Supported by National Institutes of Health grants 2T32DK007673-16, R01DK056008 (to D.B.P.), 5R01AT004821-03 and 3R01AT004821-02S1 (to K.T.W.), K01DK077956 (to M.R.F.), American College of Gastroenterology Clinical Research Award (to M.J.R.), NASPGHAN Fellow to Faculty Transition Award and George Ferry Young Investigator Award (to M.J.R.), a Vanderbilt Physician Scientist Development Award (to M.J.R.), and the Vanderbilt Digestive Diseases Research Center (NIH P30DK058404) including the Center's Pilot and Feasibility Program, Flow Cytometry and Cellular and Animal Modeling Shared Resources.
STAT6 activation in ulcerative colitis: A new target for prevention of IL-13-induced colon epithelial cell dysfunction†
Version of Record online: 9 FEB 2011
Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 17, Issue 11, pages 2224–2234, November 2011
How to Cite
Rosen, M. J., Frey, M. R., Washington, M. K., Chaturvedi, R., Kuhnhein, L. A., Matta, P., Revetta, F. L., Wilson, K. T. and Polk, D. B. (2011), STAT6 activation in ulcerative colitis: A new target for prevention of IL-13-induced colon epithelial cell dysfunction. Inflamm Bowel Dis, 17: 2224–2234. doi: 10.1002/ibd.21628
- Issue online: 10 OCT 2011
- Version of Record online: 9 FEB 2011
- Manuscript Accepted: 8 DEC 2010
- Manuscript Received: 1 DEC 2010
- ulcerative colitis;
- STAT6 transcription factor;
- suberoylanilide hydroxamic acid;
- cell membrane permeability
Interleukin 13 (IL-13) is upregulated in ulcerative colitis (UC) and increases colon epithelial permeability by inducing apoptosis and expression of the pore-forming tight junction protein claudin-2. IL-13 induces activation of signal transducer and activator of transcription 6 (STAT6). However, the STAT6 phosphorylation status in patients with UC is unknown, as is the effect of STAT6 inhibition on colonic epithelium exposed to IL-13. The study aims were to determine if mucosal STAT6 phosphorylation is increased in patients with UC, and if STAT6 inhibition attenuates IL-13-induced colon epithelial cell dysfunction.
Immunohistochemical staining for phosphorylated (p) STAT6 was performed on colonic tissue from newly diagnosed pediatric subjects with UC (early UC) or Crohn's disease (CD), colectomy tissue from adults with UC (advanced UC), and controls. Colon HT-29 and T84 cells were transfected with STAT6 small interfering RNA (siRNA), or treated with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor that inhibits STAT6, prior to IL-13 treatment.
The median score for epithelial pSTAT6 was 0 in control subjects, 2 in early UC (versus control P = 0.019), 4 in advanced UC (P = 0.003), and 0 in CD (P = 0.4). Cell transfection with STAT6 siRNA prevented IL-13-induced apoptosis and claudin-2 expression. SAHA inhibited IL-13-induced STAT6 phosphorylation, apoptosis, and claudin-2 expression, and mitigated IL-13-induced reductions in transepithelial resistance.
UC is associated with increased colonic epithelial STAT6 phosphorylation, and STAT6 inhibition prevents IL-13-induced apoptosis and barrier disruption. These data identify STAT6 as a novel target for UC treatment and support further study of SAHA as a therapeutic agent. (Inflamm Bowel Dis 2011;)