The anti-inflammatory and protective role of interleukin-38 in inflammatory bowel disease

• Published in: Journal of Clinical Biochemistry and Nutrition Vol. 70; no. 1; pp. 64 - 71
• Main Authors: Inatomi, Osamu, Andoh, Akira, Imai, Takayuki, Ohno, Masashi, Nishida, Atsushi, Kawahara, Masahiro, Chatani, Motoharu, Hoshino, Tomoaki
• Format: Journal Article
• Language: English
• Published: Japan SOCIETY FOR FREE RADICAL RESEARCH JAPAN 01.01.2022; Japan Science and Technology Agency; the Society for Free Radical Research Japan
• Subjects: Biopsy; Crohn's disease; CXC chemokines; Cytokine receptors; Cytokines; Dextran; Dextran sulfate; Dextrans; Gene expression; Immunofluorescence; Inflammatory bowel disease; Inflammatory bowel diseases; interleukin-36; interleukin-38; Interleukins; Intestine; Kinases; Lymphocytes B; Mucosa; NF-κB protein; Original; Protein expression; Protein kinase; Proteins; Receptor mechanisms; Receptors; Ulcerative colitis; interleukin-36; ulcerative colitis; interleukin-38; inflammatory bowel disease
• ISSN: 0912-0009; 1880-5086; 1880-5086
• DOI: 10.3164/jcbn.21-104

Interleukin (IL)-38 exerts an anti-inflammatory function by binding to several cytokine receptors, including the IL-36 receptor. In this study, we evaluated IL-38 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and investigated its functions. IL-38 mRNA expression in endoscopic biopsy samples was evaluated using quantitative PCR. IL-38 protein expression was analyzed using immunohistochemical technique. Dextran sulfate sodium-induced colitis was induced in C57BL/6 background IL-38KO mice. The IL-38 mRNA and protein expression were enhanced in the active mucosa of ulcerative colitis, but not in Crohn’s disease. The ratio of IL-36γ to IL-38 mRNA expression was significantly elevated in the active mucosa of UC patients. Immunofluorescence staining revealed that B cells are the major cellular source of IL-38 in the colonic mucosa. IL-38 dose-dependently suppressed the IL-36γ-induced mRNA expression of CXC chemokines (CXCL1, CXCL2, and CXCL8) in HT-29 and T84 cells. IL-38 inhibited the IL-36γ-induced activation of nuclear-factor kappa B (NF-κB) and mitogen-activated protein kinases in HT-29 cells. DSS-colitis was significantly exacerbated in IL-38KO mice compared to wild type mice. In conclusion, IL-38 may play an anti-inflammatory and protective role in the pathophysiology of IBD, in particular ulcerative colitis, through the suppression of IL-36-induced inflammatory responses.