title: Regulation of intestinal barrier function by signal transducer and activator of transcription 5b.
abstract: BACKGROUND
  Colon epithelial cell (CEC) apoptosis and nuclear factor-kappaB (NF-kappaB) activation may compromise barrier function, and it has been reported that signal transducer and activator of transcription 5b (STAT5b)-deficient mice exhibit increased susceptibility to colitis. It is hypothesised that the growth hormone (GH) target STAT5b maintains mucosal barrier integrity by promoting CEC survival and inhibiting NF-kappaB activation.
  
  
  METHODS
  The GH effect upon mucosal injury due to 2,4,6-trinitro-benzenesulfonic acid (TNBS) administration was determined in STAT5b-deficient mice and wild-type (WT) controls. The effect of STAT5b deficiency upon CEC survival and NF-kappaB activation was determined and related to differences in intestinal permeability and bacterial translocation. RNA interference (RNAi) was used to knock down STAT5b expression in the T84 CEC line, and the effect upon basal and GH-dependent regulation of proapoptotic and inflammatory pathways induced by tumour necrosis factor alpha (TNFalpha) was determined.
  
  
  RESULTS
  GH suppression of mucosal inflammation in TNBS colitis was abrogated in STAT5b-deficient mice. STAT5b deficiency led to activation of a proapoptotic pattern of gene expression in the colon, and increased mucosal permeability. The frequency of apoptotic CECs was increased in STAT5b-deficient mice while tight junction protein abundance was reduced. This was associated with upregulation of CEC Toll-like receptor 2 expression and NF-kappaB activation. STAT5b knockdown in T84 CEC increased TNFalpha-dependent NF-kappaB and caspase-3 activation. GH inhibition of TNFalpha signalling was prevented by STAT5b knockdown.
  
  
  CONCLUSIONS
  STAT5b maintains colonic barrier integrity by modulating CEC survival and NF-kappaB activation. STAT5b activation may therefore represent a novel therapeutic target in inflammatory bowel disease.
authors.affiliation: MLC 2010, Cincinnati, OH 45229-3039, USA.
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.forename: X
authors.initials: X
authors.lastname: Ren
authors.forename: I
authors.initials: I
authors.lastname: Jurickova
authors.forename: K
authors.initials: K
authors.lastname: Groschwitz
authors.forename: B A
authors.initials: BA
authors.lastname: Pasternak
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: T A
authors.initials: TA
authors.lastname: Wilson
authors.forename: S P
authors.initials: SP
authors.lastname: Hogan
authors.forename: L A
authors.initials: LA
authors.lastname: Denson
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D003106:Colon / Q000378:metabolism / Q000503:physiopathology*; D016207:Cytokines / Q000096:biosynthesis; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D013006:Growth Hormone / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D050799:STAT5 Transcription Factor / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014302:Trinitrobenzenesulfonic Acid; D013006:Growth Hormone; C505409:Casp3 protein, mouse; D053148:Caspase 3