Inflammatory cytokines and acquired growth hormone resistance.
Resistance to growth hormone (GH)-mediated induction of insulin-like growth factor I (IGF-I) is a common complication of catabolic diseases, including critical illness and post-surgical conditions. This resistance to GH is believed to be permissive to the development of protein catabolism, cachexia and wasting, which are associated with an increased mortality rate. Data from in vitro studies and animal models suggest that increased levels of inflammatory cytokines can induce cachexia and might inhibit the effects of GH on target tissues. The molecular mechanisms involved are unclear, although an effect of cytokines on GH receptor signalling has been suggested. The GH-activated pathways that mediate the increase in IGF-I levels are not well understood, thereby impeding the elucidation of the effect of inflammatory cytokines. Several signalling cascades, like the JAK-STAT and MAP kinase pathways, have been shown to be activated by GH and some inflammatory cytokines, hence raising the possibility of crosstalk on this level. Our data, however, indicate that inflammatory cytokines have little or no effect on GH-mediated JAK-STAT signalling. In this review, we discuss these results and the possibility that secondary changes in the structure of chromatin are likely to be involved in the induction of IGF-I gene transcription by GH.
von Laue
S
S
Division of Clinical Sciences, University of Sheffield, UK. von.laue@necker.fr
Ross
R J
RJ
D000818:Animals; D002100:Cachexia / Q000209:etiology*; D002843:Chromatin / Q000737:chemistry; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004351:Drug Resistance; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D053613:Janus Kinase 1; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic
D002843:Chromatin; D016207:Cytokines; D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1