title: Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium.
abstract: In inflammatory bowel diseases (IBD), intestinal barrier function is impaired as a result of deteriorations in epithelial tight junction (TJ) structure. IL-6, a pleiotropic cytokine, is elevated in IBD patients, although the role of IL-6 in barrier function remains unknown. We present evidence that IL-6 increases TJ permeability by stimulating the expression of channel-forming claudin-2, which is required for increased caudal-related homeobox (Cdx) 2 through the MEK/ERK and PI3K pathways in intestinal epithelial cells. IL-6 increases the cation-selective TJ permeability without any changes to uncharged dextran flux or cell viability in Caco-2 cells. IL-6 markedly induces claudin-2 expression, which is associated with increased TJ permeability. The colonic mucosa of mice injected with IL-6 also exhibits an increase in claudin-2 expression. The claudin-2 expression and TJ permeability induced by IL-6 are sensitive to the inhibition of gp130, MEK, and PI3K. Furthermore, expression of WT-MEK1 induces claudin-2 expression in Caco-2 cells. Claudin-2 promoter activity is increased by IL-6 in a MEK/ERK and PI3K-dependent manner, and deletion of Cdx binding sites in the promoter sequence results in a loss of IL-6-induced promoter activity. IL-6 increases Cdx2 protein expression, which is suppressed by the inhibition of MEK and PI3K. These observations may reveal an important mechanism by which IL-6 can undermine the integrity of the intestinal barrier.
authors.affiliation: Department of Biofunctional Science and Technology, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Suzuki
authors.forename: Naho
authors.initials: N
authors.lastname: Yoshinaga
authors.forename: Soichi
authors.initials: S
authors.lastname: Tanabe
mesh_terms: D000818:Animals; D001665:Binding Sites; D057167:Claudins / Q000096:biosynthesis / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D010539:Permeability; D019869:Phosphatidylinositol 3-Kinases; D011401:Promoter Regions, Genetic; D019108:Tight Junctions / Q000378:metabolism*
chemical_list: D057167:Claudins; C113371:Cldn2 protein, mouse; D015850:Interleukin-6; D019869:Phosphatidylinositol 3-Kinases; D020929:Mitogen-Activated Protein Kinase Kinases