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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.
AuthorsMichael J Rosen, Rupesh Chaturvedi, M Kay Washington, Lindsay A Kuhnhein, Preston D Moore, Scott S Coggeshall, Elizabeth M McDonough, Jörn-Hendrik Weitkamp, Amar B Singh, Lori A Coburn, Christopher S Williams, Fang Yan, Luc Van Kaer, R Stokes Peebles Jr, Keith T Wilson
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 190 Issue 4 Pg. 1849-58 (Feb 15 2013) ISSN: 1550-6606 [Electronic] United States
PMID23303670 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Adjuvants, Immunologic
  • Claudin-2
  • Cytokines
  • Haptens
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Oxazolone
Topics
  • Adjuvants, Immunologic (administration & dosage, adverse effects, antagonists & inhibitors)
  • Animals
  • Cell Line
  • Claudin-2 (antagonists & inhibitors, biosynthesis, genetics)
  • Colitis, Ulcerative (chemically induced, immunology, prevention & control)
  • Cytokines (antagonists & inhibitors, biosynthesis, genetics)
  • Disease Models, Animal
  • Down-Regulation (genetics, immunology)
  • Gene Expression Regulation (immunology)
  • Haptens (administration & dosage, adverse effects)
  • Humans
  • Intestinal Mucosa (immunology, metabolism, pathology)
  • Male
  • Mice
  • Mice, Knockout
  • Natural Killer T-Cells (immunology, metabolism, pathology)
  • Oxazolone (administration & dosage, adverse effects, antagonists & inhibitors)
  • STAT6 Transcription Factor (deficiency, genetics)
  • Severity of Illness Index
  • Th2 Cells (immunology, metabolism, pathology)

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