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Tumour necrosis factor α blockade induces an anti-inflammatory growth hormone signalling pathway in experimental colitis
  1. X Han1,
  2. N Benight1,
  3. B Osuntokun1,
  4. K Loesch2,
  5. S J Frank2,
  6. L A Denson1
  1. 1Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  2. 2Department of Cell Biology, University of Alabama at Birmingham, Alabama, USA
  1. Correspondence to:
    Dr L A Denson
    MLC 2010, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; lee.denson{at}cchmc.org

Abstract

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 T84 human colon carcinoma cells were treated with TNFα or growth hormone. Activation and expression of STAT5b, peroxisome proliferator-activated receptor gamma (PPARγ), NFκB/IκB and growth hormone receptor were determined.

Results: Growth hormone activated STAT5b and up regulated expression of PPARγ in normal mouse colon; inflamed colon was partially resistant to this. Chronic administration of growth hormone, nevertheless, significantly reduced activation of colonic NFκB (p = 0.028). Neutralisation of TNFα rapidly increased abundance of growth hormone receptor, activation of STAT5 and abundance of PPARγ in the colon, but reduced activation of NFκB in colitis. Growth hormone activated STAT5, and directly reduced TNFα 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 STAT5 and PPARγ, either through neutralisation of TNFα or chronic administration of growth hormone, may exert an anti-inflammatory effect in inflammatory bowel disease.

  • CEC, colon epithelial cells
  • EMSA, electrophoteric mobility shift assay
  • GHR, growth hormone receptor
  • GM-CSF, granulocyte-macrophage colony-stimulating factor
  • IGF1, insulin-like growth factor 1
  • IHC, immunohistochemistry
  • LPMC, lamina propria mononuclear cells
  • NFκB, nuclear factor κB
  • PBS, phosphate-buffered saline
  • PCR, polymerase chain reaction
  • PPARγ, peroxisome proliferator-activated receptor gamma
  • TNF, tumour necrosis factor

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Footnotes

  • Published Online First 15 June 2006

  • Funding: This work was supported by NIH grants DK02700, DK63956 and DK068164 (LAD), as well as the Crohns and Colitis Foundation of America (XH), the Cincinnati Children’s Hospital Research Foundation, the Children’s Digestive Health Foundation/Nestle Nutrition, the Broad Medical Research Program (LAD) and NIH grant R01 DK058259 (SJK).

  • Competing interests: LAD has received research support from Centocor, which provided the rat/mouse monoclonal anti-TNFα antibody (clone cV1q) and isotype control immunoglobulin G antibody (cVaM).

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