subunit of NF-kappaB after propanil treatment, as measured by fluorescence confocal microscopy and Western blot analysis. The p50 subunit of NF-kappaB was not found to be reduced after propanil exposure by Western blot. Electrophoretic mobility gel shift assays showed decreased DNA binding of both p65/p50 heterodimers and p50/p50 homodimers to the kappaB3 site of the TNF-alpha promoter of propanil-treated cells. The marked reduction in nuclear p65/p50 NF-kappaB levels and diminished binding to the TNF-alpha promoter in propanil-treated cells are consistent with reduced TNF-alpha levels induced by LPS. PMID:11312646

  5. 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

  6. Interaction of dietary fatty acids with tumour necrosis factor family cytokines during colon inflammation and cancer.

    PubMed

    Hofmanová, Jiřina; Straková, Nicol; Vaculová, Alena Hyršlová; Tylichová, Zuzana; Safaříková, Barbora; Skender, Belma; Kozubík, Alois

    2014-01-01

    Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF- α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NF κ B activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined.

  7. Interaction of Dietary Fatty Acids with Tumour Necrosis Factor Family Cytokines during Colon Inflammation and Cancer

    PubMed Central

    Straková, Nicol; Vaculová, Alena Hyršlová; Tylichová, Zuzana; Šafaříková, Barbora; Kozubík, Alois

    2014-01-01

    Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF-α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NFκB activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined. PMID:24876678

  8. Mechanisms of growth inhibition of primary prostate epithelial cells following gamma irradiation or photodynamic therapy include senescence, necrosis, and autophagy, but not apoptosis.

    PubMed

    Frame, Fiona M; Savoie, Huguette; Bryden, Francesca; Giuntini, Francesca; Mann, Vincent M; Simms, Matthew S; Boyle, Ross W; Maitland, Norman J

    2016-01-01

    In comparison to more differentiated cells, prostate cancer stem-like cells are radioresistant, which could explain radio-recurrent prostate cancer. Improvement of radiotherapeutic efficacy may therefore require combination therapy. We have investigated the consequences of treating primary prostate epithelial cells with gamma irradiation and photodynamic therapy (PDT), both of which act through production of reactive oxygen species (ROS). Primary prostate epithelial cells were cultured from patient samples of benign prostatic hyperplasia and prostate cancer prior to treatment with PDT or gamma irradiation. Cell viability was measured using MTT and alamar blue assay, and cell recovery by colony-forming assays. Immunofluorescence of gamma-H2AX foci was used to quantify DNA damage, and autophagy and apoptosis were assessed using Western blots. Necrosis and senescence were measured by propidium iodide staining and beta-galactosidase staining, respectively. Both PDT and gamma irradiation reduced the colony-forming ability of primary prostate epithelial cells. PDT reduced the viability of all types of cells in the cultures, including stem-like cells and more differentiated cells. PDT induced necrosis and autophagy, whereas gamma irradiation induced senescence, but neither treatment induced apoptosis. PDT and gamma irradiation therefore inhibit cell growth by different mechanisms. We suggest these treatments would be suitable for use in combination as sequential treatments against prostate cancer.

  9. Lipopolysaccharide-stimulated osteoclastogenesis is mediated by tumor necrosis factor via its P55 receptor.

    PubMed Central

    Abu-Amer, Y; Ross, F P; Edwards, J; Teitelbaum, S L

    1997-01-01

    Chronic bone infection, as attends periodontitis, is often complicated by severe osteolysis. While LPS is believed to be central to the pathogenesis of the osteolytic lesion, the mechanisms by which this bacteria-derived molecule promotes bone resorption are unknown. We find that LPS induces bone marrow macrophages (BMMs) to express c-src, a protooncogene product that we demonstrate is a specific marker of commitment to the osteoclast phenotype. We next turned to possible soluble mediators of LPS-induced c-src. Of a number of osteoclastogenic cytokines tested, only TNF-alpha mirrors the c-src-enhancing effect of LPS. Suggesting that LPS augmentation of c-src is TNF-mediated, endotoxin sequentially induces BMM expression of TNF, followed by c-src. TNF and c-src expression, by cultured BMMs derived from LPS-injected mice, reflects duration of exposure to circulating endotoxin, intimating that endotoxin's effect in vivo is also mediated by TNF. Consistent with these findings, thalidomide (which antagonizes TNF action) attenuates c-src induction by LPS. An anti-TNF antibody blocks LPS enhancement of c-src mRNA, validating the cytokine's modulating role in vitro. Using BMMs of TNF receptor-deleted mice, we demonstrate that TNF induction of c-src is transmitted through the cytokine's p55, but not p75, receptor. Most importantly, LPS administered to wild-type mice prompts osteoclast precursor differentiation, manifest by profound osteoclastogenesis in marrow cultured ex vivo, and by a profusion of marrow-residing cells expressing the osteoclast marker tartrate resistant acid phosphatase, in vivo. In contrast, LPS does not substantially enhance osteoclast proliferation in mice lacking the p55TNF receptor, confirming that LPS-induced osteoclastogenesis is mediated by TNF in vivo via this receptor. Thus, therapy targeting TNF and/or its p55 receptor presents itself as a means of preventing the osteolysis of chronic bacterial infection. PMID:9294124

  10. Soluble Tumor Necrosis Factor Receptor 1 Released by Skin-Derived Mesenchymal Stem Cells Is Critical for Inhibiting Th17 Cell Differentiation.

    PubMed

    Ke, Fang; Zhang, Lingyun; Liu, Zhaoyuan; Yan, Sha; Xu, Zhenyao; Bai, Jing; Zhu, Huiyuan; Lou, Fangzhou; Cai, Wei; Sun, Yang; Gao, Yuanyuan; Wang, Hong; Wang, Honglin

    2016-03-01

    T helper 17 (Th17) cells play an important role in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Th17 cell differentiation from naïve T cells can be induced in vitro by the cytokines transforming growth factor β1 and interleukin-6. However, it remains unclear whether other regulatory factors control the differentiation of Th17 cells. Mesenchymal stem cells (MSCs) have emerged as a promising candidate for inhibiting Th17 cell differentiation and autoimmune diseases. Despite the fact that several molecules have been linked to the immunomodulatory function of MSCs, many other key MSC-secreted regulators that are involved in inhibiting Th17 cell polarization are ill-defined. In this study, we demonstrated that the intraperitoneal administration of skin-derived MSCs (S-MSCs) substantially ameliorated the development of EAE in mice. We found that the proinflammatory cytokine tumor necrosis factor (TNF)-α, a key mediator in the pathophysiology of MS and EAE, was capable of promoting Th17 cell differentiation. Moreover, under inflammatory conditions, we demonstrated that S-MSCs produced high amounts of soluble TNF receptor 1 (sTNFR1), which binds TNF-α and antagonizes its function. Knockdown of sTNFR1 in S-MSCs decreased their inhibitory effect on Th17 cell differentiation ex vivo and in vivo. Thus, our data identified sTNFR1 and its target TNF-α as critical regulators for Th17 cell differentiation, suggesting a previously unrecognized mechanism for MSC therapy in Th17-mediated autoimmune diseases.

  11. Attenuation of Nitrogen Mustard-Induced Pulmonary Injury and Fibrosis by Anti-Tumor Necrosis Factor-α Antibody.

    PubMed

    Malaviya, Rama; Sunil, Vasanthi R; Venosa, Alessandro; Verissimo, Vivianne L; Cervelli, Jessica A; Vayas, Kinal N; Hall, LeRoy; Laskin, Jeffrey D; Laskin, Debra L

    2015-11-01

    Nitrogen mustard (NM) is a bifunctional alkylating agent that causes acute injury to the lung that progresses to fibrosis. This is accompanied by a prominent infiltration of macrophages into the lung and upregulation of proinflammatory/profibrotic cytokines including tumor necrosis factor (TNF)α. In these studies, we analyzed the ability of anti-TNFα antibody to mitigate NM-induced lung injury, inflammation, and fibrosis. Treatment of rats with anti-TNFα antibody (15 mg/kg, iv, every 9 days) beginning 30 min after intratracheal administration of NM (0.125 mg/kg) reduced progressive histopathologic alterations in the lung including perivascular and peribronchial edema, macrophage/monocyte infiltration, interstitial thickening, bronchiolization of alveolar walls, fibrin deposition, emphysema, and fibrosis. NM-induced damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage (BAL) protein and cell content, was also reduced by anti-TNFα antibody, along with expression of the oxidative stress marker, heme oxygenase-1. Whereas the accumulation of proinflammatory/cytotoxic M1 macrophages in the lung in response to NM was suppressed by anti-TNFα antibody, anti-inflammatory/profibrotic M2 macrophages were increased or unchanged. Treatment of rats with anti-TNFα antibody also reduced NM-induced increases in expression of the profibrotic mediator, transforming growth factor-β. This was associated with a reduction in NM-induced collagen deposition in the lung. These data suggest that inhibiting TNFα may represent an efficacious approach to mitigating lung injury induced by mustards.

  12. Cloning of Human Tumor Necrosis Factor (TNF) Receptor cDNA and Expression of Recombinant Soluble TNF-Binding Protein

    NASA Astrophysics Data System (ADS)

    Gray, Patrick W.; Barrett, Kathy; Chantry, David; Turner, Martin; Feldmann, Marc

    1990-10-01

    The cDNA for one of the receptors for human tumor necrosis factor (TNF) has been isolated. This cDNA encodes a protein of 455 amino acids that is divided into an extracellular domain of 171 residues and a cytoplasmic domain of 221 residues. The extracellular domain has been engineered for expression in mammalian cells, and this recombinant derivative binds TNFα with high affinity and inhibits its cytotoxic activity in vitro. The TNF receptor exhibits similarity with a family of cell surface proteins that includes the nerve growth factor receptor, the human B-cell surface antigen CD40, and the rat T-cell surface antigen OX40. The TNF receptor contains four cysteine-rich subdomains in the extra-cellular portion. Mammalian cells transfected with the entire TNF receptor cDNA bind radiolabeled TNFα with an affinity of 2.5 x 10-9 M. This binding can be competitively inhibited with unlabeled TNFα or lymphotoxin (TNFβ).

  13. Analysis of the mechanisms involved in the stimulation of neutrophil apoptosis by tumour necrosis factor

    PubMed Central

    Salamone, Gabriela; Trevani, Analía; Martínez, Diego; Vermeulen, Mónica; Gamberale, Romina; Fernández-Calotti, Paula; Raiden, Silvina; Giordano, Mirta; Geffner, Jorge

    2004-01-01

    We have previously reported that human neutrophils pretreated with tumour necrosis factor-α (TNF-α) and then exposed to a variety of agents such as immune complexes, zymosan, phorbol 12-myristate 13-acetate (PMA), C5a, fMLP, or granulocyte–macrophage colony-stimulating factor (GM-CSF), undergo a dramatic stimulation of apoptosis, suggesting that TNF-α is able to prime an apoptotic death programme which can be rapidly triggered by different stimuli. We report here that this response involves the participation of Mac-1 (CD11b/CD18), is dependent on caspases 3, 8 and 9, and is associated with both a loss of mitochondrial transmembrane potential and a down-regulation in expression of the anti-apoptotic protein, Mcl-1. Interestingly, we also found that the anti-apoptotic cytokine interleukin-1 (IL-1) improves the ability of TNF-α to promote apoptosis, supporting the notion than TNF-α, acting together with IL-1, may favour the depletion of neutrophils from the inflammatory areas during the course of acute inflammation. PMID:15500622

  14. Calcitriol inhibits tumor necrosis factor alpha and macrophage inflammatory protein-2 during lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Tan, Zhu-Xia; Chen, Yuan-Hua; Xu, Shen; Qin, Hou-Ying; Wang, Hua; Zhang, Cheng; Xu, De-Xiang; Zhao, Hui

    2016-08-01

    Acute lung injury is a common complication of sepsis in intensive care unit patients with an extremely high mortality. The present study investigated the effects of calcitriol, the active form of vitamin D, on tumor necrosis factor alpha (TNF-α) and macrophage inflammatory protein-2 (MIP-2) in sepsis-induced acute lung injury. Mice were intraperitoneally (i.p.) injected with lipopolysaccharide (LPS, 1.0mg/kg) to establish the animal model of sepsis-induced acute lung injury. Some mice were i.p. injected with calcitriol (1.0μg/kg) before LPS injection. An obvious infiltration of inflammatory cells in the lungs was observed beginning at 1h after LPS injection. Correspondingly, TNF-α and MIP-2 in sera and lung homogenates were markedly elevated in LPS-treated mice. Interestingly, calcitriol obviously alleviated LPS-induced infiltration of inflammatory cells in the lungs. Moreover, calcitriol markedly attenuated LPS-induced elevation of TNF-α and MIP-2 in sera and lung homogenates. Further analysis showed that calcitriol repressed LPS-induced p38 mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) phosphorylation. In addition, calcitriol blocked LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) p65 and p50 subunit in the lungs. Taken together, these results suggest that calcitriol inhibits inflammatory cytokines production in LPS-induced acute lung injury.

  15. Erythropoietin Levels Increase during Cerebral Malaria and Correlate with Heme, Interleukin-10 and Tumor Necrosis Factor-Alpha in India.

    PubMed

    Dalko, Esther; Tchitchek, Nicolas; Pays, Laurent; Herbert, Fabien; Cazenave, Pierre-André; Ravindran, Balachandran; Sharma, Shobhona; Nataf, Serge; Das, Bidyut; Pied, Sylviane

    2016-01-01

    Cerebral malaria (CM) caused by Plasmodium falciparum parasites often leads to the death of infected patients or to persisting neurological sequelae despite anti-parasitic treatments. Erythropoietin (EPO) was recently suggested as a potential adjunctive treatment for CM. However diverging results were obtained in patients from Sub-Saharan countries infected with P. falciparum. In this study, we measured EPO levels in the plasma of well-defined groups of P. falciparum-infected patients, from the state of Odisha in India, with mild malaria (MM), CM, or severe non-CM (NCM). EPO levels were then correlated with biological parameters, including parasite biomass, heme, tumor necrosis factor (TNF)-α, interleukin (IL)-10, interferon gamma-induced protein (IP)-10, and monocyte chemoattractant protein (MCP)-1 plasma concentrations by Spearman's rank and multiple correlation analyses. We found a significant increase in EPO levels with malaria severity degree, and more specifically during fatal CM. In addition, EPO levels were also found correlated positively with heme, TNF-α, IL-10, IP-10 and MCP-1 during CM. We also found a significant multivariate correlation between EPO, TNF-α, IL-10, IP-10 MCP-1 and heme, suggesting an association of EPO with a network of immune factors in CM patients. The contradictory levels of circulating EPO reported in CM patients in India when compared to Africa highlights the need for the optimization of adjunctive treatments according to the targeted population. PMID:27441662

  16. Modulation of tumor necrosis factor alpha expression in mouse brain after exposure to aluminum in drinking water.

    PubMed

    Tsunoda, M; Sharma, R P

    1999-11-01

    Aluminum, a known neurotoxic substance and a ground-water pollutant, is a possible contributing factor in various nervous disorders including Alzheimer's disease. It has been hypothesized that cytokines are involved in aluminum neurotoxicity. We investigated the alterations in mRNA expression of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and interferon gamma (IFNgamma), cytokines related to neuronal damage, in cerebrum and peripheral immune cells of mice after exposure to aluminum through drinking water. Groups of male BALB/c mice were administered aluminum ammonium sulfate in drinking water ad libitum at 0, 5, 25, and 125 ppm aluminum for 1 month. An additional group received 250 ppm ammonium as ammonium sulfate. After treatment, the cerebrum, splenic macrophages and lymphocytes were collected. The expression of TNFalpha mRNA in cerebrum was significantly increased among aluminum-treated groups compared with the control, in a dose-dependent manner. Other cytokines did not show any aluminum-related effects. In peripheral cells, there were no significant differences of cytokine mRNA expressions among treatment groups. Increased expression of TNFalpha mRNA by aluminum in cerebrum may reflect activation of microglia, a major source of TNFalpha in this brain region. Because the aluminum-induced alteration in cytokine message occurred at aluminum concentrations similar to those noted in contaminated water, these results may be relevant in considering the risk of aluminum neurotoxicity in drinking water.

  17. Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

    PubMed Central

    Orihara, Kanami; Matsuda, Akio

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) and bronchial asthma are common respiratory diseases that are caused by chronic inflammation of the airways. Although these diseases are mediated by substantially distinct immunological reactions, especially in mild cases, they both show increased numbers of neutrophils, increased production of tumor necrosis factor-alpha (TNF-α) and poor responses to corticosteroids, particularly in patients with severe diseases. These immunological alterations may contribute strongly to airway structural changes, commonly referred to as airway remodeling. Microvascular alterations, a component of airway remodeling and caused by chronic inflammation, are observed and appear to be clinically involved in both diseases. It has been well established that vascular endothelial growth factor (VEGF) plays important roles in the airway microvascular alterations in mild and moderate cases of both diseases, but any role that VEGF might play in severe cases of these diseases remains unclear. Here, we review recent research findings, including our own data, and discuss the possibility that TNF-α and its associated CXC chemokines play roles in microvascular alterations that are even more crucial than those of VEGF in patients with severe COPD or asthma. PMID:19281078

  18. Erythropoietin Levels Increase during Cerebral Malaria and Correlate with Heme, Interleukin-10 and Tumor Necrosis Factor-Alpha in India

    PubMed Central

    Dalko, Esther; Tchitchek, Nicolas; Pays, Laurent; Herbert, Fabien; Cazenave, Pierre-André; Ravindran, Balachandran; Sharma, Shobhona; Nataf, Serge; Das, Bidyut; Pied, Sylviane

    2016-01-01

    Cerebral malaria (CM) caused by Plasmodium falciparum parasites often leads to the death of infected patients or to persisting neurological sequelae despite anti-parasitic treatments. Erythropoietin (EPO) was recently suggested as a potential adjunctive treatment for CM. However diverging results were obtained in patients from Sub-Saharan countries infected with P. falciparum. In this study, we measured EPO levels in the plasma of well-defined groups of P. falciparum-infected patients, from the state of Odisha in India, with mild malaria (MM), CM, or severe non-CM (NCM). EPO levels were then correlated with biological parameters, including parasite biomass, heme, tumor necrosis factor (TNF)-α, interleukin (IL)-10, interferon gamma-induced protein (IP)-10, and monocyte chemoattractant protein (MCP)-1 plasma concentrations by Spearman’s rank and multiple correlation analyses. We found a significant increase in EPO levels with malaria severity degree, and more specifically during fatal CM. In addition, EPO levels were also found correlated positively with heme, TNF-α, IL-10, IP-10 and MCP-1 during CM. We also found a significant multivariate correlation between EPO, TNF-α, IL-10, IP-10 MCP-1 and heme, suggesting an association of EPO with a network of immune factors in CM patients. The contradictory levels of circulating EPO reported in CM patients in India when compared to Africa highlights the need for the optimization of adjunctive treatments according to the targeted population. PMID:27441662

  19. Local Overexpression of V1a-Vasopressin Receptor Enhances Regeneration in Tumor Necrosis Factor-Induced Muscle Atrophy

    PubMed Central

    Costa, Alessandra; Toschi, Angelica; Murfuni, Ivana; Pelosi, Laura; Sica, Gigliola; Adamo, Sergio; Scicchitano, Bianca Maria

    2014-01-01

    Skeletal muscle atrophy occurs during disuse and aging, or as a consequence of chronic diseases such as cancer and diabetes. It is characterized by progressive loss of muscle tissue due to hypotrophic changes, degeneration, and an inability of the regeneration machinery to replace damaged myofibers. Tumor necrosis factor (TNF) is a proinflammatory cytokine known to mediate muscle atrophy in many chronic diseases and to inhibit skeletal muscle regeneration. In this study, we investigated the role of Arg-vasopressin-(AVP-)dependent pathways in muscles in which atrophy was induced by local overexpression of TNF. AVP is a potent myogenesis-promoting factor and is able to enhance skeletal muscle regeneration by stimulating Ca2+/calmodulin-dependent kinase and calcineurin signaling. We performed morphological and molecular analyses and demonstrated that local over-expression of the AVP receptor V1a enhances regeneration of atrophic muscle. By upregulating the regeneration/differentiation markers, modulating the inflammatory response, and attenuating fibrogenesis, the stimulation of AVP-dependent pathways creates a favourable environment for efficient and sustained muscle regeneration and repair even in the presence of elevated levels of TNF. This study highlights a novel in vivo role for AVP-dependent pathways, which may represent an interesting strategy to counteract muscle decline in aging or in muscular pathologies. PMID:24971321

  20. Calcitriol inhibits tumor necrosis factor alpha and macrophage inflammatory protein-2 during lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Tan, Zhu-Xia; Chen, Yuan-Hua; Xu, Shen; Qin, Hou-Ying; Wang, Hua; Zhang, Cheng; Xu, De-Xiang; Zhao, Hui

    2016-08-01

    Acute lung injury is a common complication of sepsis in intensive care unit patients with an extremely high mortality. The present study investigated the effects of calcitriol, the active form of vitamin D, on tumor necrosis factor alpha (TNF-α) and macrophage inflammatory protein-2 (MIP-2) in sepsis-induced acute lung injury. Mice were intraperitoneally (i.p.) injected with lipopolysaccharide (LPS, 1.0mg/kg) to establish the animal model of sepsis-induced acute lung injury. Some mice were i.p. injected with calcitriol (1.0μg/kg) before LPS injection. An obvious infiltration of inflammatory cells in the lungs was observed beginning at 1h after LPS injection. Correspondingly, TNF-α and MIP-2 in sera and lung homogenates were markedly elevated in LPS-treated mice. Interestingly, calcitriol obviously alleviated LPS-induced infiltration of inflammatory cells in the lungs. Moreover, calcitriol markedly attenuated LPS-induced elevation of TNF-α and MIP-2 in sera and lung homogenates. Further analysis showed that calcitriol repressed LPS-induced p38 mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) phosphorylation. In addition, calcitriol blocked LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) p65 and p50 subunit in the lungs. Taken together, these results suggest that calcitriol inhibits inflammatory cytokines production in LPS-induced acute lung injury. PMID:27216047

  1. Ultrastructural studies on the effect of tumor necrosis factor on the interaction of neutrophils and Naegleria fowleri.

    PubMed

    Michelson, M K; Henderson, W R; Chi, E Y; Fritsche, T R; Klebanoff, S J

    1990-03-01

    Naegleria fowleri is the common etiologic agent of primary amebic meningoencephalitis (PAM). We investigated the interaction of human neutrophils with Naegleria trophozoites and examined the effect of neutrophil stimulation by the recombinant human tumor necrosis factor (TNF) on this interaction. As indicated by scanning and transmission electron microscopy, TNF stimulated the adherence of neutrophils to N. fowleri with destruction of the ameba. Neutrophil iodination, an indirect measure of stimulation, increased from 0.81 +/- 0.23 nmol/10(7) cells/hr to 2.41 +/- 0.62 nmol/10(7) cells/hr following the addition of TNF to the neutrophil-N. fowleri mixture (P less than 0.05). This was independent of complement or specific immunoglobulin. Ingestion of neutrophils by Naegleria trophozoites was observed following more prolonged incubation, particularly in the absence of TNF. These findings suggest a role for TNF-mediated destruction of Naegleria trophozoites by neutrophils in host defense, and that ingestion of host neutrophils by Naegleria trophozoites ma