IFN-g-Mediated Induction of an Apical IL-10 Receptor on Polarized Intestinal Epithelia

Douglas J. Kominsky, Eric L. Campbell, Stefan F. Ehrentraut, Kelly E. Wilson, Caleb J. Kelly, Louise E. Glover, Colm B. Collins, Amanda J. Bayless, Bejan Saeedi, Evgenia Dobrinskikh, Brittelle E. Bowers, Christopher F. MacManus, Werner Müller, Sean P. Colgan, Dunja Bruder

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Cytokines secreted at sites of inflammation impact the onset, progression, and resolution of inflammation. In this article, we investigated potential proresolving mechanisms of IFN-g in models of inflammatory bowel disease. Guided by initial microarray analysis, in vitro studies revealed that IFN-g selectively induced the expression of IL-10R1 on intestinal epithelia. Further analysis revealed that IL-10R1 was expressed predominantly on the apical membrane of polarized epithelial cells. Receptor activation functionally induced canonical IL-10 target gene expression in epithelia, concomitant with enhanced barrier restitution. Furthermore, knockdown of IL-10R1 in intestinal epithelial cells results in impaired barrier function in vitro. Colonic tissue isolated from murine colitis revealed that levels of IL-10R1 and suppressor of cytokine signaling 3 were increased in the epithelium and coincided with increased tissue IFN-g and IL-10 cytokines. In parallel, studies showed that treatment of mice with rIFN-g was sufficient to drive expression of IL-10R1 in the colonic epithelium. Studies of dextran sodium sulfate colitis in intestinal epithelialspecific IL-10R1-null mice revealed a remarkable increase in disease susceptibility associated with increased intestinal permeability. Together, these results provide novel insight into the crucial and underappreciated role of epithelial IL-10 signaling in the maintenance and restitution of epithelial barrier and of the temporal regulation of these pathways by IFN-g. Copyright © 2014 by The American Association of Immunologists, Inc.
    Original languageEnglish
    Pages (from-to)1267-1276
    Number of pages9
    JournalJournal of Immunology
    Volume192
    Issue number3
    DOIs
    Publication statusPublished - 1 Feb 2014

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