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

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 292; no. 6; p. G1793
• Main Authors: Ahmed, Tamer A, Buzzelli, Mark D, Lang, Charles H, Capen, John B, Shumate, Margaret L, Navaratnarajah, Maithili, Nagarajan, Murali, Cooney, Robert N
• Format: Journal Article
• Language: English
• Published: United States 01-06-2007
• Subjects: Animals; Cell Line; Chromatin - metabolism; Genes, Reporter; Hepatocytes - drug effects; Hepatocytes - metabolism; Human Growth Hormone - metabolism; Human Growth Hormone - pharmacology; Humans; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Interleukin-6 - metabolism; Interleukin-6 - pharmacology; Luciferases; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Promoter Regions, Genetic; Rats; Receptors, Prolactin - genetics; Receptors, Prolactin - metabolism; Recombinant Proteins - metabolism; RNA, Messenger - metabolism; Signal Transduction - drug effects; STAT5 Transcription Factor - metabolism; Time Factors; Transcription, Genetic - drug effects; Transfection
• ISSN: 0193-1857
• DOI: 10.1152/ajpgi.00547.2006

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.