Pro- and anti-inflammatory roles of interleukin (IL)-33, IL-36, and IL-38 in inflammatory bowel disease

Interleukin-33 (IL-33), IL-36, and IL-38 are members of the IL-1 cytokine family. The expression of each cytokine has been reported to be increased in the inflamed mucosa of patients with inflammatory bowel disease (IBD). IL-33 and IL-36 have been studied for pro- and anti-inflammatory functions, and IL-38 has been characterized as an anti-inflammatory cytokine by antagonizing the IL-36 receptor (IL-36R). IL-33 is a nuclear cytokine constitutively expressed by certain cell types such as epithelial, endothelial, and fibroblast-like cells and released on necrotic cell death. IL-33 mainly induces type 2 immune response through its receptor suppression tumorigenicity 2 (ST2) from Th2 cells and type 2 innate lymphoid cells (ILC2s), but also by stimulating Th1 cells, regulatory T cells, and CD8⁺ T cells. IL-36 cytokines consist of three agonists: IL-36α, IL-36β, and IL-36γ, and two receptor antagonists: IL-36R antagonist (IL-36Ra) and IL-38. All IL-36 cytokines bind to the IL-36R complex and exert various functions through NF-κB and mitogen-activated protein kinase (MAPK) pathways in inflammatory settings. IL-33 and IL-36 also play a crucial role in intestinal fibrosis characteristic manifestation of CD. In this review, we focused on the current understanding of the pro- and anti-inflammatory roles of IL-33, IL-36, and IL38 in experimental colitis and IBD patients.