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

Background: Neutralisation of tumour necrosis factor alpha (TNF alpha) 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 TNF alpha reduce mucosal inflammation in experimental colitis, whether this involved activation of STAT5 in the gut is not known. Aim: To determine whether TNFa 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-TNF alpha antibody, and T84 human colon carcinoma cells were treated with TNF alpha or growth hormone. Activation and expression of STAT5b, peroxisome proliferator-activated receptor gamma (PPAR gamma), NF kappa B/I kappa B and growth hormone receptor were determined. Results: Growth hormone activated STAT5b and up regulated expression of PPAR gamma in normal mouse colon; inflamed colon was partially resistant to this. Chronic administration of growth hormone, nevertheless, significantly reduced activation of colonic NF kappa B (p=0.028). Neutralisation of TNF alpha rapidly increased abundance of growth hormone receptor, activation of STAT5 and abundance of PPAR gamma in the colon, but reduced activation of NF kappa B in colitis. Growth hormone activated STAT5, and directly reduced TNF alpha activation of NFkB, in T84 cells. Conclusions: Reduced activation of colonic STAT5 and expression of PPAR gamma may contribute to persistent mucosal inflammation in colitis. Up regulation of STAT5 and PPAR gamma, either through neutralisation of TNF alpha or chronic administration of growth hormone, may exert an anti-inflammatory effect in inflammatory bowel disease.