IL‐36γ and IL‐36Ra Reciprocally Regulate Colon Inflammation and Tumorigenesis by Modulating the Cell–Matrix Adhesion Network and Wnt Signaling

• Published in: Advanced science 2022-04, Vol.9 (10), p.e2103035-n/a
• Main Authors: Yang, Wei, Dong, Hong‐Peng, Wang, Peng, Xu, Zhi‐Gao, Xian, Jiahuan, Chen, Jiachen, Wu, Hai, Lou, Yang, Lin, Dandan, Zhong, Bo
• Format: Article
• Language: English
• Subjects: Animals; Bone marrow; Carcinogenesis; Cell-Matrix Junctions; cell–matrix adhesion; Clinical trials; Colitis - chemically induced; colon cancer; Colorectal cancer; Cytokines; Disease; Drinking water; IL‐36γ, IL‐36Ra; Inflammation; Inflammatory bowel disease; Interleukin-1; Interleukins; Kinases; Mice; Mice, Knockout; Morphology; Mutation; Proteins; Psoriasis; Roles; Skin; tumor microenvironment; Tumorigenesis; Wnt signaling; Wnt Signaling Pathway
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202103035

Inflammatory bowel disease and colorectal cancer are associated with dysregulation of cytokine networks. However, it is challenging to target cytokines for effective intervention because of the overlapping functions and unpredictable interactions of cytokines in such diverse networks. Here, it is shown that IL‐36γ and IL‐36Ra, an agonist and an antagonist for IL‐36R signaling respectively, reciprocally regulate the experimental colitis and the colon cancer development in mice. Knockout or neutralization of IL‐36γ alleviates dextran sulfate sodium (DSS)‐induced colitis and inhibits colon cancer development, whereas knockout of IL‐36Ra exacerbates DSS‐induced colitis and promotes colonic tumorigenesis in multiple colon cancer models in mice. Mechanistically, IL‐36γ upregulates extracellular matrix and cell–matrix adhesion molecules and facilitates Wnt signaling, which is mitigated by IL‐36Ra or IL‐36γ neutralizing antibody. Consistently, IL‐36γ levels are positively correlated with extracellular matrix levels and β‐catenin levels in human colorectal tumor biopsies. These findings suggest the critical role of IL‐36γ and IL‐36Ra in gut inflammation and tumorigenesis and indicate that targeting the IL‐36γ/IL‐36Ra signal balance provides potential therapeutic strategy for inflammatory bowel disease and gastrointestinal cancers. Inflammatory bowel disease and colorectal cancer are associated with dysregulation of cytokine networks. Here, it is shown that IL‐36γ promotes and IL‐36Ra reciprocally inhibits the experimental colitis and the colon cancer development in mice by modulating the cell–matrix network and Wnt signaling. These findings indicate that targeting IL‐36γ provides potential therapeutic strategy for inflammatory bowel disease and gastrointestinal cancers.