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.
Keywords:
Crohn disease; NOD2; TLR; genetics; ulcerative colitis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / metabolism
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ADAM17 Protein
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Acetylmuramyl-Alanyl-Isoglutamine / pharmacology
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Caspase 8 / metabolism*
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Cells, Cultured
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Genetic Predisposition to Disease*
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Humans
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Interleukin-1 / metabolism*
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Ligands
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Macrophages / drug effects
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Macrophages / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Mycobacterium / metabolism
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Myeloid Cells / drug effects
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Myeloid Cells / metabolism
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NF-kappa B / metabolism
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Nod2 Signaling Adaptor Protein / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Polymorphism, Single Nucleotide / genetics*
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Receptors, Pattern Recognition / metabolism*
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Receptors, Tumor Necrosis Factor, Member 25 / metabolism
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Signal Transduction* / drug effects
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Solubility
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Tissue Inhibitor of Metalloproteinase-3 / metabolism
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Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics*
Substances
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Interleukin-1
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Ligands
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NF-kappa B
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NOD2 protein, human
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Nod2 Signaling Adaptor Protein
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Receptors, Pattern Recognition
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Receptors, Tumor Necrosis Factor, Member 25
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TNFRSF25 protein, human
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TNFSF15 protein, human
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Tissue Inhibitor of Metalloproteinase-3
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Tumor Necrosis Factor Ligand Superfamily Member 15
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Acetylmuramyl-Alanyl-Isoglutamine
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Phosphatidylinositol 3-Kinases
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Mitogen-Activated Protein Kinases
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Caspase 8
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ADAM Proteins
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ADAM17 Protein
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ADAM17 protein, human