STAT6 Deficiency Ameliorates Severity of Oxazolone Colitis by Decreasing Expression of Claudin-2 and Th2-Inducing Cytokines
| Autor: | Lindsay A. Kuhnhein, Rupesh Chaturvedi, Luc Van Kaer, Elizabeth M. McDonough, R. Stokes Peebles, Jörn-Hendrik Weitkamp, M. Kay Washington, Fang Yan, Keith T. Wilson, Michael J. Rosen, Amar B. Singh, Preston D. Moore, Lori A. Coburn, Christopher S. Williams, Scott S. Coggeshall |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Thymic stromal lymphopoietin medicine.medical_treatment T cell Immunology Down-Regulation Inflammation Biology Severity of Illness Index Article Cell Line Oxazolone Mice chemistry.chemical_compound Th2 Cells Immune system Adjuvants Immunologic parasitic diseases medicine Animals Humans Immunology and Allergy Claudin-2 Intestinal Mucosa Colitis Mice Knockout integumentary system respiratory system Natural killer T cell medicine.disease Disease Models Animal Cytokine medicine.anatomical_structure Gene Expression Regulation chemistry Cancer research Cytokines Natural Killer T-Cells Colitis Ulcerative medicine.symptom STAT6 Transcription Factor Haptens |
| Zdroj: | The Journal of Immunology. 190:1849-1858 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1201373 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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