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The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation.

ABSTRACT: The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells through its receptor DR3 (TNFRSF25) and is required for autoimmune pathology driven by diverse T-cell subsets. TL1A has been linked to human inflammatory bowel disease (IBD), but its pathogenic role is not known. We generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13-dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal T-cell receptor (TCR) repertoire, suggesting that they are driven by components in the intestinal flora. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Tregs. Finally, blocking TL1A-DR3 interactions abrogates 2,4,6 trinitrobenzenesulfonic acid (TNBS) colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and interleukin 13 (IL-13) responses that results in small intestinal inflammation, and also establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.

SUBMITTER: Meylan F

PROVIDER: S-EPMC3437258 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation.

Meylan F F Song Y-J YJ Fuss I I Villarreal S S Kahle E E Malm I-J IJ Acharya K K Ramos H L HL Lo L L Mentink-Kane M M MM Wynn T A TA Migone T-S TS Strober W W Siegel R M RM

Mucosal immunology 20101027 2

The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells through its receptor DR3 (TNFRSF25) and is required for autoimmune pathology driven by diverse T-cell subsets. TL1A has been linked to human inflammatory bowel disease (IBD), but its pathogenic role is not known. We generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13-dependent inflammatory small bowel pathology that strikingly resembles ...[more]

PMID: 20980995

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Project description:BACKGROUND:TNF-like cytokine 1A (TL1A) is a subgroup of the tumor necrosis factor superfamily that exerts pleiotropic effects on cell proliferation, inflammation, activation, and differentiation of immune cells. The purpose of the current study is to investigate the clinical significance of TL1A expression in coronary and peripheral blood of patients with acute coronary syndrome (ACS) to determine if TL1A levels can serve as an accurate prognostic indicator. METHODS:A total of 141 patients undergoing coronary angiography were divided into 4 groups: Control (n?=?35), Unstable Angina (UA) (n?=?35), acute non-ST segment elevation myocardial infarction (NSTEMI) (n?=?37), and acute ST segment elevation myocardial infarction (STEMI) (n?=?34). The levels of TL1A, MPO, hs-CRP, and IL-10 were detected in coronary and peripheral blood using enzyme linked immunosorbent assay (ELISA), and the MACE incidence rates were compared during 26.3 months of follow-up. RESULTS:TL1A levels were not significantly different between the UA group and control group. In the UA group, TL1A levels were not significantly different between coronary blood and peripheral blood. However, TL1A levels were higher in the STEMI and NSTEMI groups than in the control group (P?<?.05). Moreover, TL1A levels in the coronary blood of the STEMI and NSTEMI groups were higher than in the peripheral blood (P?<?.05). The expression of TL1A in the coronary blood was the highest in the STEMI group. In addition, TL1A level in the coronary blood was highly correlated with levels in the peripheral blood (correlation coefficient: 0.899, P?<?.001). The hs-CRP and MPO levels in the coronary and peripheral blood of all the UA, NSTEMI, and STEMI groups were higher than the control group. Plasma IL-10 levels in all the UA, NSTEMI and STEMI groups were lower than those in the control group. Plasma TL1A level was positively correlated with the cTnI level, degree of coronary thrombus burden, occurrence of slow coronary flow / no coronary reflow and MACE, but negatively correlated with the IL-10 level or non-correlated with the Syntax score. CONCLUSION:Plasma TL1A concentration levels can be used as a predictor of inflammatory response and prognosis in patients with ACS. TRIAL REGISTRATION:ClinicalTrials.gov, number: NCT02430025; Unique Protocol ID: FJPH20150101; Brief Title: Fujian Province Cardiovascular Diseases Study (FJCVD).

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The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation.

Publications

The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation.

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