Endotoxin attenuates growth hormone-induced hepatic insulin-like growth factor I expression by inhibiting JAK2/STAT5 signal transduction and STAT5b DNA binding

Gram- negative sepsis with release of endotoxin is a frequent cause of cachexia that develops partly because of resistance to growth hormone ( GH) with reduced insulinlike growth factor- I ( IGF- I) expression. We set out to more fully characterize the mechanisms for the resistance and to determine whether in addition to a defect in the janus kinase 2 ( JAK2)- signal transducer and activator of transcription ( STAT) 5b pathway, required for GH- induced IGF- I expression, there might also be a more distal defect. Conscious rats were given endotoxin and studied 4 h later. In liver of these animals, GH- induced JAK2 and STAT5 phosphorylation was impaired and appeared to be caused, at least in part, by a marked increase in hepatic tumor necrosis factor-alpha and interleukin- 6 mRNA expression accompanied by elevated levels of inhibitors of GH signaling, namely cytokine- inducible suppressors of cytokine signaling- 1 and - 3 and cytokine- inducible SH2 protein ( CIS). Nuclear phosphorylated STAT5b levels were significantly depressed to 61% of the control values and represent a potential cause of the reduced GH- induced IGF- I expression. In addition, binding of phosphorylated STAT5b to DNA was reduced to an even greater extent and averaged 17% of the normal control value. This provides a further explanation for the impaired IGF- I gene transcription. Interestingly, when endotoxintreated rats were treated with GH, there was a marked increase in proinflammatory cytokine gene expression in the liver. If such a response were to occur in humans, this might provide a partial explanation for the adverse effect of GH treatment reported in critically ill patients.