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

M Hedl, C Abraham - … of the National Academy of Sciences, 2014 - National Acad Sciences
M Hedl, C Abraham
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
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 …
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-κB/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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