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24367025
IFN-γ-mediated induction of an apical IL-10 receptor on polarized intestinal epithelia.

J Immunol, 2014/2/01;192(3):1267-76.

Kominsky DJ[1], Campbell EL, Ehrentraut SF, Wilson KE, Kelly CJ, Glover LE, Collins CB, Bayless AJ, Saeedi B, Dobrinskikh E, Bowers BE, MacManus CF, Müller W, Colgan SP, Bruder D

Affiliations

PMID: 24367025DOI: 10.4049/jimmunol.1301757

Impact factor: 5.426

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-γ in models of inflammatory bowel disease. Guided by initial microarray analysis, in vitro studies revealed that IFN-γ 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-γ and IL-10 cytokines. In parallel, studies showed that treatment of mice with rIFN-γ was sufficient to drive expression of IL-10R1 in the colonic epithelium. Studies of dextran sodium sulfate colitis in intestinal epithelial-specific 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-γ.
MeSH terms
Animals; Cell Line; Cell Polarity; Colitis; Cytokines; Dextran Sulfate; Dextrans; Epithelial Cells; Fluorescein-5-isothiocyanate; Gene Expression Regulation; Humans; Interferon-gamma; Interleukin-10; Interleukin-10 Receptor alpha Subunit; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Permeability; Recombinant Proteins; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins
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