title: STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines.
abstract: Patients suffering from ulcerative colitis (UC) exhibit chronic colonic inflammation caused by a dysregulated mucosal immune response and epithelial barrier disruption. Th2 cytokines, including IL-13, have been implicated in the pathogenesis of UC. IL-13 induces phosphorylation of STAT6, and we previously demonstrated increased epithelial p-STAT6 in children with UC. In this study, we investigated the role of STAT6 in oxazolone colitis, a murine model of UC, by inducing colitis in STAT6-deficient (STAT6(-/-)) and wild type (WT) mice. We observed increased epithelial cell, T cell, macrophage, and NKT cell STAT6 phosphorylation, as well as increased p-STAT6(+) IL-13-producing NKT cells, in colitic WT mice. Colitis was attenuated in STAT6(-/-) mice, with improvements in weight, colon length, and histopathology. There was decreased induction of the pore-forming tight junction protein claudin-2 in STAT6(-/-) mice. Similarly, short hairpin RNA STAT6 knockdown reduced claudin-2 induction and transepithelial resistance decrease in IL-13-treated human T84 cells. Tissue expression of IL-13, IFN-γ, IL-17, and IL-10 mRNA was similarly induced in WT and STAT6(-/-) colitic mice; however, we observed increased mRNA expression for the Th2-inducing cytokines IL-33 and thymic stromal lymphopoietin in WT mice with colitis, which was abrogated in STAT6(-/-) mice. Mesenteric lymph node cells from STAT6(-/-) mice with colitis exhibited reduced secretion of IL-4, IL-5, IL-13, and IFN-γ. IL-33 augmented mesenteric lymph node cell secretion of IL-5, IL-13, IL-6, and IFN-γ. These data implicate STAT6 in the pathogenesis of colitis in vivo with important roles in altering epithelial barrier function and regulating Th2-inducing cytokine production.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rosen
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Kuhnhein
authors.forename: Preston D
authors.initials: PD
authors.lastname: Moore
authors.forename: Scott S
authors.initials: SS
authors.lastname: Coggeshall
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McDonough
authors.forename: Jörn-Hendrik
authors.initials: JH
authors.lastname: Weitkamp
authors.forename: Amar B
authors.initials: AB
authors.lastname: Singh
authors.forename: Lori A
authors.initials: LA
authors.lastname: Coburn
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Williams
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors; D000818:Animals; D002460:Cell Line; D062446:Claudin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006241:Haptens / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010081:Oxazolone / Q000008:administration & dosage* / Q000009:adverse effects / Q000037:antagonists & inhibitors; D050800:STAT6 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D012720:Severity of Illness Index; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D062446:Claudin-2; D016207:Cytokines; D006241:Haptens; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D010081:Oxazolone