title: A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8-induced IL-1.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Yale University, New Haven, CT 06510.
authors.forename: Matija
authors.initials: M
authors.lastname: Hedl
authors.affiliation: Department of Internal Medicine, Yale University, New Haven, CT 06510 clara.abraham@yale.edu.
authors.forename: Clara
authors.initials: C
authors.lastname: Abraham
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D053181:Caspase 8 / Q000378:metabolism*; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009161:Mycobacterium / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051192:Receptors, Pattern Recognition / Q000378:metabolism*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics*
chemical_list: D007375:Interleukin-1; D008024:Ligands; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051192:Receptors, Pattern Recognition; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506033:TNFRSF25 protein, human; C117026:TNFSF15 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D053181:Caspase 8; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: Crohn disease; NOD2; TLR; genetics; ulcerative colitis