Journal
FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.840719
Keywords
IL-38; NLRP3; IL-1 alpha; IL-1 beta; colitis; IBD; inflammatory bowel diseases
Categories
Funding
- Interleukin Foundation
- NIH National Research Service Award (NRSA) fellowship [F30DK120072]
- NIH Medical Scientist Training Program (MSTP) training grant [T32GM008497]
- NIH [DK129410, AI-15614, DK1047893, DK50189, DK095491]
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IL-38 is a recently discovered cytokine that is primarily produced by B lymphocytes and functions to suppress inflammation. Studies have shown that a deficiency of IL-38 may contribute to the worsening of ulcerative colitis and Crohn's disease, and this is likely due to the disinhibition of the NLRP3 inflammasome and increased production of pro-inflammatory cytokines.
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-1 beta precursor into active IL-1 beta. Expression of IL-1 alpha, 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.
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