title: Glucocorticoids regulate barrier function and claudin expression in intestinal epithelial cells via MKP-1.
abstract: Barrier dysfunction is pivotal to the pathogenesis of inflammatory bowel diseases (IBD) and collagenous colitis. Glucocorticoids restore barrier function in Crohn's disease, but whether this reflects attenuated inflammation or an epithelial-specific action has not yet been addressed. Using filter-grown Caco-2 monolayers as an in vitro model of the intestinal epithelial barrier, we observed that glucocorticoids induced a time- and dose-dependent increase in transepithelial electrical resistance (TEER) in a glucocorticoid receptor-dependent manner without altering flux of larger solutes or changing principal tight junction architecture. This was accompanied by reduced paracellular cation flux, reduced expression of the pore-forming tight junction component claudin-2, and upregulation of the sealing tight junction protein claudin-4. In contrast, expression of occludin, claudin-1, -7, or -8 was not altered. Dexamethasone increased expression and activity of MAPK phosphatase-1 and inhibition of this phosphatase prevented the glucocorticoid-induced changes in TEER and claudin expression, whereas inhibiting p38 or MEK1/2 was not sufficient to replicate the glucocorticoid effects. Upon exposure to IFN-γ, TNF-α, or IL-1β, TEERs declined in dexamethasone-treated cells but remained consistently higher than in cells not receiving glucocorticoids. Treatment with IFN/TNF resulted in an upregulation of claudin-2 that was significantly attenuated by dexamethasone, whereas increased claudin-2 expression upon IL-1β stimulation was not affected by glucocorticoids. Taken together, barrier augmentation might represent a previously unrecognized mechanism of action, potentially contributing to the therapeutic efficacy of glucocorticoids in IBD and collagenous colitis.
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology Campus Virchow Klinikum and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fischer
authors.forename: Markus
authors.initials: M
authors.lastname: Gluth
authors.forename: Friderike
authors.initials: F
authors.lastname: Weege
authors.forename: Ulrich-Frank
authors.initials: UF
authors.lastname: Pape
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Baumgart
authors.forename: Franz
authors.initials: F
authors.lastname: Theuring
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D057167:Claudins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D062793:Occludin / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D057167:Claudins; D005938:Glucocorticoids; D062793:Occludin; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: IL-1β; claudin; collagenous colitis; inflammatory bowel disease; tight junction