title: Signal transducer and activator of transcription 5b promotes mucosal tolerance in pediatric Crohn's disease and murine colitis.
abstract: Growth hormone (GH) regulates anabolic metabolism via activation of the STAT5b transcription factor and reduces mucosal inflammation in colitis. Peroxisome proliferator-activated receptor (PPAR) gamma suppresses mucosal inflammation and is regulated by GH through STAT5b. We hypothesized that the GH:STAT5b axis influences susceptibility to colitis via regulation of local PPARgamma abundance. Colon biopsies from children with newly diagnosed Crohn's disease (CD) and controls were exposed to GH in short-term organ culture. Trinitrobenzene sulfonic acid (TNBS) administration was used to induce colitis in STAT5b-deficient mice and wild-type controls, with and without rosiglitazone pretreatment. GH receptor, STAT5b, PPARgamma, and nuclear factor kappaB activation and expression were determined. Epithelial cell GH receptor expression and GH-dependent STAT5b activation and PPARgamma expression were reduced in CD colon. STAT5b-deficient mice exhibited reduced basal PPARgamma nuclear abundance and developed more severe proximal colitis after TNBS administration. This was associated with a significant increase in mucosal nuclear factor kappaB activation at baseline and after TNBS administration. Rosiglitazone ameliorated colitis in wild-type mice but not STAT5b-deficient mice. GH-dependent STAT5b activation is impaired in affected CD colon and contributes to chronic mucosal inflammation via down-regulation of local PPARgamma expression. Therapeutic activation of the GH:STAT5b axis therefore represents a novel target for restoring both normal anabolic metabolism and mucosal tolerance in CD.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, MLC 2010, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.forename: Bankole
authors.initials: B
authors.lastname: Osuntokun
authors.forename: Nancy
authors.initials: N
authors.lastname: Benight
authors.forename: Kimberly
authors.initials: K
authors.lastname: Loesch
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Frank
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D003092:Colitis / Q000628:therapy*; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D003424:Crohn Disease / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000077154:Rosiglitazone; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage
chemical_list: D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D047495:PPAR gamma; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D014302:Trinitrobenzenesulfonic Acid; C051815:somatotropin-binding protein