Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 169, Issue 6, Pages 1999-2013Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2006.060186
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Funding
- NCRR NIH HHS [M01 RR008084, M01 RR 08084] Funding Source: Medline
- NIDDK NIH HHS [DK63956, R01 DK058259, R56 DK058259, R01 DK002700, DK058259, R03 DK063956, R24 DK064403, K08 DK002700, DK02700, R24 DK64403] Funding Source: Medline
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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 PPAR gamma 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 wildtype controls, with and without rosiglitazone pretreatment. GH receptor, STAT5b, PPAR gamma, and nuclear factor kappa B activation and expression were determined. Epithelial cell GH receptor expression and GH-dependent STAT5b activation and PPAR gamma expression were reduced in CD colon. STAT5b-deficient mice exhibited reduced basal PPAR gamma nuclear abundance and developed more severe proximal colitis after TNBS administration. This was associated with a significant increase in mucosal nuclear factor kappa 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 gamma 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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