Tumour necrosis factor α blockade induces an anti-inflammatory growth hormone signalling pathway in experimental colitis

Han, X.; Benight, N.; Osuntokun, B.; Loesch, K.; Frank, S. J.; Denson, L. A.
January 2007
Gut;Jan2007, Vol. 56 Issue 1, p73
Academic Journal
Background: Neutralisation of tumour necrosis factor α (TNFα)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 TNFα reduce mucosal inflammation in experimental colitis, whether this involved activation of STAT5 in the gut is not known. Aim: To determine whether TNFα 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-TNFα antibody, and 184 human colon carcinoma cells were treated with TNFα or growth hormone. Activation and expression of STAT5b, peroxisome proliferator-activated receptor gamma (PPARγ), NFκB/∣κB and growth hormone receptor were determined. Results: Growth hormone activated STAT5b and up regulated expression of PPAR1 in normal mouse colon; inflamed colon was partially resistant to this. Chronic administration of growth hormone, nevertheless, significantly reduced activation of colonic NFKB (p=0.028}. Neutralisation of TNFκ rapidly increased abundance of growth hormone receptor, activation of STAT5 and abundance of PPARγ in the colon, but reduced activation of NFKB in colitis. Growth hormone activated STAT5, and directly reduced TNFκ activation of NFκB, in T84 cells. Conclusions: Reduced activation of colonic STAT5 and expression of PPARγ may contribute to persistent mucosal inflammation in colitis. Up regulation of 51A15 and PPARγ, either through neutralisation of TNFα or chronic administration of growth hormone, may exert an anti-inflammatory effect in inflammatory bowel disease.


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