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(American Journal of Pathology. 2006;169:1999-2013.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060186

Signal Transducer and Activator of Transcription 5b Promotes Mucosal Tolerance in Pediatric Crohn’s Disease and Murine Colitis

Xiaonan Han^*, Bankole Osuntokun^*, Nancy Benight^*, Kimberly Loesch, Stuart J. Frank and Lee A. Denson^*

From the Department of Pediatrics,^* Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio; the Departments of Cell Biology and Medicine, University of Alabama, Birmingham, Alabama; and the Endocrinology Section, Medical Service, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama

Growth hormone (GH) regulates anabolic metabolism via activation of the STAT5b transcription factor and reduces mucosal inflammation in colitis. Peroxisome proliferator-activated receptor (PPAR) 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 PPAR 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, PPAR, and nuclear factor B activation and expression were determined. Epithelial cell GH receptor expression and GH-dependent STAT5b activation and PPAR expression were reduced in CD colon. STAT5b-deficient mice exhibited reduced basal PPAR nuclear abundance and developed more severe proximal colitis after TNBS administration. This was associated with a significant increase in mucosal nuclear factor B 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 PPAR expression. Therapeutic activation of the GH:STAT5b axis therefore represents a novel target for restoring both normal anabolic metabolism and mucosal tolerance in CD.

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