STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of Claudin-2 and Th2-inducing cytokines

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. Jr., Keith T. Wilson

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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.

Original languageEnglish (US)
Pages (from-to)1849-1858
Number of pages10
JournalJournal of Immunology
Volume190
Issue number4
DOIs
StatePublished - Feb 15 2013

Fingerprint

Claudin-2
Oxazolone
Colitis
Interleukin-13
Cytokines
Ulcerative Colitis
Natural Killer T-Cells
Interleukin-5
Zonula Occludens-2 Protein
Lymph Nodes
Phosphorylation
Mucosal Immunity
Messenger RNA
Interleukin-17
Interleukin-4
Interleukin-10
Small Interfering RNA
Interleukin-6
Colon
Epithelial Cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Rosen, M. J., Chaturvedi, R., Washington, M. K., Kuhnhein, L. A., Moore, P. D., Coggeshall, S. S., ... Wilson, K. T. (2013). STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of Claudin-2 and Th2-inducing cytokines. Journal of Immunology, 190(4), 1849-1858. https://doi.org/10.4049/jimmunol.1201373

STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of Claudin-2 and Th2-inducing cytokines. / Rosen, Michael J.; Chaturvedi, Rupesh; Washington, M. Kay; Kuhnhein, Lindsay A.; Moore, Preston D.; Coggeshall, Scott S.; McDonough, Elizabeth M.; Weitkamp, Jörn Hendrik; Singh, Amar B.; Coburn, Lori A.; Williams, Christopher S.; Yan, Fang; Van Kaer, Luc; Peebles. Jr., R. Stokes; Wilson, Keith T.

In: Journal of Immunology, Vol. 190, No. 4, 15.02.2013, p. 1849-1858.

Research output: Contribution to journalArticle

Rosen, MJ, Chaturvedi, R, Washington, MK, Kuhnhein, LA, Moore, PD, Coggeshall, SS, McDonough, EM, Weitkamp, JH, Singh, AB, Coburn, LA, Williams, CS, Yan, F, Van Kaer, L, Peebles. Jr., RS & Wilson, KT 2013, 'STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of Claudin-2 and Th2-inducing cytokines', Journal of Immunology, vol. 190, no. 4, pp. 1849-1858. https://doi.org/10.4049/jimmunol.1201373
Rosen, Michael J. ; Chaturvedi, Rupesh ; Washington, M. Kay ; Kuhnhein, Lindsay A. ; Moore, Preston D. ; Coggeshall, Scott S. ; McDonough, Elizabeth M. ; Weitkamp, Jörn Hendrik ; Singh, Amar B. ; Coburn, Lori A. ; Williams, Christopher S. ; Yan, Fang ; Van Kaer, Luc ; Peebles. Jr., R. Stokes ; Wilson, Keith T. / STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of Claudin-2 and Th2-inducing cytokines. In: Journal of Immunology. 2013 ; Vol. 190, No. 4. pp. 1849-1858.
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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.",
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AU - Rosen, Michael J.

AU - Chaturvedi, Rupesh

AU - Washington, M. Kay

AU - Kuhnhein, Lindsay A.

AU - Moore, Preston D.

AU - Coggeshall, Scott S.

AU - McDonough, Elizabeth M.

AU - Weitkamp, Jörn Hendrik

AU - Singh, Amar B.

AU - Coburn, Lori A.

AU - Williams, Christopher S.

AU - Yan, Fang

AU - Van Kaer, Luc

AU - Peebles. Jr., R. Stokes

AU - Wilson, Keith T.

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N2 - 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.

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