IL17REL encodes a decoy receptor that suppresses IL-17 family cytokine signaling to control intestinal inflammation 1. Mechanistically, IL17REL competes with IL-17RA for IL-17A binding, thereby antagonizing pro-inflammatory IL-17 signaling 1. TGFβ1 induces IL17REL transcription, and expression correlates with TGFB1 levels in inflammatory bowel disease 1. Genetically, IL17REL variants are associated with inflammatory bowel disease (IBD) susceptibility, with some variants losing functional decoy receptor activity 1. Protective variants have been identified in ulcerative colitis populations 2. IL17REL is also implicated in gene-microbiota interactions affecting IBD pathogenesis through modulation of short-chain fatty acid biosynthesis pathways 3. Additionally, IL17REL variants show male-specific association with Kawasaki disease susceptibility 4. Clinically, IL17REL represents a therapeutic target with dual significance. Mouse studies demonstrate that wild-type IL17REL knock-in alleviates colitis, while direct protein administration reduces colitis symptoms 1. In melanoma, IL17REL downregulation is associated with worse outcomes, and overexpression suppresses melanoma cell proliferation and migration 5, suggesting broader therapeutic potential beyond inflammatory diseases.