Growth hormone inhibits signal transducer and activator of transcription 3 activation and reduces disease activity in murine colitis.
OBJECTIVE
Constitutive signal transducer and activator of transcription (STAT) 3 activation promotes chronic inflammation and epithelial proliferation in murine colitis and human inflammatory bowel disease. SHP-2, through binding to the glycoprotein 130 signaling receptor, negatively regulates STAT3 activation. Growth hormone reduces disease activity and promotes mucosal healing in colitis and can activate SHP-2.


METHODS
We hypothesized that growth hormone administration would reduce disease activity in experimental colitis and that this would involve modulation of SHP-2/glycoprotein 130 association and STAT3 activation.


RESULTS
Growth hormone administration improved weight gain and colon histology in interleukin 10-null mice with colitis. Growth hormone reduced apoptosis and increased proliferation of crypt epithelial cells while increasing apoptosis of lamina propria mononuclear cells. Growth hormone increased SHP-2/glycoprotein 130 association and reduced colonic STAT3 activation in interleukin 10-null mice and in biopsy samples from patients with Crohn's colitis. Expression of the antiapoptotic protein bcl-2 was increased in crypt epithelial cells after growth hormone treatment. Growth hormone increased SHP-2/glycoprotein 130 binding and reduced interleukin 6-dependent STAT3 activation in the T84 human colon carcinoma and Jurkat human T-cell leukemia lines.


CONCLUSIONS
Growth hormone administration improves weight gain and reduces disease activity in interleukin 10-null mice with colitis. The improvement in disease activity is associated with increased SHP-2/glycoprotein 130 binding and reduced STAT3 activation in both murine and Crohn's colitis. Growth hormone may be a useful therapy in inflammatory bowel disease, in terms of both improving anabolic metabolism and enhancing mucosal healing.
Han
Xiaonan
X
Cincinnati Children's Hospital Medical cetner and the University of Cincinnati College of Medicine, Ohio, USA.
Sosnowska
Danuta
D
Bonkowski
Erin L
EL
Denson
Lee A
LA
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002648:Child; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms; D003424:Crohn Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D013006:Growth Hormone / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019169:Jurkat Cells; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*
D015703:Antigens, CD; D017252:CD3 Complex; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10; D050822:Cytokine Receptor gp130; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse