Interleukin-6 inhibits growth hormone-mediated gene expression in hepatocytes

During systemic inflammation, the liver becomes unresponsive to growth hormone ( GH), resulting in decreased plasma insulin- like growth factor- I ( IGF- I) with concomitant reductions in lean body mass. Transgenic mice that overexpress IL- 6 also demonstrate impaired growth and decreased IGF- I. To determine whether IL- 6 directly inhibits GH- inducible gene expression, CWSV- 1 hepatocytes were incubated with IL- 6 ( 10 ng/ml), then stimulated with recombinant human GH ( 500 ng/ ml, 18 h). The increase in IGF- I and serine protease inhibitor 2.1 ( Spi 2.1) mRNA in GH- treated cells was inhibited by treatment with IL- 6 for 24 h. To investigate potential mechanisms, we examined the effects of IL- 6 on GH receptor ( GHR) expression and GH signaling via the JAK/signal transducer and activator of transcription ( STAT) and MAP kinase pathways. Incubation of cells with IL- 6 ( 10 ng/ ml, 24 h) had no effect on GHR abundance or signaling proteins JAK2, STAT5b, and ERK1/2. Although GH transiently increased ( 2- to 5- fold) the tyrosine phosphorylation of GHR, JAK2, STAT5b, and ERK1/2, IL- 6 did not alter these phosphorylation events. However, nuclear protein from IL- 6- treated cells demonstrated reduced STAT5 DNA binding ( by EMSA) at 15 min ( -20%) and 60 min ( -43%) after GH stimulation. To determine whether IL- 6 inhibits GH- inducible promoter activity, CWSV- 1 cells were transfected with Spi 2.1 or prolactin receptor promoter luciferase vectors, incubated with or without IL- 6, then stimulated with GH. The induction of both Spi 2.1 ( 7.5- fold) and prolactin receptor ( 4- fold) promoter activity by GH was inhibited by IL- 6. In summary, IL- 6 mediates hepatic GH resistance by a time- dependent inhibition of GH- inducible promoter activity that is associated with reductions in STAT5 DNA binding.