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J Immunol. 2017 Nov 1;199(9):3316-3325. doi: 10.4049/jimmunol.1700152. Epub 2017 Sep 22.

IL-22 Increases Permeability of Intestinal Epithelial Tight Junctions by Enhancing Claudin-2 Expression.

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Department of Oncology Research, MedImmune, Gaithersburg, MD 20878; and.
Department of Respiratory, Inflammation and Autoimmune Research, MedImmune, Gaithersburg, MD 20878.
Department of Oncology Research, MedImmune, Gaithersburg, MD 20878; and


Dysfunction of the epithelial barrier is a hallmark of inflammatory intestinal diseases. The intestinal epithelial barrier is maintained by expression of tight junctions that connect adjacent epithelial cells and seal the paracellular space. IL-22 is critical for the maintenance of intestinal barrier function through promoting antipathogen responses and regeneration of epithelial tissues in the gut. However, little is known about the effects of IL-22 on the regulation of tight junctions in the intestinal epithelium. In this study we report that IL-22 signals exclusively through the basolateral side of polarized Caco-2 cell monolayers. IL-22 treatment does not affect the flux of uncharged macromolecules across cell monolayers but significantly reduces transepithelial electrical resistance (TEER), indicating an increase of paracellular permeability for ions. IL-22 treatment on Caco-2 monolayers and on primary human intestinal epithelium markedly induces the expression of Claudin-2, a cation-channel-forming tight junction protein. Furthermore, treatment of IL-22 in mice upregulates Claudin-2 protein in colonic epithelial cells. Knocking down Claudin-2 expression with small interfering RNA reverses the reduction of TEER in IL-22-treated cells. Moreover, IL-22-mediated upregulation of Claudin-2 and loss of TEER can be suppressed with the treatment of JAK inhibitors. In summary, our results reveal that IL-22 increases intestinal epithelial permeability by upregulating Claudin-2 expression through the JAK/STAT pathway. These results provide novel mechanistic insights into the role of IL-22 in the regulation and maintenance of the intestinal epithelial barrier.

[Indexed for MEDLINE]

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