title: Tumor necrosis factor alpha blockade restores growth hormone signaling in murine colitis.
abstract: OBJECTIVE
  Cytokines including tumor necrosis factor alpha (TNFalpha) may create a state of growth hormone (GH) resistance in Crohn's disease. Anabolic effects of GH are mediated via phosphorylation of the signal transducer and activator of transcription (STAT)5b transcription factor. Although GH resistance in other settings has been linked to a defect in janus kinase-STAT signaling, the molecular basis for GH resistance in colitis was not known. We hypothesized that the GH-induced phosphorylation of STAT5b would be impaired in colitis, and that TNFalpha blockade would restore GH signaling.
  
  
  METHODS
  Growth, body composition, and molecular regulators of GH signaling were determined in interleukin-10 null mice with chronic colitis and wild-type controls, +/- treatment with an anti-TNFalpha antibody.
  
  
  RESULTS
  Interleukin-10 null mice exhibited significant alterations in growth, body composition, and feed efficiency. Liver insulin-like growth factor 1 expression was reduced in colitic mice. This was associated with down-regulation of GH receptor (GHR) expression and impaired GH-dependent STAT5b activation. Down-regulation of GHR expression was associated with reduced nuclear abundance and DNA binding of the GHR gene-promoter transactivator, Sp3. TNFalpha down-regulated GHR abundance and prevented GH-induced tyrosine phosphorylation of STAT5 in rat hepatocytes in culture. TNFalpha neutralization up-regulated liver GHR abundance and restored GH activation of STAT5 and serum insulin-like growth factor 1 levels in colitic mice; this preceded improvements in weight gain and disease activity.
  
  
  CONCLUSIONS
  GH resistance in experimental colitis is caused by down-regulation of GHR expression, thereby reducing GH-dependent STAT5 activation. TNFalpha blockade restores liver GH signaling and improves anabolic metabolism in this setting.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DiFedele
authors.forename: Jiman
authors.initials: J
authors.lastname: He
authors.forename: Erin L
authors.initials: EL
authors.lastname: Bonkowski
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Held
authors.forename: Alan
authors.initials: A
authors.lastname: Bohan
authors.forename: Ram K
authors.initials: RK
authors.lastname: Menon
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
mesh_terms: D000818:Animals; D001823:Body Composition; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D003092:Colitis / Q000378:metabolism / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006130:Growth Disorders / Q000378:metabolism / Q000503:physiopathology*; D013006:Growth Hormone / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D008894:Milk Proteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051705:Sp3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008894:Milk Proteins; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; C497122:Sp3 protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D051705:Sp3 Transcription Factor; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone