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Niu, Fengfeng, Heng Ru, Wei Ding, Songying Ouyang, and Zhi-Jie Liu. "Structural biology study of human TNF receptor associated factor 4 TRAF domain." Protein & Cell 4, no. 9 (August 27, 2013): 687–94. http://dx.doi.org/10.1007/s13238-013-3068-z.
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Arch, Robert H., and Craig B. Thompson. "4-1BB and Ox40 Are Members of a Tumor Necrosis Factor (TNF)-Nerve Growth Factor Receptor Subfamily That Bind TNF Receptor-Associated Factors and Activate Nuclear Factor κB." Molecular and Cellular Biology 18, no. 1 (January 1, 1998): 558–65. http://dx.doi.org/10.1128/mcb.18.1.558.
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ABSTRACT Members of the tumor necrosis factor (TNF)-nerve growth factor (NGF) receptor family have been shown to be important costimulatory molecules for cellular activation. 4-1BB and Ox40 are two recently described members of this protein family which are expressed primarily on activated T cells. To gain insight into the signaling pathways employed by these factors, yeast two-hybrid library screens were performed with the cytoplasmic domains of 4-1BB and Ox40 as baits. TNF receptor-associated factor 2 (TRAF2) was identified as an interacting protein in both screens. The ability of both 4-1BB and Ox40 to interact with TRAF2 was confirmed in mammalian cells by coimmunoprecipitation studies. When the binding of the receptors to other TRAF proteins was investigated, 4-1BB and Ox40 displayed distinct binding patterns. While 4-1BB bound TRAF2 and TRAF1, Ox40 interacted with TRAF3 and TRAF2. Using deletion and alanine scanning analysis, we defined the elements in the cytoplasmic domains of both receptors that mediate these interactions. The 4-1BB receptor was found to have two independent stretches of acidic residues that can mediate association of the TRAF molecules. In contrast, a single TRAF binding domain was identified in the cytoplasmic tail of Ox40. The cytoplasmic domains of both receptors were shown to activate nuclear factor κB in a TRAF-dependent manner. Taken together, our results indicate that 4-1BB and Ox40 bind TRAF proteins to initiate a signaling cascade leading to activation of nuclear factor κB.
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Glauner, Heike, Daniela Siegmund, Hassan Motejadded, Peter Scheurich, Frank Henkler, Ottmar Janssen, and Harald Wajant. "Intracellular localization and transcriptional regulation of tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4)." European Journal of Biochemistry 269, no. 19 (September 18, 2002): 4819–29. http://dx.doi.org/10.1046/j.1432-1033.2002.03180.x.
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Kalkan, Tuzer, Yasuno Iwasaki, Chong Yon Park, and Gerald H. Thomsen. "Tumor Necrosis Factor-Receptor–associated Factor-4 Is a Positive Regulator of Transforming Growth Factor-β Signaling That Affects Neural Crest Formation." Molecular Biology of the Cell 20, no. 14 (July 15, 2009): 3436–50. http://dx.doi.org/10.1091/mbc.e08-03-0325.
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The transforming growth factor (TGF)-β superfamily regulates cell proliferation, apoptosis, differentiation, migration, and development. Canonical TGFβ signals are transduced to the nucleus via Smads in both major signaling branches, bone morphogenetic protein (BMP) or Activin/Nodal/TGFβ. Smurf ubiquitin (Ub) ligases attenuate these pathways by targeting Smads and other signaling components for degradation by the 26S proteasome. Here, we identify tumor necrosis factor (TNF)-receptor–associated factor-4 (TRAF4) as a new target of Smurf1, which polyubiquitylates TRAF4 to trigger its proteasomal destruction. Unlike other TRAF family members, which mediate signal transduction by TNF, interleukin, or Toll-like receptors, we find that TRAF4 potentiates BMP and Nodal signaling. In the frog Xenopus laevis, TRAF4 mRNA is stored maternally in the egg animal pole, and in the embryo it is expressed in the gastrula marginal zone, neural plate, and cranial and trunk neural crest. Knockdown of embryonic TRAF4 impairs signaling, neural crest development and neural folding, whereas TRAF4 overexpression boosts signaling and expands the neural crest. In human embryonic kidney 293 cells, small interfering RNA knockdown of Smurf1 elevates TRAF4 levels, indicating endogenous regulation of TRAF4 by Smurf1. Our results uncover new functions for TRAF4 as a Smurf1-regulated mediator of BMP and Nodal signaling that are essential for neural crest development and neural plate morphogenesis.
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Meng, Xianzhong, Lihua Ao, Yong Song, Christopher D. Raeburn, David A. Fullerton, and Alden H. Harken. "Signaling for myocardial depression in hemorrhagic shock: roles of Toll-like receptor 4 and p55 TNF-α receptor." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 288, no. 3 (March 2005): R600—R606. http://dx.doi.org/10.1152/ajpregu.00182.2004.
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Hemorrhagic shock causes myocardial contractile depression. Although this myocardial disorder is associated with increased expression of tumor necrosis factor-α (TNF-α), the role of TNF-α as a myocardial depressant factor in hemorrhagic shock remains to be determined. Moreover, it is unclear which TNF-α receptor mediates the myocardial depressive effects of TNF-α. Toll-like receptor 4 (TLR4) regulates cellular expression of proinflammatory mediators following lipopolysaccharide stimulation and may be involved in the tissue inflammatory response to injury. The contribution of TLR4 signaling to tissue TNF-α response to hemorrhagic shock and TLR4’s role in myocardial depression during hemorrhagic shock are presently unknown. We examined the relationship of TNF-α production to myocardial depression in a mouse model of nonresuscitated hemorrhagic shock, assessed the influence of TLR4 mutation, resulting in defective signaling, on TNF-α production and myocardial depression, and determined the roles of TNF-α and TNF-α receptors in myocardial depression using a gene knockout (KO) approach. Hemorrhagic shock resulted in increased plasma and myocardial TNF-α (4.9- and 4.5-fold, respectively) at 30 min and induced myocardial contractile depression at 4 h. TLR4 mutation abolished the TNF-α response and attenuated myocardial depression (left ventricular developed pressure of 43.0 ± 6.2 mmHg in TLR4 mutant vs. 30.0 ± 3.6 mmHg in wild type, P < 0.05). TNF-α KO also attenuated myocardial depression in hemorrhagic shock, and the p55 receptor KO, but not the p75 receptor KO, mimicked the effect of TNF-α KO. The results suggest that TLR4 plays a novel role in signaling to the TNF-α response during hemorrhagic shock and that TNF-α through the p55 receptor activates a pathway leading to myocardial depression. Thus TLR4 and the p55 TNF-α receptor represent therapeutic targets for preservation of cardiac mechanical function during hemorrhagic shock.
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Cai, Dongqing, Munira Xaymardan, Jacquelyne M. Holm, Jingang Zheng, Jorge R. Kizer, and Jay M. Edelberg. "Age-associated impairment in TNF-α cardioprotection from myocardial infarction." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 2 (August 2003): H463—H469. http://dx.doi.org/10.1152/ajpheart.00144.2003.
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Age-associated dysfunction in cardiac microvascular endothelial cells with impaired induction of cardioprotective platelet-derived growth factor (PDGF)-dependent pathways suggests that alterations in critical vascular receptor(s) may contribute to the increased severity of cardiovascular pathology in older persons. In vivo murine phage-display peptide library biopanning revealed a senescent decrease in cardiac microvascular binding of phage epitopes homologous to tumor necrosis factor-α (TNF-α), suggesting that its receptor(s) may be downregulated in older cardiac endothelial cells. Immunostaining demonstrated that TNF-receptor 1 (TNF-R1) density was significantly lower in the subendocardial endothelium of the aging murine heart. Functional studies confirmed the senescent dysregulation of TNF-α receptor pathways, demonstrating that TNF-α induced PDGF-B expression in cardiac microvascular endothelial cells of 4-mo-old, but not 24-mo-old, rats. Moreover, TNF-α mediated cardioprotective pathways were impaired in the aging heart. In young rat hearts, injection of TNF-α significantly reduced the extent of myocardial injury after coronary ligation: TNF-α, 7.9 ± 1.9% left ventricular injury ( n = 4) versus PBS, 16.2 ± 7.9% ( n = 10; P < 0.05). The addition of PDGF-AB did not augment the cardioprotective action of TNF-α. In myocardial infarctions of older hearts, however, TNF-α induced significant postcoronary occlusion mortality (TNF-α 80% vs. PBS 0%; n = 10 each, P < 0.05) that was reversed by the coadministration of PDGF-AB. Overall, these studies demonstrate that aging-associated alterations in TNF-α receptor cardiac microvascular pathways may contribute to the increased cardiovasular pathology of the aging heart. Strategies targeted at restoring TNF-α receptor-mediated expression of PDGF-B may improve cardiac microvascular function and provide novel approaches for treatment and possible prevention of cardiovascular disease in older individuals.
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Zepp, Jarod A., Caini Liu, Wen Qian, Ling Wu, Muhammet F. Gulen, Zizhen Kang, and Xiaoxia Li. "Cutting Edge: TNF Receptor-Associated Factor 4 Restricts IL-17–Mediated Pathology and Signaling Processes." Journal of Immunology 189, no. 1 (May 30, 2012): 33–37. http://dx.doi.org/10.4049/jimmunol.1200470.
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Wang, Yue, Brent R. Weil, Jeremy L. Herrmann, Aaron M. Abarbanell, Jiangning Tan, Troy A. Markel, Megan L. Kelly, and Daniel R. Meldrum. "MEK, p38, and PI-3K mediate cross talk between EGFR and TNFR in enhancing hepatocyte growth factor production from human mesenchymal stem cells." American Journal of Physiology-Cell Physiology 297, no. 5 (November 2009): C1284—C1293. http://dx.doi.org/10.1152/ajpcell.00183.2009.
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Human bone marrow mesenchymal stem cells (MSCs) are a potent source of growth factors, which are partly responsible for their beneficial paracrine effects. We reported previously that transforming growth factor-α (TGF-α), a putative mediator of wound healing and the injury response, increases the release of vascular endothelial growth factor (VEGF), augments tumor necrosis factor-α (TNF-α)-stimulated VEGF production, and activates mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI-3K) pathway in human MSCs. The experiments described in this report indicate that TGF-α increases MSC-derived hepatocyte growth factor (HGF) production. TGF-α-stimulated HGF production was abolished by inhibition of MEK, p38, PI-3K, or by small interfering RNA (siRNA) targeting TNF receptor 2 (TNFR2), but was not attenuated by siRNA targeting TNF receptor 1 (TNFR1). Ablation of TNFR1 significantly increased basal and stimulated HGF. A potent synergy between TGF-α and TNF-α was noted in MSC HGF production. This synergistic effect was abolished by MEK, P38, PI-3K inhibition, or by ablation of both TNF receptors using siRNA. We conclude that 1) novel cross talk occurs between tumor necrosis factor receptor and TGF-α/epidermal growth factor receptor in stimulating MSC HGF production; 2) this cross talk is mediated, at least partially, via activation of MEK, p38, and PI-3K; 3) TGF-α stimulates MSCs to produce HGF by MEK, p38, PI-3K, and TNFR2-dependent mechanisms; and 4) TNFR1 acts to decrease basal TGF-α and TNF-α-stimulated HGF.
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HAVLA, JOACHIM, PETER LOHSE, LISA ANN GERDES, REINHARD HOHLFELD, and TANIA KÜMPFEL. "Symptoms Related to Tumor Necrosis Factor Receptor 1-associated Periodic Syndrome, Multiple Sclerosis, and Severe Rheumatoid Arthritis in Patients Carrying the TNF Receptor Superfamily 1A D12E/p.Asp41Glu Mutation." Journal of Rheumatology 40, no. 3 (January 15, 2013): 261–64. http://dx.doi.org/10.3899/jrheum.120729.
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Objective.Tumor necrosis factor (TNF) receptor 1–associated periodic syndrome (TRAPS) is an autoinflammatory disorder caused by autosomal dominantly inherited mutations in the TNF receptor superfamily 1A (TNFRSF1A) gene. The D12E substitution has been described only once to date, in a 4-year-old boy with fever.Methods.For DNA sequence analysis of the TNFRSF1A gene, genomic DNA was isolated, amplified by PCR, purified, and sequenced.Results.We describe 3 families (8 subjects) with the TNFRSF1A D12E substitution and TRAPS-related symptoms, in 4 cases associated with the autoimmune diseases multiple sclerosis and rheumatoid arthritis.Conclusion.The clinical phenotype might be associated with the TNFRSF1A D12E mutation. There is a close pathophysiological relationship between TNF signaling and autoimmune disorders.
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Luo, Jiing Chyuan, Vivian Yvonne Shin, Ying Hua Yang, William Ka Kei Wu, Yi Ni Ye, Wallace Hau Leung So, Full Young Chang, and Chi Hin Cho. "Tumor necrosis factor-α stimulates gastric epithelial cell proliferation." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 1 (January 2005): G32—G38. http://dx.doi.org/10.1152/ajpgi.00093.2004.
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TNF-α is a cytokine produced during gastric mucosal injury. We examined whether TNF-α could promote mucosal repair by stimulation of epithelial cell proliferation and explored further the underlying mechanisms in a rat gastric mucosal epithelial cell line (RGM-1). TNF-α treatment (1–10 ng/ml) for 12 or 24 h significantly increased cell proliferation but did not induce apoptosis in RGM-1 cells. TNF-α treatment significantly increased cytosolic phospholipase A2 and cyclooxygenase-2 (COX-2) protein expression and PGE2 level but did not affect the protein levels of EGF, basic fibroblast growth factor, and COX-1 in RGM-1 cells. The mRNA of TNF receptor (TNF-R) 2 but not of TNF-R1 was also increased. Dexamethasone dose dependently inhibited the stimulatory effect of TNF-α on cell proliferation, which was associated with a significant decrease in cellular COX-2 expression and PGE2 level. A selective COX-2 inhibitor 3-(3-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one (DFU) by itself had no effect on basal cell proliferation but significantly reduced the stimulatory effect of TNF-α on RMG-1 cells. Combination of dexamethasone and DFU did not produce an additive effect. PGE2 significantly reversed the depressive action of dexamethasone on cell proliferation. These results suggest that TNF-α plays a regulatory role in epithelial cell repair in the gastric mucosa via the TNF-α receptor and activation of the arachidonic acid/PG pathway.
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Yang, Won Seok, Nam Jeong Han, Jin Ju Kim, Mee Jeong Lee, and Su-Kil Park. "TNF-α Activates High-Mobility Group Box 1 - Toll-Like Receptor 4 Signaling Pathway in Human Aortic Endothelial Cells." Cellular Physiology and Biochemistry 38, no. 6 (2016): 2139–51. http://dx.doi.org/10.1159/000445570.
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Background/Aims: Toll-like receptor 4 (TLR4) interacts with endogenous substances as well as lipopolysaccharide. We explored whether TLR4 is implicated in tumor necrosis factor-α (TNF-α) signal transduction in human aortic endothelial cells. Methods: The pathway was evaluated by transfection of siRNAs, immunoprecipitation and Western blot analysis. Results: TNF-α activated spleen tyrosine kinase (Syk) within 10 min, which led to endothelin-1 (ET-1) production. TLR4 was also rapidly activated by TNF-α stimulation, as shown by recruitment of interleukin-1 receptor-associated kinase 1 to TLR4 and its adaptor molecule, myeloid differentiation factor 88 (MyD88). siRNA depletion of TLR4 markedly attenuated TNF-α-induced Syk activation and ET-1 production. TLR4 inhibitor (CLI-095), TLR4-neutralizing antibody and siRNA depletion of MyD88 also attenuated TNF-α-induced Syk activation. Syk was co-immunoprecipitated with TLR4, and TNF-α activated Syk bound to TLR4. High-mobility group box 1 (HMGB1) was rapidly released and associated with TLR4 after TNF-α stimulation with a peak at 5 min, which was prevented by N-acetylcysteine, an antioxidant. Glycyrrhizin (HMGB1 inhibitor), HMGB1-neutralizing antibody and siRNA depletion of HMGB1 all suppressed TNF-α-induced Syk activation and ET-1 production. Conclusion: Upon TNF-α stimulation, TLR4 is activated by HMGB1 that is immediately released after the generation of reactive oxygen species, and plays a crucial role in the signal transduction.
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Voog, Eric, Jacques Bienvenu, Krzysztof Warzocha, Isabelle Moullet, Charles Dumontet, Catherine Thieblemont, Guillaume Monneret, Marie-Claude Gutowski, Bertrand Coiffier, and Gilles Salles. "Factors That Predict Chemotherapy-Induced Myelosuppression in Lymphoma Patients: Role of the Tumor Necrosis Factor Ligand-Receptor System." Journal of Clinical Oncology 18, no. 2 (January 1, 2000): 325. http://dx.doi.org/10.1200/jco.2000.18.2.325.
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PURPOSE: To analyze factors that predict the occurrence of chemotherapy-induced myelosuppression and, in particular, the role of the tumor necrosis factor (TNF) ligand-receptor system in lymphoma patients at the beginning of their treatment. PATIENTS AND METHODS: We investigated the predictive factors for myelosuppression after the first course of chemotherapy in a cohort of 101 consecutive, previously untreated lymphoma patients receiving regimens that include doxorubicin and cyclophosphamide. Plasma samples were tested at baseline by enzyme-linked immunosorbent assay for TNF and its soluble receptors. Univariate and multivariate analyses were performed with a forward regression procedure that included all of the parameters that were found to be significant in the univariate analysis. The dose of chemotherapy and the prophylactic treatment with granulocyte colony-stimulating factor were deliberately included in this model. RESULTS: Sixty-seven patients experienced World Health Organization (WHO) grade 4 neutropenia, and 37 patients experienced febrile neutropenia, which was responsible for WHO grade 2 through 4 infections in 23 patients. In multiparametric regression analysis, the occurrence of grade 4 neutropenia was associated with high doses of cyclophosphamide (odds ratio [OR], 19.8; P = .008) and high levels of soluble p75-R-TNF (OR, 8.52; P = .001). The duration of grade 4 neutropenia for more than 5 days was associated with the lack of hematopoietic growth factor administration (OR, 6.76; P = .004) and high levels of soluble p75-R-TNF (OR, 5.84; P = .0023). The occurrence of febrile neutropenia was associated with high doses of cyclophosphamide (OR, 4.7; P = .007), altered performance status (OR, 18.8; P < .0001) and high levels of soluble p75-R-TNF (OR, 3.49; P = .029). CONCLUSION: This study indicates that in addition to the dose of chemotherapy and the administration of hematopoietic growth factors, poor performance status and high p75-R-TNF levels can predict the occurrence of chemotherapy-induced myelosuppression in lymphoma patients. This model may help in selecting patients for prophylactic growth factor administration.
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Gherardi, RK, L. Belec, M. Soubrier, D. Malapert, M. Zuber, JP Viard, L. Intrator, JD Degos, and FJ Authier. "Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome." Blood 87, no. 4 (February 15, 1996): 1458–65. http://dx.doi.org/10.1182/blood.v87.4.1458.bloodjournal8741458.
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The polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome is a rare multisystem disorder of obscure pathogenesis associated with osteosclerotic myeloma. Circulating levels of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-alpha) interleukin-1 beta [IL-1 beta], IL-2, IL-6, and interferon-gamma [IFN- gamma]), anti-inflammatory cytokines (transforming growth factor beta 1 [TGF beta 1], IL-4, IL-10, and IL-13), the cytokine carrier protein alpha 2 macroglobulin, IL-1 receptor antagonist (IL-1ra), soluble TNF receptors (sTNFr) p55 and p75, and soluble IL-6 receptor (sIL-6r) were determined in 15 patients with POEMS syndrome and 15 with multiple myeloma. Patients with POEMS syndrome had higher serum levels of IL-1 beta, TNF-alpha, and IL-6 and lower serum levels of TGF beta 1 than did patients with multiple myeloma. Serum levels of IL-2, IL-4, IL-10, IL- 13, IFN-gamma, alpha 2 macroglobulin, and sIL-6r were similar in both groups. IL-1ra and sTNFrs were increased in POEMS syndrome, but out of proportion to the increase of IL-1 beta and TNF-alpha. Serial evaluations in 1 patient showed that proinflammatory cytokine serum levels paralleled disease activity assessed by platelet count and neurologic involvement. Our results suggest that the manifestations of POEMS syndrome might be regarded as the result of a marked activation of the proinflammatory cytokine network (IL-1 beta, IL-6, and TNF- alpha) associated with a weak or even decreased (TGF beta 1) antagonistic reaction insufficient to counteract the noxious effects of cytokines.
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Xu, Xue, Mei-Yu Qi, Shuang Liu, Xu-Ting Song, Jia-Nan Zhang, Yu-Fei Zhai, Ming-Hai Lu, Hong-Bing Han, Zheng-Xing Lian, and Yu-Chang Yao. "TLR4 overexpression enhances saturated fatty acid–induced inflammatory cytokine gene expression in sheep." European Journal of Inflammation 16 (January 2018): 205873921879297. http://dx.doi.org/10.1177/2058739218792976.
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Saturated fatty acids (SFAs) can directly stimulate innate immune responses, thereby exacerbating inflammatory aspects of metabolic syndrome. Dietary SFAs act as ligands of Toll-like receptor 4 (TLR4), triggering associated signaling pathways. In this study, we investigated the role of TLR4 in palm oil SFA-associated inflammatory cytokine gene expression in monocytes/macrophages and adipose tissue using TLR4-overexpressing genetically modified sheep. SFA stimulation resulted in upregulation of interleukin-6 ( IL-6), tumor necrosis factor-α ( TNF-α), interleukin-8 ( IL-8), interferon-γ ( IFN-γ), and interleukin-10 ( IL-10), and TLR4 overexpression enhanced such SFA-induced inflammatory cytokine expression. Moreover, SFAs markedly activated MyD88-dependent signaling, including IL-1 receptor–associated kinase 4 ( IRAK4), TNF receptor–associated factor 6 ( TRAF6), and nuclear factor-κB ( NF-κB). Taken together, our results indicate that TLR4 overexpression enhances the SFA-induced inflammatory response through MyD88-dependent signaling in monocytes/macrophages and adipose tissue.
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Artis, David, Neil E. Humphreys, Allison J. Bancroft, Nancy J. Rothwell, Christopher S. Potten, and Richard K. Grencis. "Tumor Necrosis Factor α Is a Critical Component of Interleukin 13–Mediated Protective T Helper Cell Type 2 Responses during Helminth Infection." Journal of Experimental Medicine 190, no. 7 (October 4, 1999): 953–62. http://dx.doi.org/10.1084/jem.190.7.953.
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In vivo manipulation of cytokine and/or cytokine receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility is associated with a T helper cell type 1 (Th1) cytokine response. Using gene-targeted mice deficient in tumor necrosis factor (TNF) receptor signaling and anti–TNF-α monoclonal antibody treatment, we have extended these studies to reveal a critical role for TNF-α in regulation of Th2 cytokine–mediated host protection. In vivo blockade of TNF-α in normally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the duration of treatment. IL-13–mediated worm expulsion in IL-4 knockout (KO) mice was also shown to be TNF-α dependent, and could be enhanced by administration of recombinant TNF-α. Furthermore, TNF receptor KO mice failed to expel T. muris, producing high levels of parasite-specific immunoglobulin G2a and the generation of a predominantly Th1 response, suggesting that the absence of TNF function from the onset of infection dramatically alters the phenotype of the response. These results provide the first demonstration of the role of TNF-α in regulating Th2 cytokine–mediated responses at mucosal sites, and have implications for the design of rational therapies against helminth infection and allergy.
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Thalmaier, Ulrike, Norbert Lehn, Klaus Pfeffer, Manfred Stolte, Michael Vieth, and Wulf Schneider-Brachert. "Role of Tumor Necrosis Factor Alpha in Helicobacter pylori Gastritis in Tumor Necrosis Factor Receptor 1-Deficient Mice." Infection and Immunity 70, no. 6 (June 2002): 3149–55. http://dx.doi.org/10.1128/iai.70.6.3149-3155.2002.
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ABSTRACT Increased gastric production of interleukin 8 and tumor necrosis factor alpha (TNF-α) has been implicated in the pathogenesis of Helicobacter pylori-associated gastroduodenal disease. In the present study we used a mouse model to demonstrate whether loss of the tumor necrosis factor receptor 1 (TNF-R1) function leads to differences in gastric inflammation or the systemic immune response in H. pylori infection. Six different clinical isolates of H. pylori (three cytotoxin-positive and three cytotoxin-negative strains) were adapted to C57BL/6 mice. TNF-R1-deficient (TNF-R1−/−) mice (n = 19) and isogenetic controls (n = 24) were infected and sacrificed after 4 weeks of infection. Inflammation of the stomach and the humoral immune response to H. pylori were evaluated by histological, immunohistochemical, and serological methods. There was no detectable difference in the grade or activity of gastritis in TNF-R1−/− mice when they were compared with wild-type mice, but the number of lymphoid aggregates was slightly reduced in the gastric mucosa of TNF-R1−/− mice. Interestingly, total immunoglobulin G (IgG), as well as IgG1, IgG2b, and IgG3, H. pylori-specific antibody titers were significantly higher in wild-type mice. As revealed by immunoblot analysis, the difference in reactivity against H. pylori antigens was not based on a failure to recognize single H. pylori antigens in TNF-R1−/− mice. We therefore suggest that TNF-R1-mediated TNF-α signals might support a systemic humoral immune response against H. pylori and that the gastric inflammatory response to H. pylori infection seems to be independent of TNF-R1-mediated signals.
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Bagchi, Ashim K., Gauri Akolkar, Soma Mandal, Prathapan Ayyappan, Xi Yang, and Pawan K. Singal. "Toll-like receptor 2 dominance over Toll-like receptor 4 in stressful conditions for its detrimental role in the heart." American Journal of Physiology-Heart and Circulatory Physiology 312, no. 6 (June 1, 2017): H1238—H1247. http://dx.doi.org/10.1152/ajpheart.00800.2016.
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It has been suggested that Toll-like receptor (TLR)4 promotes IL-10-mediated cardiac cell survival, whereas another receptor, TLR2, from the same family, is detrimental. Here, we examined the interactive role of these two innate signaling molecules under stressful conditions, including IL-10 knockout (IL-10−/−) mice, global ischemia-reperfusion (I/R) injury in rat hearts, and in vitro short hairpin RNA experimental models in the presence or absence of IL-10 (10 ng/ml). Circulating and myocardial levels of TNF-α as well as apoptosis and fibrosis were higher in IL-10−/− mice. The increase in TLR2 in IL-10−/− hearts indicated its negative regulation by IL-10. Ex vivo I/R also caused a marked upregulation of TLR2 and TNF-α as well as apoptotic and fibrotic signals. However, a 40-min reperfusion with IL-10 triggered an increase in TLR4 expression and improved recovery of cardiac function. The increase in IL-1 receptor-associated kinase (IRAK)-M and IRAK-2 activity during I/R injury suggested their role in TLR2 signaling. In vitro inhibition of TLR4 activity as a consequence of RNA inhibition-mediated suppression of myeloid differentiation gene (MyD)88 suggested MyD88-dependent activation of TLR4. The inclusion of IL-10 during reperfusion also downregulated the expression of IRAK-2, TNF-α receptor-associated factor 1-interacting protein (TRAIP) and apoptotic signals, caspase-3, and the Bax-to-Bcl-xL ratio. IL-10 reduced the TNF-α receptor-associated increase in TRAIP-induced apoptosis during I/R injury, which led to an increase in IL-1β to mitigate transforming growth factor-β receptor type I-mediated fibrosis. The IL-10 mitigation of these changes suggests that the stimulation through TLR4 signaling promotes IRAK-4 and phosphorylates IRAK-1 instead of IRAK-2 and may be an important therapeutic approach in restoring heart health in stress. NEW & NOTEWORTHY Under stress conditions such as downregulation of the IL-10 gene or ischemia-reperfusion injury, Toll-like receptor (TLR)4 and IL-1 receptor-associated kinase (IRAK)-1 activation is suppressed, along with the upregulation of TLR-2 and IRAK-2, resulting in fibrosis and apoptosis. It is suggested that IL-10 helps to maintain heart function during stress via myeloid differentiation gene 88/IRAK-4/IRAK-1-dependent TLR4 signaling.
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Kuhné, Michelle R., Michael Robbins, John E. Hambor, Matthew F. Mackey, Yoko Kosaka, Toshihide Nishimura, Jason P. Gigley, Randolph J. Noelle, and David M. Calderhead. "Assembly and Regulation of the CD40 Receptor Complex in Human B Cells." Journal of Experimental Medicine 186, no. 2 (July 21, 1997): 337–42. http://dx.doi.org/10.1084/jem.186.2.337.
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CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily. Studies with human B cells show that the binding of CD154 (gp39, CD40L) to CD40 recruits TNF receptor– associated factor 2 (TRAF2) and TRAF3 to the receptor complex, induces the downregulation of the nonreceptor-associated TRAFs in the cell and induces an increased expression of Fas on the cell surface. Combined signaling through the interluekin 4 receptor and CD40 induces an increased expression of Fas with a commensurate increase in the level of TRAF2, but not TRAF3, that is recruited to the receptor complex. In contrast, engagement of the membrane immunoglobulin and CD40 limits Fas upregulation and reduces the recruitment of TRAF2, relative to TRAF3, to the CD40 receptor complex. These studies show that the TRAF composition of the CD40 receptor complex can be altered by signals that influence B cell differentiation.
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Gitte, Sachin, Pradhan G., and Santoshi M. "Tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS): a rare cause of recurrent fever." International Journal of Research in Medical Sciences 6, no. 7 (June 25, 2018): 2537. http://dx.doi.org/10.18203/2320-6012.ijrms20182852.
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The one year old male child presented with fever on and off, associated with periorbital swelling and arthritis. Infectious, rheumatological and oncological diagnoses were ruled out. Further follow-up over 4-5 years revealed that, the child continued to have similar episodes every month and investigated for almost all possible causes but no conclusive diagnosis was made. Hence evaluation for rare causes of periodic fever was considered. Genetic testing revealed mutation in a novel variant of TNFRSF1A gene, thus confirming Tumor necrosis factor receptorassociated periodic syndrome (TRAPS). Tumor necrosis factor receptorassociated periodic syndrome (TRAPS) is an autosomal dominant inherited condition of periodic fever and joint pain. Here we are presenting a case of this rare syndrome.
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Ma, Bruce Y., Sebastian A. Mikolajczak, Ali Danesh, Karoline A. Hosiawa, Cheryl M. Cameron, Akifumi Takaori-Kondo, Takashi Uchiyama, David J. Kelvin, and Atsuo Ochi. "The expression and the regulatory role of OX40 and 4-1BB heterodimer in activated human T cells." Blood 106, no. 6 (September 15, 2005): 2002–10. http://dx.doi.org/10.1182/blood-2004-04-1622.
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Abstract OX40 and 4-1BB are members of the tumor necrosis factor (TNF) family of costimulatory receptors whose signaling is important for differential immune responses mediated by CD4+ or CD8+ T cells. Although activated T cells may acquire OX40/4-1BB double-positive phenotype and signaling from each receptor is expected to influence cell functions, the relevance between OX40 and 4-1BB has never been investigated before. While we were investigating the expression of OX40 and 4-1BB on activated human T cells, we found that they colocalize. The study of receptor gene–transfected cells showed that both receptors coendocytose and the complex of OX40 and 4-1BB was detected by specific ligands or antibodies (Abs). The heterodimer of OX40 and 4-1BB was identified by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) under nonreduced conditions and was associated with the tumor receptor–associated factor (TRAF) family proteins in a unique manner. Furthermore, the stimulation of OX40/4-1BB rendered cells sensitive to apoptosis induced by TNF-α that accompanied reduced activation of nuclear factor-κB (NF-κB). Finally, the OX40/4-1BB stimulation repressed the mitogen response in activated CD25+CD4+ T cells and preactivated CD8+ T cells. Thus, the OX40/4-1BB heterodimer appears to represent a unique regulatory receptor in activated T cells.
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Ishigami, Junichi, Jonathan Taliercio, Harold I Feldman, Anand Srivastava, Raymond Townsend, Debbie L Cohen, Edward Horwitz, et al. "Inflammatory Markers and Incidence of Hospitalization With Infection in Chronic Kidney Disease." American Journal of Epidemiology 189, no. 5 (November 1, 2019): 433–44. http://dx.doi.org/10.1093/aje/kwz246.
