title: 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.
authors.affiliation: pRED Inflammation Discovery Therapeutic Area, Hoffmann-La Roche, Nutley, New Jersey, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jin
authors.forename: J
authors.initials: J
authors.lastname: Chin
authors.forename: S
authors.initials: S
authors.lastname: Seeber
authors.forename: J
authors.initials: J
authors.lastname: Niewoehner
authors.forename: B
authors.initials: B
authors.lastname: Weiser
authors.forename: N
authors.initials: N
authors.lastname: Beaucamp
authors.forename: J
authors.initials: J
authors.lastname: Woods
authors.forename: C
authors.initials: C
authors.lastname: Murphy
authors.forename: A
authors.initials: A
authors.lastname: Fanning
authors.forename: F
authors.initials: F
authors.lastname: Shanahan
authors.forename: K
authors.initials: K
authors.lastname: Nally
authors.forename: R
authors.initials: R
authors.lastname: Kajekar
authors.forename: A
authors.initials: A
authors.lastname: Salas
authors.forename: N
authors.initials: N
authors.lastname: Planell
authors.forename: J
authors.initials: J
authors.lastname: Lozano
authors.forename: J
authors.initials: J
authors.lastname: Panes
authors.forename: H
authors.initials: H
authors.lastname: Parmar
authors.forename: J
authors.initials: J
authors.lastname: DeMartino
authors.forename: S
authors.initials: S
authors.lastname: Narula
authors.forename: D A
authors.initials: DA
authors.lastname: Thomas-Karyat
mesh_terms: D000368:Aged; D019138:Antibodies, Blocking / Q000494:pharmacology; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D018450:Disease Progression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D007422:Intestines / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D009928:Organ Specificity; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019138:Antibodies, Blocking; D017252:CD3 Complex; D018836:Inflammation Mediators; D055651:NK Cell Lectin-Like Receptor Subfamily B; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha