Hypo-osmotic stress induces the epithelial alarmin IL-33 in the colonic barrier of ulcerative colitis

Abstract

Epithelial alarmins are gaining interest as therapeutic targets for chronic infammation. The nuclear alarmin interleukin-33 (IL-33) is upregulated in the colonic mucosa of acute ulcerative colitis (UC) and may represent an early instigator of the infammatory cascade. However, it is not clear what signals drive the expression of IL-33 in the colonic mucosa, nor is the exact role of IL-33 elucidated. We established an ex vivo model using endoscopic colonic biopsies from healthy controls and UC patients. Colonic biopsies exposed to hypo-osmotic medium induced a strong nuclear IL-33 expression in colonic crypts in both healthy controls and UC biopsies. Mucosal IL33 mRNA was also signifcantly increased following hypo-osmotic stress in healthy controls compared to non-stimulated biopsies (fold change 3.9, p-value < 0.02). We observed a modest induction of IL-33 in response to TGF-beta-1 stimulation, whereas responsiveness to infammatory cytokines TNF and IFN-gamma was negligible. In conclusion our fndings indicate that epithelial IL-33 is induced by hypo-osmotic stress, rather than prototypic proinfammatory cytokines in colonic ex vivo biopsies. This is a novel fnding, linking a potent cytokine and alarmin of the innate immune system with cellular stress mechanisms and mucosal infammation