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Abstract Persons with chronic kidney disease (CKD) are at high risk of infection. While low-grade inflammation could impair immune response, it is unknown whether inflammatory markers are associated with infection risk in this clinical population. Using 2003–2013 data from the Chronic Renal Insufficiency Cohort Study (3,597 participants with CKD), we assessed the association of baseline plasma levels of 4 inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1RA), and transforming growth factor-β (TGF-β)) with incident hospitalization with major infection (pneumonia, urinary tract infection, cellulitis and osteomyelitis, and bacteremia and sepsis). During follow-up (median 7.5 years), 36% (n = 1,290) had incident hospitalization with major infection. In multivariable Cox analyses with each inflammatory marker modeled as a restricted cubic spline, higher levels of IL-6 and TNF-α were monotonically associated with increased risk of hospitalization with major infection (for 95th vs. 5th percentile, hazard ratio = 2.11 (95% confidence interval: 1.68, 2.66) for IL-6 and 1.88 (95% confidence interval: 1.51, 2.33) for TNF-α), while corresponding associations for IL-1RA or TGF-β were nonsignificant. Thus, higher plasma levels of IL-6 and TNF-α, but not IL-1RA or TGF-β, were significantly associated with increased risk of hospitalization with major infection. Future studies should investigate whether inflammatory pathways that involve IL-6 and TNF-α increase susceptibility to infection among individuals with CKD.
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Yu, Xiaofei, Huanfa Yi, Chunqing Guo, Daming Zuo, Yanping Wang, Hyung L. Kim, John R. Subjeck, and Xiang-Yang Wang. "Pattern Recognition Scavenger Receptor CD204 Attenuates Toll-like Receptor 4-induced NF-κB Activation by Directly Inhibiting Ubiquitination of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6." Journal of Biological Chemistry 286, no. 21 (April 1, 2011): 18795–806. http://dx.doi.org/10.1074/jbc.m111.224345.
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Longhi, Luca, Carlo Perego, Fabrizio Ortolano, Silvia Aresi, Stefano Fumagalli, Elisa R. Zanier, Nino Stocchetti, and Maria-Grazia De Simoni. "Tumor Necrosis Factor in Traumatic Brain Injury: Effects of Genetic Deletion of p55 or p75 Receptor." Journal of Cerebral Blood Flow & Metabolism 33, no. 8 (April 24, 2013): 1182–89. http://dx.doi.org/10.1038/jcbfm.2013.65.
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The role of tumor necrosis factor (TNF) and its receptors after traumatic brain injury (TBI) remains unclear. We evaluated the effects of genetic deletion of either p55 or p75 TNF receptor on neurobehavioral outcome, histopathology, DNA damage and apoptosis-related cell death/survival gene expression (bcl-2/bax), and microglia/macrophage (M/M) activation in wild-type (WT) and knockout mice after TBI. Injured p55 (– / –) mice showed a significant attenuation while p75 (– / –) mice showed a significant worsening of sensorimotor deficits compared with WT mice over 4 weeks postinjury. At the same time point, contusion volume in p55 (– / –) mice (11.1 ± 3.3 mm3) was significantly reduced compared with WT (19.7 ± 3.4 mm3) and p75 (– / –) mice (20.9 ± 3.2 mm3). At 4 hours postinjury, bcl-2/bax ratio mRNA expression was increased in p55 (– / –) compared with p75 (– / –) mice and was associated with reduced DNA damage terminal deoxynucleotidyl transferaseYmediated dUTP nick end labeling (TUNEL-positivity), reduced CD11b expression and increased Ym1 expression at 24 hours postinjury in p55 (– / –) compared with p75 (– / –) mice, indicative of a protective M/M response. These data suggest that TNF may exacerbate neurobehavioral deficits and tissue damage via p55 TNF receptor whose inhibition may represent a specific therapeutic target after TBI.
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Baer, Mark, Allan Dillner, Richard C. Schwartz, Constance Sedon, Sergei Nedospasov, and Peter F. Johnson. "Tumor Necrosis Factor Alpha Transcription in Macrophages Is Attenuated by an Autocrine Factor That Preferentially Induces NF-κB p50." Molecular and Cellular Biology 18, no. 10 (October 1, 1998): 5678–89. http://dx.doi.org/10.1128/mcb.18.10.5678.
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ABSTRACT Macrophages are a major source of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), which are expressed during conditions of inflammation, infection, or injury. We identified an activity secreted by a macrophage tumor cell line that negatively regulates bacterial lipopolysaccharide (LPS)-induced expression of TNF-α. This activity, termed TNF-α-inhibiting factor (TIF), suppressed the induction of TNF-α expression in macrophages, whereas induction of three other proinflammatory cytokines (interleukin-1β [IL-1β], IL-6, and monocyte chemoattractant protein 1) was accelerated or enhanced. A similar or identical inhibitory activity was secreted by IC-21 macrophages following LPS stimulation. Inhibition of TNF-α expression by macrophage conditioned medium was associated with selective induction of the NF-κB p50 subunit. Hyperinduction of p50 occurred with delayed kinetics in LPS-stimulated macrophages but not in fibroblasts. Overexpression of p50 blocked LPS-induced transcription from a TNF-α promoter reporter construct, showing that this transcription factor is an inhibitor of the TNF-α gene. Repression of the TNF-α promoter by TIF required a distal region that includes three NF-κB binding sites with preferential affinity for p50 homodimers. Thus, the selective repression of the TNF-α promoter by TIF may be explained by the specific binding of inhibitory p50 homodimers. We propose that TIF serves as a negative autocrine signal to attenuate TNF-α expression in activated macrophages. TIF is distinct from the known TNF-α-inhibiting factors IL-4, IL-10, and transforming growth factor β and may represent a novel cytokine.
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Qin, Bolin, Richard A. Anderson, and Khosrow Adeli. "Tumor necrosis factor-α directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 5 (May 2008): G1120—G1129. http://dx.doi.org/10.1152/ajpgi.00407.2007.
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Insulin-resistant states are commonly associated with both increased circulating levels of tumor necrosis factor (TNF)-α and hepatic overproduction of very low density lipoproteins (VLDL). Here, we provide evidence that increased TNF-α can directly stimulate the hepatic assembly and secretion of apolipoprotein B (apoB) 100-containing VLDL1, using the Syrian golden hamster, an animal model that closely resembles humans in hepatic VLDL-apoB100 metabolism. In vivo TNF-α infusion for 4 h in chow-fed hamsters induced whole-body insulin resistance on the basis of euglycemic hyperinsulinemic clamp studies. Immunoprecipitation and immunoblotting analysis of livers from TNF-α-treated hamsters indicated decreased tyrosine phosphorylation of insulin receptor (IR)-β, IR substrate-1 (Tyr), Akt (Ser473), p38, ERK1/2, and JNK but increased serine phosphorylation of IRS-1 (Ser307) and Shc. TNF-α infusion also significantly increased hepatic production of total circulating apoB100 and VLDL-apoB100 in both fasting and postprandial (fat load) states. Ex vivo experiments, using cultured primary hepatocytes from hamsters, also showed TNF-α-induced VLDL-apoB100 oversecretion, an effect that was blocked by TNF receptor 2 antibody. Unexpectedly, TNF-α decreased the sterol regulatory element-binding protein-1c mass and mRNA levels but significantly increased microsomal triglyceride transfer protein mass and mRNA levels in primary hepatocytes. In summary, these data provide direct evidence that TNF-α induces whole-body insulin resistance and impairs hepatic insulin signaling accompanied by overproduction of apoB100-containing VLDL particles, an effect likely mediated via TNF receptor 2.
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Moors, Marlena A., Liwu Li, and Steven B. Mizel. "Activation of Interleukin-1 Receptor-Associated Kinase by Gram-Negative Flagellin." Infection and Immunity 69, no. 7 (July 1, 2001): 4424–29. http://dx.doi.org/10.1128/iai.69.7.4424-4429.2001.
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ABSTRACT Flagellin from various species of gram-negative bacteria activates monocytes to produce proinflammatory cytokines. We have analyzed the pathway by which Salmonella enteritidis flagellin (FliC) activates murine and human monocyte/macrophage-like cell lines. Since lipopolysaccharide (LPS), the principal immune stimulatory component of gram-negative bacteria, is known to signal through Toll-like receptor 4 (TLR4), we tested the possibility that FliC also signals via TLR4. When murine HeNC2 cells were stimulated with LPS in the presence of a neutralizing anti-TLR4 monoclonal antibody, tumor necrosis factor alpha (TNF-α) and nitric oxide (NO) production were markedly reduced. In contrast, FliC-mediated TNF-α and NO production were minimally affected by the anti-TLR4 antibody. Furthermore, FliC, unlike LPS, stimulated TNF-α production in the TLR4 mutant cell line, GG2EE, indicating that TLR4 is not essential for FliC-mediated signaling. To test the possibility that FliC signals via another TLR, we measured FliC-mediated activation of interleukin-1 (IL-1) receptor-associated kinase (IRAK), a central component in IL-1R/TLR signaling. FliC induced IRAK activation in HeNC2 and GG2EE cells as well as in the human promonocytic cell line THP-1. IRAK activation was rapid in HeNC2 cells, with maximal activity observed after 5 min of treatment with FliC. In addition, FliC-mediated IRAK activation exhibited the same concentration dependence as was demonstrated for the induction of TNF-α. These results represent the first demonstration of IRAK activation by a purified bacterial protein and strongly suggest that a TLR distinct from TLR4 is involved in the macrophage inflammatory response to FliC.
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Shang, Jian, Lixia Li, Xiaobing Wang, Huaqin Pan, Shi Liu, Ruohang He, Jin Li, and Qiu Zhao. "Disruption of Tumor Necrosis Factor Receptor-Associated Factor 5 Exacerbates Murine Experimental Colitis via Regulating T Helper Cell-Mediated Inflammation." Mediators of Inflammation 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/9453745.
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Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) is a key mediator of TNF receptor superfamily members and is important in both T helper (Th) cell immunity and the regulation of multiple signaling pathways. To clarify TRAF5’s influence on inflammatory bowel diseases (IBDs), we investigated TRAF5 deficiency’s effect on dextran sulfate sodium- (DSS-) induced colitis. Colitis was induced in TRAF5 knockout (KO) mice and their wild-type (WT) littermates by administering 3% DSS orally for 7 days. The mice were then sacrificed, and their colons were removed. Our data suggested that KO mice were more susceptible to DSS-induced colitis. TRAF5 deficiency significantly enhanced IFN-γ, IL-4, and IL-17a mRNA and protein levels in the colons of DSS-fed mice, and the mRNA expression of T-bet and GATA-3 was also markedly elevated. However, ROR-αand ROR-γt mRNA levels did not differ between DSS-induced KO and WT mice. Flow cytometry showed increased frequencies of Th2 and IFN-γ/IL-17a-coproducing CD4+T cells in the colons of DSS-induced KO mice. Additionally, TRAF5 deficiency significantly enhanced the activation of NF-κB in CD4+T cells after DSS administration. These results indicated that TRAF5 deficiency significantly aggravated DSS-induced colitis, most likely by regulating Th cell-mediated inflammation.
