Tumour necrosis factor alpha blockade induces an anti-inflammatory growth hormone signalling pathway in experimental colitis.
BACKGROUND
Neutralisation of tumour necrosis factor alpha (TNFalpha) restores systemic growth hormone function in patients with Crohn's disease, and induces mucosal healing. Anabolic effects of growth hormone depend on activation of the STAT5 transcription factor. Although it has recently been reported that both administration of growth hormone and neutralisation of TNFalpha reduce mucosal inflammation in experimental colitis, whether this involved activation of STAT5 in the gut is not known.


OBJECTIVE
To determine whether TNFalpha blockade in colitis up regulates a growth hormone:STAT5 signalling pathway in the colon.


METHODS
Interleukin 10-deficient mice and wild-type controls received growth hormone or anti-TNFalpha antibody, and T84 human colon carcinoma cells were treated with TNFalpha or growth hormone. Activation and expression of STAT5b, peroxisome proliferator-activated receptor gamma (PPARgamma), NFkappaB/IkappaB and growth hormone receptor were determined.


RESULTS
Growth hormone activated STAT5b and up regulated expression of PPARgamma in normal mouse colon; inflamed colon was partially resistant to this. Chronic administration of growth hormone, nevertheless, significantly reduced activation of colonic NFkappaB (p = 0.028). Neutralisation of TNFalpha rapidly increased abundance of growth hormone receptor, activation of STAT5 and abundance of PPARgamma in the colon, but reduced activation of NFkappaB in colitis. Growth hormone activated STAT5, and directly reduced TNFalpha activation of NFkappaB, in T84 cells.


CONCLUSIONS
Reduced activation of colonic STAT5 and expression of PPARgamma may contribute to persistent mucosal inflammation in colitis. Up regulation of STAT5 and PPARgamma, either through neutralisation of TNFalpha or chronic administration of growth hormone, may exert an anti-inflammatory effect in inflammatory bowel disease.
Han
X
X
Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Benight
N
N
Osuntokun
B
B
Loesch
K
K
Frank
S J
SJ
Denson
L A
LA
D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000378:metabolism*; D003106:Colon / Q000378:metabolism; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000172:deficiency; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000032:analysis; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology; D015854:Up-Regulation / Q000502:physiology
D016328:NF-kappa B; D047495:PPAR gamma; D011986:Receptors, Somatotropin; C498144:Rela protein, mouse; D050799:STAT5 Transcription Factor; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019382:Human Growth Hormone; D016753:Interleukin-10