IL-38 Gene Deletion Worsens Murine Colitis.

Autor:	de Graaf DM; Department of Medicine, University of Colorado Denver, Aurora, CO, United States.; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands., Wang RX; Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.; Medical Scientist Training Program, University of Colorado School of Medicine, Aurora, CO, United States., Amo-Aparicio J; Department of Medicine, University of Colorado Denver, Aurora, CO, United States., Lee JS; Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States., Dowdell AS; Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States., Tengesdal IW; Department of Medicine, University of Colorado Denver, Aurora, CO, United States., Marchetti C; Department of Medicine, University of Colorado Denver, Aurora, CO, United States., Colgan SP; Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States., Joosten LAB; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania., Dinarello CA; Department of Medicine, University of Colorado Denver, Aurora, CO, United States.; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 May 26; Vol. 13, pp. 840719. Date of Electronic Publication: 2022 May 26 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.840719
Abstrakt:	IL-38 is a recently discovered cytokine and member of the IL-1 Family. In the IL-1 Family, IL-38 is unique because the cytokine is primarily a B lymphocyte product and functions to suppress inflammation. Studies in humans with inflammatory bowel disease (IBD) suggest that IL-38 may be protective for ulcerative colitis or Crohn's disease, and that IL-38 acts to maintain homeostasis in the intestinal tract. Here we investigated the role of endogenous IL-38 in experimental colitis in mice deficient in IL-38 by deletion of exons 1-4 in C57 BL/6 mice. Compared to WT mice, IL-38 deficient mice subjected to dextran sulfate sodium (DSS) showed greater severity of disease, more weight loss, increased intestinal permeability, and a worse histological phenotype including increased neutrophil influx in the colon. Mice lacking IL-38 exhibited elevated colonic Nlrp3 mRNA and protein levels, increased caspase-1 activation, and the concomitant increased processing of IL-1β precursor into active IL-1β. Expression of IL-1α, an exacerbator of IBD, was also upregulated. Colonic myleloperoxidase protein and Il17a , and Il17f mRNA levels were higher in the IL-38 deficient mice. Daily treatment of IL-38 deficient mice with an NLRP3 inhibitor attenuated diarrhea and weight loss during the recovery phase. These data implicate endogenous IL-38 as an anti-inflammatory cytokine that reduces DSS colitis severity. We propose that a relative deficiency of IL-38 contributes to IBD by disinhibition of the NLRP3 inflammasome. Competing Interests: LJ serves on Olatec’s scientific advisory board and receives compensation. CD serves as chairman of Olatec’s scientific advisory board, is co-chief scientific officer, receives compensation, and has equity in Olatec. CM serves as director for Olatec’s innovative science program and has equity in Olatec. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 de Graaf, Wang, Amo-Aparicio, Lee, Dowdell, Tengesdal, Marchetti, Colgan, Joosten and Dinarello.)
Databáze:	MEDLINE
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