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Chen, Xingyong, Xiaogeng Shi, Xu Zhang, Huixin Lei, Simei Long, Huanxing Su, Zhong Pei, and Ruxun Huang. "Scutellarin Attenuates Hypertension-Induced Expression of Brain Toll-Like Receptor 4/Nuclear Factor Kappa B." Mediators of Inflammation 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/432623.
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Hypertension is associated with low-grade inflammation, and Toll-like receptor 4 (TLR4) has been shown to be linked to the development and maintenance of hypertension. This study aimed to investigate the effects of scutellarin (administered by oral gavage daily for 2 weeks) on brain TLR4/nuclear factor kappa B-(NF-κB-) mediated inflammation and blood pressure in renovascular hypertensive (using the 2-kidney, 2-clip method) rats. Immunofluorescence and western immunoblot analyses revealed that hypertension contributed to the activation of TLR4 and NF-κB, accompanied by significantly enhanced expression of proinflammatory mediators, such as tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and interleukin-18 (IL-18). Furthermore, expression of the antiapoptotic protein, myeloid cell leukemia-1 (Mcl1), was decreased, and the pro-apoptotic proteins, Bax and cleavedcaspase-3 p17 were increased in combined cerebral cortical/striatal soluble lysates. Scutellarin significantly lowered blood pressure and attenuated the number of activated microglia and macrophages in brains of hypertensive rats. Furthermore, scutellarin significantly reduced the expression of TLR4, NF-κB p65, TNF-α, IL-1β, IL-18, Bax and cleaved-caspase-3 p17, and increased the expression of Mcl1. Overall, these results revealed that scutellarin exhibits anti-inflammatory and anti-apoptotic properties and decreases blood pressure in hypertensive rats. Therefore, scutellarin may be a potential therapeutic agent in hypertension-associated diseases.
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Cabrera, M., M. A. Shaw, C. Sharples, H. Williams, M. Castes, J. Convit, and J. M. Blackwell. "Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis." Journal of Experimental Medicine 182, no. 5 (November 1, 1995): 1259–64. http://dx.doi.org/10.1084/jem.182.5.1259.
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Recent studies have shown that mucocutaneous leishmaniasis (MCL), a severe and debilitating form of American cutaneous leishmaniasis (ACL) caused by Leishmania braziliensis infection, is accompanied by high circulating levels of tumor necrosis factor (TNF)-alpha. Analysis of TNF polymorphisms in Venezuelan ACL patients and endemic unaffected controls demonstrates a high relative risk (RR) of 7.5 (P < 0.001) of MCL disease in homozygotes for allele 2 of a polymorphism in intron 2 of the TNF-beta gene, especially in females (RR = 9.5; P < 0.001) compared with males (RR = 4; P < 0.05). A significantly higher frequency (P < 0.05) of allele 2 at the -308-basepair TNF-alpha gene polymorphism was also observed in MCL patients (0.18) compared with endemic control subjects (0.069), again associated with a high relative risk of disease (RR = 3.5; P < 0.05) even in the heterozygous condition. Because both the TNF-alpha and TNF-beta polymorphisms have previously been linked with functional differences in TNF-alpha levels, these data suggest that susceptibility to the mucocutaneous form of disease may be directly associated with regulatory polymorphisms affecting TNF-alpha production.
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Abe, Koichiro, Felix O. Yarovinsky, Takaya Murakami, Alexander N. Shakhov, Alexei V. Tumanov, Daisuke Ito, Ludmila N. Drutskaya, et al. "Distinct contributions of TNF and LT cytokines to the development of dendritic cells in vitro and their recruitment in vivo." Blood 101, no. 4 (February 15, 2003): 1477–83. http://dx.doi.org/10.1182/blood.v101.4.1477.
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TNF/LTα/LTβ (tumor necrosis factor/lymphotoxin-α/lymphotoxin-β) triple knockout (KO) mice show a significant reduction of dendritic cell (DC) number in the spleen, presumably due to defective recruitment and/or production. To distinguish between these possibilities, DCs were generated from bone marrow (BM) cultures prepared from wild-type (wt) and mutant mice in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The yield of CD11c+major histocompatibility complex (MHC) class II+DCs generated from TNF/LTα/LTβ−/− BM culture was significantly reduced compared with wt BM culture. In order to further dissect the individual pathways responsible for defective DC properties observed in TNF/LTα/LTβ−/− mice, the panel of TNF/LT ligand and receptor single KO mice were used. The production of DCs from BM culture was significantly reduced in TNF−/− and TNF receptor (TNFR) p55−/− mice, but normal in LTα−/−, LTβ−/−, LTβR−/−mice. Recombinant TNF (rTNF) exogenously added to TNF/LTα/LTβ−/− BM cultures could reverse this defect, and blocking antibodies showed partial effect on BM cultures of wt mice. Conversely, numbers of mature DCs in spleen were significantly decreased in LTα−/−, LTβ−/−, LTβR−/− mice, but not in TNF−/− and TNFRp55−/− mice. These results reveal 2 distinct contributions of TNF/LT cytokines. First, TNF acting through TNF receptor is involved in the development/maturation of DCs in BM progenitor cultures, but this function appears to be redundant in vivo. Second, the microenvironment in peripheral lymphoid organs associated with LTα/LTβ-LTβR signaling and chemokine production is critical for recruitment efficiency of DCs, and this pathway is indispensable.
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Li, Qian, and Bobby J. Cherayil. "Role of Toll-Like Receptor 4 in Macrophage Activation and Tolerance during Salmonella enterica Serovar Typhimurium Infection." Infection and Immunity 71, no. 9 (September 2003): 4873–82. http://dx.doi.org/10.1128/iai.71.9.4873-4882.2003.
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ABSTRACT Toll-like receptors (TLRs) play an important role in the innate immune response, particularly in the initial interaction between the infecting microorganism and phagocytic cells, such as macrophages. We investigated the role of TLR4 during infection of primary murine peritoneal macrophages with Salmonella enterica serovar Typhimurium. We found that macrophages from the C3H/HeJ mouse strain, which carries a functionally inactive Tlr4 gene, exhibit marked impairment of tumor necrosis factor alpha (TNF-α) secretion in response to S. enterica serovar Typhimurium infection. However, activation of extracellular growth factor-regulated kinase and NF-κB signaling pathways was relatively unaffected, as was increased expression of TNF-α mRNA. Furthermore, macrophage tolerance, which is associated with increased expression of the NF-κB p50 and p52 subunits, was induced by S. enterica serovar Typhimurium even in the absence of functional TLR4. These results indicate that during infection of macrophages by S. enterica serovar Typhimurium, TLR4 signals are required at a posttranscriptional step to maximize secretion of TNF-α. Signals delivered by pattern recognition receptors other than TLR4 are sufficient for the increased expression of the TNF-α transcript and at least some genes associated with macrophage tolerance.
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Engelmann, H., H. Holtmann, C. Brakebusch, Y. S. Avni, I. Sarov, Y. Nophar, E. Hadas, O. Leitner, and D. Wallach. "Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity." Journal of Biological Chemistry 265, no. 24 (August 1990): 14497–504. http://dx.doi.org/10.1016/s0021-9258(18)77330-4.
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Lockett, Angelia, Mark G. Goebl, and Maureen A. Harrington. "Transient membrane recruitment of IRAK-1 in response to LPS and IL-1β requires TNF R1." American Journal of Physiology-Cell Physiology 295, no. 2 (August 2008): C313—C323. http://dx.doi.org/10.1152/ajpcell.00500.2007.
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The transcription factor NF-κB is an essential regulator of the innate immune response that functions as the first line of defense against infections. Activation of the innate immune response by bacterial lipopolysaccharide (LPS) triggers production of tumor necrosis factor-α (TNF-α) followed by interleukin-1 (IL-1). The IL-1 receptor associated kinase-1 (IRAK-1) is an integral component of the LPS, TNF-α, and IL-1 signaling pathways that regulate NF-κB. Thus we hypothesized that IRAK-1 coordinates cellular NF-κB responses to LPS, TNF-α, and IL-1. In contrast to TNF-α where IRAK-1 subcellular localization does not change, treatment with LPS or IL-1 leads to a loss in cytoplasmic IRAK-1 with a coordinate increase in plasma membrane associated modified IRAK-1. In fibroblasts lacking the type 1 TNF-α receptor (TNF R1), IRAK-1 turnover is altered and modification of IRAK-1 in the plasma membrane is decreased in response to LPS and IL-1, respectively. When NF-κB controlled gene expression is measured, fibroblasts lacking TNF R1 are hyperresponsive to LPS, whereas a more variable response to IL-1 is seen. Further analysis of the LPS response revealed that plasma membrane-associated IRAK-1 is found in Toll 4, IL-1, and TNF R1-containing complexes. The data presented herein suggest a model whereby the TNF R1-IRAK-1 interaction integrates the cellular response to LPS, TNF-α, and IL-1, culminating in a cell poised to activate TNF-α-dependent NF-κB controlled gene expression. In the absence of TNF R1-dependent events, exposure to LPS or IL-1 leads to hyperactivation of the inflammatory response.
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Brach, MA, HJ Buhring, HJ Gruss, LK Ashman, WD Ludwig, RH Mertelsmann, and F. Herrmann. "Functional expression of c-kit by acute myelogenous leukemia blasts is enhanced by tumor necrosis factor-alpha through posttranscriptional mRNA stabilization by a labile protein." Blood 80, no. 5 (September 1, 1992): 1224–30. http://dx.doi.org/10.1182/blood.v80.5.1224.1224.
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Abstract The c-kit proto-oncogene encodes a transmembrane glycoprotein identical to the receptor for the recently cloned stem cell factor (SCF). The present study examines constitutive synthesis of transcripts in primary acute myelogenous leukemia (AML) blasts and the effects of recombinant human tumor necrosis factor (TNF)-alpha on c-kit mRNA expression in these cells. The c-kit transcripts were detectable at low levels in 10 of 10 different AML samples investigated. TNF treatment of AML cells was associated with enhanced c-kit mRNA expression in all specimens. Nuclear run-on transcription assays indicated that the c-kit gene was transcriptionally active in all leukemias examined and the rate of transcription was unaffected by exposure to TNF, suggesting posttranscriptional control mechanisms of c-kit mRNA accumulation. In the absence of TNF, the half-life of c-kit transcripts was 2 to 3 hours, while in TNF-treated AML cells, c-kit half-life was found to be 5 to 9 hours. Inhibition of protein synthesis reduced TNF-induced c-kit mRNA expression by Northern blot analysis, but did not affect the rate of c-kit gene transcription. In the presence of inhibition of protein synthesis, the half-life of c-kit transcripts in TNF-induced leukemia cells decreased to 2 to 4 hours. These findings indicate that levels of c-kit mRNA are controlled by a labile protein that is involved in TNF- mediated stabilization of c-kit transcripts. The effects of TNF-alpha also extended to the protein level in that TNF-alpha treatment of primary AMLs was associated with enhanced surface expression of the SCF receptor by some of these cells. While exogenous SCF induced clonogenic growth of all primary AML samples investigated, TNF-alpha failed to stimulate leukemic cells to proliferate. However, the combination of SCF and TNF-alpha resulted in synergistic growth stimulation in seven of nine different AML specimens investigated. The finding of transmodulation of the SCF receptor through posttranscriptional modifications might further contribute to our understanding of the synergistic interplay of TNF-alpha and SCF.
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Brach, MA, HJ Buhring, HJ Gruss, LK Ashman, WD Ludwig, RH Mertelsmann, and F. Herrmann. "Functional expression of c-kit by acute myelogenous leukemia blasts is enhanced by tumor necrosis factor-alpha through posttranscriptional mRNA stabilization by a labile protein." Blood 80, no. 5 (September 1, 1992): 1224–30. http://dx.doi.org/10.1182/blood.v80.5.1224.bloodjournal8051224.
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The c-kit proto-oncogene encodes a transmembrane glycoprotein identical to the receptor for the recently cloned stem cell factor (SCF). The present study examines constitutive synthesis of transcripts in primary acute myelogenous leukemia (AML) blasts and the effects of recombinant human tumor necrosis factor (TNF)-alpha on c-kit mRNA expression in these cells. The c-kit transcripts were detectable at low levels in 10 of 10 different AML samples investigated. TNF treatment of AML cells was associated with enhanced c-kit mRNA expression in all specimens. Nuclear run-on transcription assays indicated that the c-kit gene was transcriptionally active in all leukemias examined and the rate of transcription was unaffected by exposure to TNF, suggesting posttranscriptional control mechanisms of c-kit mRNA accumulation. In the absence of TNF, the half-life of c-kit transcripts was 2 to 3 hours, while in TNF-treated AML cells, c-kit half-life was found to be 5 to 9 hours. Inhibition of protein synthesis reduced TNF-induced c-kit mRNA expression by Northern blot analysis, but did not affect the rate of c-kit gene transcription. In the presence of inhibition of protein synthesis, the half-life of c-kit transcripts in TNF-induced leukemia cells decreased to 2 to 4 hours. These findings indicate that levels of c-kit mRNA are controlled by a labile protein that is involved in TNF- mediated stabilization of c-kit transcripts. The effects of TNF-alpha also extended to the protein level in that TNF-alpha treatment of primary AMLs was associated with enhanced surface expression of the SCF receptor by some of these cells. While exogenous SCF induced clonogenic growth of all primary AML samples investigated, TNF-alpha failed to stimulate leukemic cells to proliferate. However, the combination of SCF and TNF-alpha resulted in synergistic growth stimulation in seven of nine different AML specimens investigated. The finding of transmodulation of the SCF receptor through posttranscriptional modifications might further contribute to our understanding of the synergistic interplay of TNF-alpha and SCF.
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Fernandez-Gonzalo, Rodrigo, José A. De Paz, Paula Rodriguez-Miguelez, María J. Cuevas, and Javier González-Gallego. "Effects of eccentric exercise on toll-like receptor 4 signaling pathway in peripheral blood mononuclear cells." Journal of Applied Physiology 112, no. 12 (June 15, 2012): 2011–18. http://dx.doi.org/10.1152/japplphysiol.01499.2011.
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This study aimed to investigate the response of the toll-like receptor 4 (TLR4) signaling pathway to an acute bout of eccentric exercise, and to assess whether eccentric training attenuated the effects induced by acute eccentric exercise. Twenty men (22.4 ± 0.5 yr) were divided into a control group (CG, n = 8) and a training group (TG, n = 12). Both groups performed two acute eccentric bouts on a squat machine in a 9-wk interval. During this time, TG followed a 6-wk eccentric training program (3 session/wk; 3–5 sets of 10 repetitions with loads ranging between the 40 and 50% of maximal isometric voluntary contraction). CD14, TLR4, and TNF-α mRNA levels, and CD14, TLR4, myeloid differentiation factor 88, tumor necrosis factor receptor-associated factor 6, TIR-domain-containing adapter-inducing interferon-β, phospho-IκB kinases, phospho-IκB, phospho-ERK-1/2, and TNF-α protein concentration were measured in peripheral blood mononuclear cells, before, immediately, and 2 h after each eccentric bout. The first acute eccentric bout triggered a proinflammatory response mediated by an upregulation of all of the factors measured within the TLR4 signaling pathway. Following the training period and after the second acute bout, CG showed a similar proinflammatory response than that seen after the first bout. However, the eccentric training intervention decreased significantly the protein concentration of all factors analyzed in TG compared with results obtained after the first bout. These results suggest that the TLR4-signaling pathway plays a critical role in the proinflammatory response seen after acute eccentric exercise. This response was attenuated after an eccentric training program through myeloid differentiation factor 88-dependent and -independent pathways.
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Neznanov, Nickolay, Anna Kondratova, Konstantin M. Chumakov, Brigitte Angres, Bakhyt Zhumabayeva, Vadim I. Agol, and Andrei V. Gudkov. "Poliovirus Protein 3A Inhibits Tumor Necrosis Factor (TNF)-Induced Apoptosis by Eliminating the TNF Receptor from the Cell Surface." Journal of Virology 75, no. 21 (November 1, 2001): 10409–20. http://dx.doi.org/10.1128/jvi.75.21.10409-10420.2001.
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ABSTRACT Viral infections often trigger host defensive reactions by activating intrinsic (intracellular) and extrinsic (receptor-mediated) apoptotic pathways. Poliovirus is known to encode an antiapoptotic function(s) suppressing the intrinsic pathway. Here, the effect of poliovirus nonstructural proteins on cell sensitivity to tumor necrosis factor (TNF)-induced (i.e., receptor-mediated) apoptosis was studied. This sensitivity is dramatically enhanced by the viral proteinase 2A, due, most likely, to inhibition of cellular translation. On the other hand, cells expressing poliovirus noncapsid proteins 3A and 2B exhibit strong TNF resistance. Expression of 3A neutralizes the proapoptotic activity of 2A and results in a specific suppression of TNF signaling, including the lack of activation of NF-κB, due to elimination of the TNF receptor from the cell surface. In agreement with this, poliovirus infection results in a dramatic decrease in TNF receptor abundance on the surfaces of infected cells as early as 4 h postinfection. Poliovirus proteins that confer resistance to TNF interfere with endoplasmic reticulum-Golgi protein trafficking, and their effect on TNF signaling can be imitated by brefeldin A, suggesting that the mechanism of poliovirus-mediated resistance to TNF is a result of aberrant TNF receptor trafficking.
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Krueger, Friedrich, Kai Kappert, Anna Foryst-Ludwig, Frederike Kramer, Markus Clemenz, Aleksandra Grzesiak, Manuela Sommerfeld, et al. "AT1-receptor blockade attenuates outward aortic remodeling associated with diet-induced obesity in mice." Clinical Science 131, no. 15 (July 13, 2017): 1989–2005. http://dx.doi.org/10.1042/cs20170131.
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The renin–angiotensin system (RAS) and obesity have been implicated in vascular outward remodeling, including aneurysms, but the precise mechanisms are not yet understood. We investigated the effect of the angiotensin receptor type 1 (AT1-receptor) antagonist telmisartan on aortic outward remodeling in a diet-induced obesity model in mice. C57/Black6J mice were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 14 weeks. One group of HFD mice was additionally exposed to telmisartan (3 mg/kg per day) for the last 4 weeks. HFD led to aortic outward remodeling, characterized by increased proteolysis, along with structural changes, such as fragmentation of elastic fibers and decreased elastin content. Vascular damage was associated with up-regulation of matrix metalloproteinase (MMP)-2 (MMP-2), MMP-3, MMP-12, cathepsin D, and cathepsin B. HFD aortae exhibited an enhanced inflammatory status, characterized by tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) colocalized with adipocytes in the adventitia. HFD resulted in a significant increase in aortic dimensions, evident by ultrasound measurements. Telmisartan abolished aortic dilatation and preserved elastin content. HFD induced enhanced expression of aortic MMP-2, MMP-9, and TNF-α was abrogated by telmisartan. Adventitial proteolytic and inflammatory factors were also examined in samples from human abdominal aneurysms. The expression of TNF-α, IL-1β, and MMP-9 was higher in the adventitial fat of diseased vessels compared with healthy tissues. Finally, adipocytes treated with TNF-α showed enhanced MMP-2, MMP-3, and cathepsin D, which was prevented by telmisartan. Taken together, HFD in mice induced aortic dilatation with up-regulation of matrix degrading and inflammatory pathways similar to those seen in human aortic aneurysmatic tissue. The HFD-induced vascular pathology was reduced by AT1-receptor antagonist telmisartan.
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Gruss, HJ, and SK Dower. "Tumor necrosis factor ligand superfamily: involvement in the pathology of malignant lymphomas." Blood 85, no. 12 (June 15, 1995): 3378–404. http://dx.doi.org/10.1182/blood.v85.12.3378.bloodjournal85123378.
Full textAbstract:
The TNF receptor superfamily members are all type I membrane glycoproteins with typical homology in the extracellular domain of variable numbers of cysteine-rich repeats (overall homologies, 25% to 30%). In contrast, the TNF ligand superfamily members (with the exception of LT alpha) are type II membrane glycoproteins with homology to TNF in the extracellular domain (overall homologies, 20%). TNF and LT alpha are trimeric proteins and are composed of beta-strands forming a beta-jellyroll. The homology of the beta-strand regions for the TNF ligand superfamily members suggest a similar beta-sandwich structure and possible trimeric or multimeric complex formation for most or all members. A genetic linkage, as evidence for evolutionary relatedness, is found by chromosomal cluster of TNFR p80, CD30, 4–1BB, and OX40 for 1p36; TNFR p60, TNFR-RP, and CD27 for 12p13; TNF, LT alpha, and LT beta for 6 (MHC locus); CD27L and 4–1BBL for 19p13; and FASL and OX40L for 1q25. Of the TNF ligand superfamily, TNF, LT alpha, and LT beta and their receptors (TNFR p60, TNFR p80, and TNFR-RP) interact in a complex fashion of cross-binding. However, the other family members presently have a one ligand/one receptor binding principle (CD27/CD27L, CD30/CD30L, CD40/CD40L, 4–1BB/4–1BBL, OX40/gp34, and FAS/FASL). In general, the members of the TNF ligand superfamily mediate interaction between different hematopoietic cells, such as T cell/B cell, T cell/monocyte, and T cell/T cell. Signals can be transduced not only through the receptors but also through at least some of the ligands. The transduced signals can be stimulatory or inhibitory depending on the target cell or the activation state. Taken together, TNF superfamily ligands show for the immune response an involvement in the induction of cytokine secretion and the upregulation of adhesion molecules, activation antigens, and costimulatory proteins, all known to amplify stimulatory and regulatory signals. On the other hand, differences in the distribution, kinetics of induction, and requirements for induction support a defined role for each of the ligands for T-cell-mediated immune responses. The shedding of members of the TNF receptor superfamily could limit the signals mediated by the corresponding ligands as a functional regulatory mechanism. Induction of cytotoxic cell death, observed for TNF, LT alpha, CD30L, CD95L, and 4–1BBL, is another common functional feature of this cytokine family. Further studies have to identify unique versus redundant biologic and physiologic functions for each of the TNF superfamily ligands.(ABSTRACT TRUNCATED AT 400 WORDS)
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Chevalier, S., N. Macdonald, and R. A. Roberts. "Induction of DNA replication by peroxisome proliferators is independent of both tumour necrosis factor (alpha) priming and EGF-receptor tyrosine kinase activity." Journal of Cell Science 112, no. 24 (December 15, 1999): 4785–91. http://dx.doi.org/10.1242/jcs.112.24.4785.
