title: STAT6 activation in ulcerative colitis: a new target for prevention of IL-13-induced colon epithelial cell dysfunction.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, Nashville, TN, USA. michael.rosen@vanderbilt.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rosen
authors.forename: Mark R
authors.initials: MR
authors.lastname: Frey
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Kuhnhein
authors.forename: Poojitha
authors.initials: P
authors.lastname: Matta
authors.forename: Frank L
authors.initials: FL
authors.lastname: Revetta
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.forename: D Brent
authors.initials: DB
authors.lastname: Polk
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D018793:Interleukin-13 / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D000077337:Vorinostat
chemical_list: C491875:CLDN2 protein, human; D057167:Claudins; D006877:Hydroxamic Acids; D018793:Interleukin-13; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D000077337:Vorinostat