Signal transducer and activator of transcription 5b promotes mucosal tolerance in pediatric Crohn's disease and murine colitis.
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.
Han
Xiaonan
X
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.
Osuntokun
Bankole
B
Benight
Nancy
N
Loesch
Kimberly
K
Frank
Stuart J
SJ
Denson
Lee A
LA
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
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