The Roles of IL-36 Cytokines in Inflammatory Diseases and Cancers

The IL-36 family belongs to the IL-1 superfamily and has four members, including three agonists (IL-36α/β/γ) and one antagonist (IL-36Ra). IL-36 becomes active after the cleavage of N-terminal sequences by proteases. Activated IL-36 binds to IL-36R and recruits IL-1RAcP to form a ternary complex, thereby activating the downstream pro-inflammatory signaling pathway. IL-36Ra competitively binds to IL-36R with increased affinity over IL-36 agonists to prevent the recruitment of IL-1RAcP, thereby blocking the pro-inflammatory signaling. Dysregulation of IL-36 results in generalized pustular psoriasis, arthritis, infectious diseases and inflammatory bowel disease. Recent advances also reveal critical roles of IL-36 in NSCLC (non-small cell lung cancer) and colon cancer. In addition, neutralizing antibodies against IL-36γ have been implicated in attenuation of tumorigenesis and colon fibrosis in mouse models. This review first introduces the basic characteristics and signaling pathways of IL-36 cytokines, and then summarizes the roles of IL-36 cytokines in inflammatory diseases and tumorigenesis by modulating the immune microenvironment. Finally, this review looks forward to the potential application of targeting IL-36 and IL-36R signaling pathway in regulating inflammatory diseases and tumorigenesis.

CSTR: 32200.14.cjcb.2022.04.0020