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

Abstract

Tumor necrosis factor (TNF)-like cytokine 1A (TL1A)/TNF superfamily member 15 (TNFSF15) is a proinflammatory cytokine and TNFα superfamily member that is linked preclinically and clinically to inflammatory bowel disease (IBD). By homology and function, TNFα 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 TNFα pathway. We found that TL1A induces proinflammatory cytokines, including TNFα, from isolated human CD4+CD161+ T cells, whereas these cells were resistant to TNFα treatment. Anti-TNFα 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 upstream of TNFα, driving its expression from CD161+ T cells, but is also independent of TNFα. These findings may have therapeutic IBD implications.

A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1

“…TNFSF15 is elevated in intestinal tissues and serum of IBD patients (38,39). That the TNFSF15 region rs6478108 A risk allele is a gain of function is consistent with these human and mouse findings.…”

The Tumor Necrosis Factor Superfamily Members TWEAK, TNFSF15 and Fibroblast Growth Factor-Inducible Protein 14 Are Upregulated in Proliferative Diabetic Retinopathy

“…Treatment with anti-TNF-α agents significantly decreased TNFSF15 serum levels [34]. Similarly, expression of TNFSF15 is increased in the mucosa of inflammatory bowel disease patients [29,30,32]. Several studies suggested that TNFSF15 is a severity factor and that upregulation of TNFSF15 expression can promote mucosal inflammation and gut fibrosis that is caused by increased collagen deposition and number of fibroblasts [31,41].…”

“…For example, treatment with recombinant TNFSF15 caused induction of MMP-9, IL-8 and TNF-α in several cell types [29,35,39]. These mediators are implicated in the progression of PDR.…”

“…These mediators are implicated in the progression of PDR. Recent studies have clearly shown that TNFSF15 is upregulated and possibly implicated in the pathogenesis of several chronic inflammatory conditions including inflammatory bowel disease [29,30,31,32], rheumatoid arthritis [33,34,35,36,37], psoriatic skin lesions [38], and atherosclerosis [39]. The serum and synovial fluid levels of TNFSF15 are elevated in patients with rheumatoid arthritis [33,34,35], and TNFSF15 aggravated collagen-induced arthritis in mice [35].…”

“…In addition, TNFSF15 helps to modulate the immune system by stimulating T cell activation, T helper 1 cytokine production and dendritic cell maturation [15,16]. Recent studies have clearly shown that TNFSF15 is upregulated and possibly implicated in the pathogenesis of several chronic inflammatory conditions [29,30,31,32,33,34,35,36,37,38,39]. …”