Full textAbstract:
Peroxisome proliferators (PPs) cause hepatocyte proliferation and tumorigenesis in rodent liver. PPs induce hepatocyte DNA synthesis although the mechanism is unclear. Tumour necrosis factor (alpha) (TNF(alpha)) and epidermal growth factor (EGF) have been implicated in mediating this growth response since these factors induce a threefold and 17.2-fold increase, respectively, in DNA synthesis in rat primary hepatocyte cultures. Previously, others have suggested that TNF(alpha) acts as a primer to sensitise hepatocytes to the proliferative effects of growth factors. Indeed, here we show that costimulation with TNF(alpha) and a suboptimal (4-20% of optimal) concentration of EGF permits an 11.7-fold increase in DNA synthesis in rat primary hepatocyte cultures. The PP nafenopin induced a 2. 3-fold increase in DNA synthesis but there was no further increase upon co-administration of either TNF(alpha) or a suboptimal concentration of EGF. Furthermore, there was no gross dysregulation of the CDK and cyclin protein expression profile upon stimulation with nafenopin. Using a specific epidermal growth factor receptor tyrosine kinase inhibitor (4-(3-chloro-4-fluorophenylamino)-7-methoxy-6- (3-?1-pyrolidino)-propoxyquinazoline, EGFR-TKI), we show that signalling through EGF-R is not required for nafenopin-induced DNA synthesis. The EGFR-TKI also prevented progression into S phase upon stimulation with TNF(alpha), but DNA synthesis was not reduced to control levels, indicating that TNF(alpha) has a mitogenic activity in the absence of EGF signalling. Therefore, although TNF(alpha) can act as a priming factor for growth factors such as EGF, nafenopin does not appear to act via this mechanism.
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Saoulli, Katina, Soo Young Lee, Jennifer L. Cannons, Wen Chen Yeh, Angela Santana, Marni D. Goldstein, Naveen Bangia, et al. "CD28-independent, TRAF2-dependent Costimulation of Resting T Cells by 4-1BB Ligand." Journal of Experimental Medicine 187, no. 11 (June 1, 1998): 1849–62. http://dx.doi.org/10.1084/jem.187.11.1849.
Full textAbstract:
4-1BB ligand (4-1BBL) is a member of the tumor necrosis factor (TNF) family expressed on activated antigen-presenting cells. Its receptor, 4-1BB, is a member of the TNF receptor family expressed on activated CD4 and CD8 T cells. We have produced a soluble form of 4-1BBL using the baculovirus expression system. When coimmobilized on plastic with anti-CD3, soluble 4-1BBL induces interleukin (IL)-2 production by resting CD28+ or CD28− T cells, indicating that 4-1BBL can function independently of other cell surface molecules, including CD28, in costimulation of resting T cell activation. At low concentrations of anti-CD3, 4-1BBL is inferior to anti-CD28 in T cell activation. However, when 4-1BB ligand is provided together with strong TCR signals, then 4-1BBL and anti-CD28 are equally potent in stimulation of IL-2 production by resting T cells. We find that TNF receptor–associated factor (TRAF)1 or TRAF2 associate with a glutathione S-transferase–4-1BB cytoplasmic domain fusion protein in vitro. In T cells, we find that association of TRAF1 and TRAF2 with 4-1BB requires 4-1BB cross-linking. In support of a functional role for TRAF2 in 4-1BB signaling, we find that resting T cells isolated from TRAF2-deficient mice or from mice expressing a dominant negative form of TRAF2 fail to augment IL-2 production in response to soluble 4-1BBL. Thus 4-1BB, via the TRAF2 molecule, can provide CD28-independent costimulatory signals to resting T cells.
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Kim, Young-June, Teresa M. Stringfield, Yan Chen, and Hal E. Broxmeyer. "Modulation of cord blood CD8+ T-cell effector differentiation by TGF-β1 and 4-1BB costimulation." Blood 105, no. 1 (January 1, 2005): 274–81. http://dx.doi.org/10.1182/blood-2003-12-4343.
Full textAbstract:
Abstract Transforming growth factor-β1 (TGF-β1), an immunosuppressive cytokine, inhibits cytotoxic T cell (CTL) immune responses. In contrast, 4-1BB (CD137), a costimulatory molecule in the tumor necrosis factor (TNF) receptor family, amplifies CTL-mediated antitumor immune responses. We investigated whether TGF-β1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8+ T cells into effector CTL cells. TGF-β1 potently suppressed CTL differentiation of human cord blood naive CD8+ T cells as determined by reduced induction of characteristic phenotypes of effector cells and cytotoxic activity. TGF-β1-mediated suppression of CTL differentiation was abrogated by 4-1BB costimulation but not by CD28 or another member in the TNF receptor family, CD30. 4-1BB costimulation suppressed Smad2 phosphorylation induced by TGF-β1, suggesting that 4-1BB effects were at the level of TGF-β1 signaling. 4-1BB effects on the TGF-β1-mediated suppression were enhanced by interleukin 12 (IL-12) but counteracted by IL-4; 4-1BB expression was up- or down-regulated, respectively, by IL-12 and IL-4. IL-4 was more dominant than IL-12 when both cytokines were present during 4-1BB costimulation in the presence of TGF-β1. This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF-β1-mediated suppression. (Blood. 2005;105:274-281)
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Salmon-Ceron, D., F. Tubach, O. Lortholary, O. Chosidow, S. Bretagne, N. Nicolas, E. Cuillerier, et al. "Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry." Annals of the Rheumatic Diseases 70, no. 4 (December 21, 2010): 616–23. http://dx.doi.org/10.1136/ard.2010.137422.
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BackgroundAnti-tumour necrosis factor (TNF) therapy may be associated with opportunistic infections (OIs).ObjectiveTo describe the spectrum of non-tuberculosis OIs associated with anti-TNF therapy and identify their risk factors.MethodsA 3-year national French registry (RATIO) collected all cases of OI in patients receiving anti-TNF treatment for any indication in France. A case–control study was performed with three controls treated with anti-TNF agents per case, matched for gender and underlying inflammatory disease.Results45 cases were collected of non-TB OIs in 43 patients receiving infliximab (n=29), adalimumab (n=10) or etanercept (n=4) for rheumatoid arthritis (n=26), spondyloarthritides (n=3), inflammatory colitis (n=8), psoriasis (n=1) or other conditions (n=5). One-third (33%) of OIs were bacterial (4 listeriosis, 4 nocardiosis, 4 atypical mycobacteriosis, 3 non-typhoid salmonellosis), 40% were viral (8 severe herpes zoster, 3 varicella, 3 extensive herpes simplex, 4 disseminated cytomegalovirus infections), 22% were fungal (5 pneumocystosis, 3 invasive aspergillosis, 2 cryptococcosis) and 4% were parasitic (2 leishmaniasis). Ten patients (23%) required admission to the intensive care unit, and four patients (9%) died. Risk factors for OIs were treatment with infliximab (OR=17.6 (95% CI 4.3 - 72.9); p<0.0001)or adalimumab (OR=10.0 (2.3 to 44.4); p=0.002) versus etanercept, and oral steroid use >10 mg/day or intravenous boluses during the previous year (OR=6.3 (2.0 to 20.0); p=0.002).ConclusionVarious and severe OIs, especially those with intracellular micro-organisms, may develop in patients receiving anti-TNF treatment. Monoclonal anti-TNF antibody rather than soluble TNF receptor therapy and steroid use >10 mg/day are independently associated with OI.
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Tsan, Min-Fu, Robert N. Clark, Sanna M. Goyert, and Julie E. White. "Induction of TNF-α and MnSOD by endotoxin: role of membrane CD14 and Toll-like receptor-4." American Journal of Physiology-Cell Physiology 280, no. 6 (June 1, 2001): C1422—C1430. http://dx.doi.org/10.1152/ajpcell.2001.280.6.c1422.
Full textAbstract:
Endotoxin (LPS) is a potent inducer of tumor necrosis factor-α (TNF-α) and manganese superoxide dismutase (MnSOD). Recent evidence suggests that LPS induction of TNF-α and MnSOD mRNAs is mediated through distinct intracellular signal transduction pathways. Membrane CD14 (mCD14) and Toll-like receptor-4 (TLR4) mediate LPS induction of TNF-α in macrophages. In the current study, we evaluated the role of mCD14 and TLR4 in LPS induction of MnSOD using peritoneal macrophages from CD14 knockout (CD14-KO) mice and mice with the Tlr4 gene point mutation (C3H/HeJ) or deletion (C57BL/10ScCr). We studied mCD14-dependent (1 and 10 ng/ml) and mCD14-independent (1,000 ng/ml) concentrations of LPS. Compared with control (BALB/c) macrophages, LPS at 1 and 10 ng/ml failed to induce TNF-α or MnSOD mRNA in CD14-KO macrophages. However, LPS at 1,000 ng/ml induced TNF-α and MnSOD mRNAs equally in macrophages from CD14-KO and control mice. LPS (1, 10, or 1,000 ng/ml) failed to induce TNF-α or MnSOD mRNA and failed to activate nuclear factor-κB in C3H/HeJ or C57BL/10ScCr macrophages. Measurements of TNF-α and MnSOD enzyme activity paralleled TNF-α and MnSOD mRNA levels. These data demonstrate that, like TNF-α, induction of MnSOD by LPS is mediated by mCD14 and TLR4 in murine macrophages.
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Hooper, WC, DJ Phillips, MJ Ribeiro, JM Benson, VG George, EW Ades, and BL Evatt. "Tumor necrosis factor-alpha downregulates protein S secretion in human microvascular and umbilical vein endothelial cells but not in the HepG- 2 hepatoma cell line." Blood 84, no. 2 (July 15, 1994): 483–89. http://dx.doi.org/10.1182/blood.v84.2.483.483.
Full textAbstract:
Abstract Protein S deficiency, which is associated with thrombosis, can either be inherited or acquired. Recently, we reported that a decrease in free protein S was observed in 19 of 25 persons with HIV/AIDS. The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been reported to be elevated in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients and has been shown to induce a procoagulant state on the surface of endothelial cells. We report here that recombinant TNF-alpha (rTNF-alpha) downregulated protein S synthesis in the SV-40T transfected human microvascular endothelial cell line (HMEC-1) model system by approximately 70% and in primary human umbilical vein and dermal microvascular endothelial cell cultures by approximately 50%. Using the HMEC-1 model, Northern blot analysis showed a decrease in protein S RNA at 24 hours that was corroborated by Western blot analysis and enzyme- linked immunosorbent assay (ELISA) quantification. Evidence supporting the specificity of the TNF-alpha effect included the following: (1) TNF- alpha down-regulation of protein S was completely blocked by TNF neutralizing antibody; (2) the effect was transient, and protein S was restored to near normal levels after TNF was removed from cell cultures; (3) an antibody directed to the TNF RI (55-kD receptor) was shown to mimic the action of TNF-alpha on HMEC-1 cells; and (4) other proinflammatory cytokines, interleukin (IL)-1, IL-6, and TGF-beta, had no effect on protein S secretion. However, TNF-alpha showed no regulatory control over protein S synthesis in the human hepatocellular carcinoma cell line HepG-2. We suggest that TNF-alpha downregulation of protein S may be a mechanism for localized procoagulant activity and thrombosis recently reported in some AIDS patients with associated protein S deficiency.
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Hooper, WC, DJ Phillips, MJ Ribeiro, JM Benson, VG George, EW Ades, and BL Evatt. "Tumor necrosis factor-alpha downregulates protein S secretion in human microvascular and umbilical vein endothelial cells but not in the HepG- 2 hepatoma cell line." Blood 84, no. 2 (July 15, 1994): 483–89. http://dx.doi.org/10.1182/blood.v84.2.483.bloodjournal842483.
Full textAbstract:
Protein S deficiency, which is associated with thrombosis, can either be inherited or acquired. Recently, we reported that a decrease in free protein S was observed in 19 of 25 persons with HIV/AIDS. The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been reported to be elevated in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients and has been shown to induce a procoagulant state on the surface of endothelial cells. We report here that recombinant TNF-alpha (rTNF-alpha) downregulated protein S synthesis in the SV-40T transfected human microvascular endothelial cell line (HMEC-1) model system by approximately 70% and in primary human umbilical vein and dermal microvascular endothelial cell cultures by approximately 50%. Using the HMEC-1 model, Northern blot analysis showed a decrease in protein S RNA at 24 hours that was corroborated by Western blot analysis and enzyme- linked immunosorbent assay (ELISA) quantification. Evidence supporting the specificity of the TNF-alpha effect included the following: (1) TNF- alpha down-regulation of protein S was completely blocked by TNF neutralizing antibody; (2) the effect was transient, and protein S was restored to near normal levels after TNF was removed from cell cultures; (3) an antibody directed to the TNF RI (55-kD receptor) was shown to mimic the action of TNF-alpha on HMEC-1 cells; and (4) other proinflammatory cytokines, interleukin (IL)-1, IL-6, and TGF-beta, had no effect on protein S secretion. However, TNF-alpha showed no regulatory control over protein S synthesis in the human hepatocellular carcinoma cell line HepG-2. We suggest that TNF-alpha downregulation of protein S may be a mechanism for localized procoagulant activity and thrombosis recently reported in some AIDS patients with associated protein S deficiency.
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Kim, Chang Min, Young-Jin Son, Sunghwan Kim, Seo Yun Kim, and Hyun Ho Park. "Molecular basis for unique specificity of human TRAF4 for platelets GPIbβ and GPVI." Proceedings of the National Academy of Sciences 114, no. 43 (October 10, 2017): 11422–27. http://dx.doi.org/10.1073/pnas.1708688114.
Full textAbstract:
Tumor necrosis factor (TNF)-receptor associated factor 4 (TRAF4), an adaptor protein with E3-ligase activity, is involved in embryogenesis, cancer initiation and progression, and platelet receptor (GPIb-IX-V complex and GPVI)-mediated signaling for reactive oxygen species (ROS) production that initiates thrombosis at arterial shears. Disruption of platelet receptors and the TRAF4 interaction is a potential target for therapeutic intervention by antithrombotic drugs. Here, we report a crystal structure of TRAF4 (amino acid residues 290∼470) in complex with a peptide from the GPIbβ receptor (amino acid residues 177∼181). The GPIbβ peptide binds to a unique shallow surface composed of two hydrophobic pockets on TRAF4. Further studies revealed the TRAF4-binding motif Arg–Leu–X–Ala. The TRAF4-binding motif was present not only in platelet receptors but also in the TGF-β receptor. The current structure will provide a template for furthering our understanding of the receptor-binding specificity of TRAF4, TRAF4-mediated signaling, and related diseases.
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Shen, Jie, Zhangfang Li, Wenting Li, Ying Ge, Min Xie, Meng Lv, Yanfei Fan, Zhi Chen, Defu Zhao, and Yajuan Han. "Th1, Th2, and Th17 Cytokine Involvement in Thyroid Associated Ophthalmopathy." Disease Markers 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/609593.
Full textAbstract:
To determine serum cytokine profiles in Graves’ disease (GD) patients with or without active and inactive thyroid associated ophthalmopathy (TAO), we recruited 65 subjects: 10 GD only (without TAO), 25 GD + active TAO, 20 GD + TAO, and 10 healthy controls. Liquid chip assay was used to measure serum Th1/Th2/Th17 cytokines including IFN-γ(interferon-gamma), TNF-α(tumor necrosis factor-alpha), IL-1α(interleukin-1 alpha), IL-1Ra (IL-1 receptor antagonist), IL-2, IL-4, IL-6, and IL-17 and two chemokines: RANTES (regulated upon activation, normal T cell expressed and secreted) and IP-10 (IFN-γ-induced protein 10). Serum levels of TSH (thyroid stimulating hormone) receptor autoantibodies (TRAb) were measured using an enzyme linked immunosorbent assay. Compared with healthy controls, TAO patients showed significantly elevated serum levels of IFN-γ, TNF-α, IL-1α, IL-4, IL-6, IL-17, and IP-10. Comparing active and inactive TAO, serum Th1 cytokines IFN-γand TNF-αwere elevated in active TAO, while serum Th2 cytokine IL-4 was elevated in inactive TAO. Serum Th17 cytokine IL-17 was elevated in GD but reduced in both active and inactive TAO. A positive correlation was found between TRAb and IFN-γ, TNF-α, IL-1α, IL-2, IL-4, and IL-6. Taken together, serum Th1/Th2/Th17 cytokines and chemokines reflect TAO disease activity and may be implicated in TAO pathogenesis.
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Gong, Tingting, Wenbo Jiang, Zhijian Gao, Yingying Chen, and Shuying Gao. "Dibromoacetic Acid Induced Hepatotoxicity in Mice through Oxidative Stress and Toll-Like Receptor 4 Signaling Pathway Activation." Oxidative Medicine and Cellular Longevity 2019 (November 20, 2019): 1–10. http://dx.doi.org/10.1155/2019/5637235.
Full textAbstract:
Dibromoacetic acid (DBA) is one of haloacetic acids, often as a by-product of disinfection in drinking water. DBA is a multiple-organ carcinogen in rodent animals, but little research on its hepatotoxicity has been conducted and its mechanism has not been elucidated. In this study, we found that DBA could induce obvious hepatotoxcity in Balb/c mice as indicated by histological changes, increasing serum level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and accumulation of hepatic glycogen, after the mice were administered DBA at doses of 1.25, 5, and 20 mg/kg body weight for 28 days via oral gavage. In mechanism study, DBA induced oxidative stress as evidenced by increasing the level of malondialdehyde (MDA), reactive oxygen species (ROS) in the liver, advanced oxidative protein products (AOPPs) in the serum, and decreasing the level of glutathione (GSH) in the liver. DBA induced inflammation in the liver of the mice which is supported by increasing the production of tumor necrosis factor-α (TNF-α) and the mRNA levels of TNF-α, interleukin-6 (IL-6), interleukin-1β (IL-1β), and nuclear factor κB (NF-κB) in the liver. DBA also upregulated the protein levels of Toll-like receptor (TLR) 4, myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6), inhibitor of nuclear factor κB alpha (IκB-α), nuclear factor κB p65 (NF-κB p65), and the phosphoralation of P38 mitogen-activated protein kinase (P38MAPK) and c-Jun N-terminal kinase (JNK). Conclusion. DBA could induce hepatotoxicity in mice by oral exposure; the mechanism is related to oxidative stress, inflammation, and Toll-like receptor 4 signaling pathway activation.
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Yang, Won Seok, Soo Young Moon, Mee Jeong Lee, Eun Kyoung Lee, and Su-Kil Park. "Diosgenin, an Activator of 1,25D3-MARRS Receptor/ERp57, Attenuates the Effects of TNF-α by Causing ADAM10-Dependent Ectodomain Shedding of TNF Receptor 1." Cellular Physiology and Biochemistry 43, no. 6 (2017): 2434–45. http://dx.doi.org/10.1159/000484396.
Full textAbstract:
Background/Aims: We investigated how diosgenin, a steroidal sapogenin, has anti-tumor necrosis factor-α (TNF-α) effects in human aortic endothelial cells (HAECs). Methods: Tumor necrosis factor receptor 1 (TNFR1) was assessed by Western blot analysis. Intracellular Ca2+ was measured using Fluo-4 AM. Immunofluorescence staining was performed for a disintegrin and metalloprotease 10 (ADAM10). Results: Diosgenin (1 ∼ 100 nM) induced ectodomain shedding of TNFR1 within 30 min and attenuated TNF-α-induced intercellular adhesion molecule-1 (ICAM-1) expression. Upon treatment with diosgenin, extracellular Ca2+ entered into the cells via L-type calcium channels, whereas diosgenin-induced ectodomain shedding of TNFR1 was almost completely inhibited by BAPTA-AM (intracellular Ca2+ chelator), verapamil (L-type calcium channel antagonist) and the absence of extracellular Ca2+. Diosgenin caused translocation of ADAM10 to the cell surface, which was mediated by extracellular Ca2+ influx. Depletion of ADAM10 prevented diosgenin-induced ectodomain shedding of TNFR1 and abolished the inhibitory effect of diosgenin on TNF-α-induced ICAM-1 expression. Diosgenin did not induce extracellular Ca2+ influx and ectodomain shedding of TNFR1 in cells depleted of 1,25D3-membrane associated rapid response steroid-binding receptor (1,25D3-MARRS receptor/ERp57). Conclusion: Diosgenin elicits L-type calcium channel-mediated extracellular Ca2+ influx, and thereby induces ADAM10-mediated ectodomain shedding of TNFR1. This effect of diosgenin was exerted through 1,25D3-MARRS receptor/ERp57.