IL-36α expression is elevated in ulcerative colitis and promotes colonic inflammation

Abstract

A role for the IL-36 family of cytokines has been identified in the pathogenesis of psoriasis. Although significant mechanistic overlap can exist between psoriasis and inflammatory bowel disease (IBD), to date there have been no reports investigating the IL-36 family in gastrointestinal inflammation. Here we demonstrate that expression levels of IL-36α are specifically elevated in the colonic mucosa of ulcerative colitis patients. This elevated expression is mirrored in the inflamed colonic mucosa of mice, wherein IL-36 receptor deficiency confirmed this pathway as a mediator of mucosal inflammation. Il36r-/- mice exhibited reduced disease severity in an acute DSS-induced model of colitis in association with decreased innate inflammatory cell infiltration to the colon lamina propria. Consistent with these data, infection with the enteropathogenic bacteria Citrobacter rodentium, resulted in reduced innate inflammatory cell recruitment and increased bacterial colonization in the colons of il36r-/- mice. Il36r-/- mice also exhibited altered T helper cell responses in this model, with enhanced Th17 and reduced Th1 responses, demonstrating that IL-36R signaling also regulates intestinal mucosal T-cell responses. These data identify a novel role for IL-36 signaling in colonic inflammation and indicate that the IL-36R pathway may represent a novel target for therapeutic intervention in IBD.

Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease

“…IL-36 α and IL-36 γ induce the expression of CXC chemokines on human intestinal epithelial cell line HT-29 cells in dose-dependent and time-dependent manners [89]. IL-36R −/− mice reduced the intestinal inflammation in DSS-induced acute colitis, associated with decreased innate inflammatory cell infiltration into the colon lamina propria [91]. Similarly, after infection with the enteropathogenic bacteria Citrobacter rodentium , IL-36R −/− mice reduced innate inflammatory cell infiltration and increased bacterial colonization in the colon, with enhanced Th17 and reduced Th1 responses [91].…”

“…IL-36R −/− mice reduced the intestinal inflammation in DSS-induced acute colitis, associated with decreased innate inflammatory cell infiltration into the colon lamina propria [91]. Similarly, after infection with the enteropathogenic bacteria Citrobacter rodentium , IL-36R −/− mice reduced innate inflammatory cell infiltration and increased bacterial colonization in the colon, with enhanced Th17 and reduced Th1 responses [91]. Another group shows that IL-36 signaling may be important in the resolution of intestinal damage [92].…”

MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

“…IL‐36 family cytokines (IL‐36α, IL‐36β and IL‐36γ), which belong to the IL‐1 super‐family, have recently emerged as key regulators of immune responses at mucosal sites . They are expressed by a range of cell types, including mucosal epithelial cells, macrophages and dendritic cells, and induced in response to TLR signaling .…”

“…They are expressed by a range of cell types, including mucosal epithelial cells, macrophages and dendritic cells, and induced in response to TLR signaling . IL‐36 cytokines are potent stimulators of the expression of neutrophil chemokines, such as IL‐8 and chemokine (C‐X‐C motif) ligand 1 ( CXCL1 ), by mucosal epithelial cells and innate immune cells, and accordingly are important regulators of neutrophil responses during infection . IL‐36 cytokines can also regulate immune responses by stimulating the expression of T‐cell chemokines, including CXCL10 and chemokine (C‐C motif) ligand 20 ( CCL20 ) .…”

“…EBI3 also has IL‐12 family cytokine‐independent functions, including mediating IL‐6 trans ‐signaling in CD4 + T cells, and inhibiting collagen expression in dermal fibroblasts . Significantly, IL‐36 cytokines can synergize with IL‐12 to promote the Th1 polarization of naïve T cells, and conversely inhibit the development of T regulatory cells …”