Document Detail


STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines.
MedLine Citation:
PMID:  23303670     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Michael 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; Keith T Wilson
Publication Detail:
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.     Date:  2013-01-09
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  190     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-04     Completed Date:  2013-03-28     Revised Date:  2014-10-10    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1849-58     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
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
Grant Support
ID/Acronym/Agency:
3R01AT004821-02S1/AT/NCCAM NIH HHS; 5R01AT004821-04/AT/NCCAM NIH HHS; I01 BX001453/BX/BLRD VA; K08 HD061607/HD/NICHD NIH HHS; K08HD061607/HD/NICHD NIH HHS; P01 CA116087/CA/NCI NIH HHS; P30 DK058404/DK/NIDDK NIH HHS; P30DK058404/DK/NIDDK NIH HHS; R01 AT004821/AT/NCCAM NIH HHS; U19 AI095227/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Adjuvants, Immunologic; 0/Claudin-2; 0/Cytokines; 0/Haptens; 0/STAT6 Transcription Factor; 0/Stat6 protein, mouse; 15646-46-5/Oxazolone
Comments/Corrections

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