title: IFN-γ-mediated induction of an apical IL-10 receptor on polarized intestinal epithelia.
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.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kominsky
authors.forename: Eric L
authors.initials: EL
authors.lastname: Campbell
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Ehrentraut
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Wilson
authors.forename: Caleb J
authors.initials: CJ
authors.lastname: Kelly
authors.forename: Louise E
authors.initials: LE
authors.lastname: Glover
authors.forename: Colm B
authors.initials: CB
authors.lastname: Collins
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bayless
authors.forename: Bejan
authors.initials: B
authors.lastname: Saeedi
authors.forename: Evgenia
authors.initials: E
authors.lastname: Dobrinskikh
authors.forename: Brittelle E
authors.initials: BE
authors.lastname: Bowers
authors.forename: Christopher F
authors.initials: CF
authors.lastname: MacManus
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
authors.forename: Dunja
authors.initials: D
authors.lastname: Bruder
mesh_terms: D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D016264:Dextran Sulfate / Q000633:toxicity; D003911:Dextrans / Q000493:pharmacokinetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology*; D053709:Interleukin-10 Receptor alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016207:Cytokines; D003911:Dextrans; C508609:IL10 protein, human; C556062:IL10 protein, mouse; D053709:Interleukin-10 Receptor alpha Subunit; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C015219:fluorescein isothiocyanate dextran; D016753:Interleukin-10; D007371:Interferon-gamma; D016264:Dextran Sulfate; D016650:Fluorescein-5-isothiocyanate