Epithelial IL-1R2 acts as a homeostatic regulator during remission of ulcerative colitis

Abstract

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the large intestine. In most patients UC runs a remitting and relapsing course, with periods of active disease followed by phases of inactivity. Although current therapeutic options can induce remission in about 30-70% of patients, continuous pharmacological treatment is often required to avoid disease relapse. In order to promote sustained remission, endogenous mechanisms that support intestinal homeostasis and contain arising local inflammation must be identified. We aimed to identify endogenous regulatory mechanisms that may promote disease remission.

Transcriptional and protein analysis of the intestinal mucosa revealed that the IL-1 decoy receptor, interleukin-1 receptor type 2 (IL1R2), was up-regulated in remission compared to active UC and controls. IL-1R2 serves as a potent inhibitor of IL- 1 signaling by competing with IL-1R1 for IL-1, and by subsequently forming a complex with IL-1RAcP, thereby sequestering both the ligand and the accessory protein required for signal transduction.

We identified both IgA (but not IgG ) plasma cells and mucosal epithelial cells as the main producers of IL-1R2 in human colon. In order to determine IL-1R2 expression by epithelial cells, we used flow cytometry to quantify IL-1R2 production by the epithelial compartment in colonic biopsies. Samples from the involved mucosa of + UC in remission showed a significantly higher percentage of intracellular, IL-1R2 cells - + among CD45 Ep-CAM epithelial cells compared to control, uninvolved UC, and active UC samples.

Immunostaining analysis of colonic mucosa revealed a gradient expression of IL-1R2 along the crypt. In vitro expanded colonic stem cells (CoSCs) can be induced to differentiate by removing Wnt/beta-catenin activating signals from the culture media. Using this system, we demonstrated that both IL1R2 gene transcription and IL-1R2 protein secretion is significantly increased upon CoSCs in vitro differentiation. Using an ex vivo culture of intestinal epithelial crypts, we provide here novel evidence for the role of beta-catenin signaling in repressing IL-1R2 transcription and translation. Canonical Wnt signals activate beta-catenin and are critically involved in stem-cell proliferation and survival at the base of the intestinal crypts.

Moreover, blocking IL-1R2 in isolated colonic crypt cultures of UC patients in remission and T cell cultures stimulated with biopsy supernatant from UC patients in remission boosted IL-1β-dependent production of inflammation-related cytokines.

Our final objective was to address whether IL-1R2 overexpression could be related to disease outcome. In order to test this possibility, we looked at IL1R2 transcription in a cohort of UC patients in endoscopic and histologic remission that were followed up for one year after taking biopsies from the distal colon. IL1R2 transcription was significantly lower in the group of patients that relapsed during the follow-up period of 12 months compared with those patients that remained in endoscopic remission for the same amount of time. Interestingly, in patients who relapsed, IL1R2 expression negatively correlated with IFNG transcription. These data suggest that IL-1R2 may play a role in preventing disease relapse.

Collectively our results reveal that the IL-1/IL-1R2 axis is differentially regulated in the remitting intestinal mucosa of UC patients. We hypothesize that IL-1R2 in the presence of low concentrations of IL-1 may act locally as a regulator of intestinal homeostasis.