期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 37, 页码 13451-13456出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1404178111
关键词
Crohn disease; ulcerative colitis; genetics; NOD2; TLR
资金
- Broad Foundation
- National Institutes of Health [R01DK099097, R01DK077905, R56AI089789, DK062422, DK-P30-34989, U19-AI082713]
Inflammatory diseases are characterized by dysregulated cytokine production. Altered functions for most risk loci, including the inflammatory bowel disease and leprosy-associated tumor necrosis factor ligand superfamily member 15 (TNFSF15) region, are unclear. Regulation of pattern-recognition-receptor (PRR)-induced signaling and cytokines is crucial for immune homeostasis; TNFSF15: death receptor 3 (DR3) contributions to PRR responses have not been described. We found that human macrophages expressed DR3 and that TNFSF15: DR3 interactions were critical for amplifying PRR-initiated MAPK/NF-kappa B/PI3K signaling and cytokine secretion in macrophages. Mechanisms mediating TNFSF15: DR3 contributions to PRR outcomes included TACE-induced TNFSF15 cleavage to soluble TNFSF15; soluble TNFSF15 then led to TRADD/FADD/MALT-1 and caspase-8-mediated autocrine IL-1 secretion. Notably, TNFSF15 treatment also induced cytokine secretion through a caspase-8-dependent pathway in intestinal myeloid cells. Importantly, rs6478108 A disease risk-carrier macrophages demonstrated increased TNFSF15 expression and PRR-induced signaling and cytokines. Taken together, TNFSF15: DR3 interactions amplify PRR- induced signaling and cytokines, and the rs6478108 TNFSF15 disease-risk polymorphism results in a gain of function.
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