TY - JOUR
T1 - IFN-g-Mediated Induction of an Apical IL-10 Receptor on Polarized Intestinal Epithelia
AU - Kominsky, Douglas J.
AU - Campbell, Eric L.
AU - Ehrentraut, Stefan F.
AU - Wilson, Kelly E.
AU - Kelly, Caleb J.
AU - Glover, Louise E.
AU - Collins, Colm B.
AU - Bayless, Amanda J.
AU - Saeedi, Bejan J.
AU - Dobrinskikh, Evgenia
AU - Bowers, Brittelle E.
AU - MacManus, Christopher F.
AU - Müller, Werner
AU - Colgan, Sean P.
AU - Bruder, Dunja
PY - 2014/2/1
Y1 - 2014/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84893378205&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1301757
DO - 10.4049/jimmunol.1301757
M3 - Article
C2 - 24367025
AN - SCOPUS:84893378205
SN - 0022-1767
VL - 192
SP - 1267
EP - 1276
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -