title: Interleukin-10 Enhances the Intestinal Epithelial Barrier in the Presence of Corticosteroids through p38 MAPK Activity in Caco-2 Monolayers: A Possible Mechanism for Steroid Responsiveness in Ulcerative Colitis.
abstract: Glucocorticosteroids are the first line therapy for moderate-severe flare-ups of ulcerative colitis. Despite that, up to 60% of patients do not respond adequately to steroid treatment. Previously, we reported that low IL-10 mRNA levels in intestine are associated with a poor response to glucocorticoids in active Crohn's disease. Here, we test whether IL-10 can favour the response to glucocorticoids by improving the TNFα-induced intestinal barrier damage (assessed by transepithelial electrical resistance) in Caco-2 monolayers, and their possible implications on glucocorticoid responsiveness in active ulcerative colitis. We show that the association of IL-10 and glucocorticoids improves the integrity of TNFα-treated Caco-2 cells and that p38 MAPK plays a key role. In vitro, IL-10 facilitates the nuclear translocation of p38 MAPK-phosphorylated thereby modulating glucocorticoids-receptor-α, IL-10-receptor-α and desmoglein-2 expression. In glucocorticoids-refractory patients, p38 MAPK phosphorylation and membrane desmoglein-2 expression are reduced in colonic epithelial cells. These results suggest that p38 MAPK-mediated synergism between IL-10 and glucocorticoids improves desmosome straightness contributing to the recovery of intestinal epithelium and reducing luminal antigens contact with lamina propria in ulcerative colitis. This study highlights the link between the intestinal epithelium in glucocorticoids-response in ulcerative colitis.
authors.affiliation: Inflammatory Bowel Disease Unit, Research Institute of Health Sciences 'Germans Trias i Pujol', Badalona, Barcelona, Spain; CIBER, Madrid, Spain.
authors.forename: Violeta
authors.initials: V
authors.lastname: Lorén
authors.affiliation: CIBER, Madrid, Spain; Inflammatory Bowel Disease & G-I Unit, Department of Gastroenterology, 'Germans Trias i Pujol' University Hospital, Badalona, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Cabré
authors.affiliation: Department of Pathology, 'Germans Trias i Pujol' University Hospital, Badalona Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ojanguren
authors.affiliation: CIBER, Madrid, Spain; Inflammatory Bowel Disease & G-I Unit, Department of Gastroenterology, 'Germans Trias i Pujol' University Hospital, Badalona, Barcelona, Spain.
authors.forename: Eugeni
authors.initials: E
authors.lastname: Domènech
authors.affiliation: Inflammatory Bowel Disease Unit, Research Institute of Health Sciences 'Germans Trias i Pujol', Badalona, Barcelona, Spain; CIBER, Madrid, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Pedrosa
authors.affiliation: Inflammatory Bowel Disease Unit, Research Institute of Health Sciences 'Germans Trias i Pujol', Badalona, Barcelona, Spain.
authors.forename: Arce
authors.initials: A
authors.lastname: García-Jaraquemada
authors.affiliation: CIBER, Madrid, Spain; Inflammatory Bowel Disease & G-I Unit, Department of Gastroenterology, 'Germans Trias i Pujol' University Hospital, Badalona, Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Mañosa
authors.affiliation: Inflammatory Bowel Disease Unit, Research Institute of Health Sciences 'Germans Trias i Pujol', Badalona, Barcelona, Spain; CIBER, Madrid, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Manyé
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000305:Adrenal Cortex Hormones / Q000378:metabolism* / Q000494:pharmacology; D001706:Biopsy; D018938:Caco-2 Cells; D003093:Colitis, Ulcerative / Q000378:metabolism*; D051301:Desmoglein 2 / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D053701:Receptors, Interleukin-10 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000305:Adrenal Cortex Hormones; D051301:Desmoglein 2; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D053701:Receptors, Interleukin-10; D014409:Tumor Necrosis Factor-alpha; C411470:glucocorticoid receptor alpha; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases