Jin, S.,Chin, J.,Seeber, S.,Niewoehner, J.,Weiser, B.,Beaucamp, N.,Woods, J.,Murphy, C.,Fanning, A.,Shanahan, F.,Nally, K.,Kajekar, R.,Salas, A.,Planell, N.,Lozano, J.,Panes, J.,Parmar, H.,DeMartino, J.,Narula, S.,Thomas-Karyat, D. A.

2013

September

Mucosal immunology

TL1A/TNFSF15 directly induces proinflammatory cytokines, including TNF alpha, from CD3+CD161+T cells to exacerbate gut inflammation

Validated

()

6

55

886

899

Tumor necrosis factor (TNF)-like cytokine 1A (TL1A)/TNF superfamily member 15 (TNFSF15) is a proinflammatory cytokine and TNF alpha superfamily member that is linked preclinically and clinically to inflammatory bowel disease (IBD). By homology and function, TNF alpha is its closest family member. In this study, we investigated the mechanism of TL1A-induced inflammation in CD4+ T cells and compared it with the TNF alpha pathway. We found that TL1A induces proinflammatory cytokines, including TNF alpha, from isolated human CD4+ CD161+ T cells, whereas these cells were resistant to TNF alpha treatment. Anti-TNF alpha failed to block TL1A-induced cytokine production, indicating that the effects of TL1A are direct. Lastly, CD161 and TL1A expression were significantly and selectively increased in gut tissue biopsies, but not in the peripheral blood, from IBD patients. Thus, TLIA not only functions upstreamof TNF alpha, driving its expression from CD161+ T cells, but is also independent of TNF alpha. These findings may have therapeutic IBD implications.Tumor necrosis factor (TNF)-like cytokine 1A (TL1A)/TNF superfamily member 15 (TNFSF15) is a proinflammatory cytokine and TNF alpha superfamily member that is linked preclinically and clinically to inflammatory bowel disease (IBD). By homology and function, TNF alpha is its closest family member. In this study, we investigated the mechanism of TL1A-induced inflammation in CD4+ T cells and compared it with the TNF alpha pathway. We found that TL1A induces proinflammatory cytokines, including TNF alpha, from isolated human CD4+ CD161+ T cells, whereas these cells were resistant to TNF alpha treatment. Anti-TNF alpha failed to block TL1A-induced cytokine production, indicating that the effects of TL1A are direct. Lastly, CD161 and TL1A expression were significantly and selectively increased in gut tissue biopsies, but not in the peripheral blood, from IBD patients. Thus, TLIA not only functions upstreamof TNF alpha, driving its expression from CD161+ T cells, but is also independent of TNF alpha. These findings may have therapeutic IBD implications.

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