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Interleukin-6 Stimulates Hepatic Insulin-Like Growth Factor Binding Protein-4 Messenger Ribonucleic Acid and Protein¹

Unité de Diabétologie et Nutrition, Université Catholique de Louvain, 54 B-1200 Brussels, Belgium

Address all correspondence and requests for reprints to: Jean-Paul Thissen, M.D., Unité de Diabétologie et Nutrition, UCL/DIAB 5474, Avenue Hippocrate, 54, Brussels B-1200, Belgium. E-mail: thissen{at}diab.ucl.ac.be

Sepsis and bacterial lipopolysaccharide (LPS) injection decrease circulating concentrations of insulin-like growth factor (IGF)-I and induce an increase in IGFBP-1 and IGFBP-4 that may have impact upon IGF-I anabolic actions. Although the mechanisms responsible for the IGFBP-1 increase in response to LPS have already been unraveled, the cause for the IGFBP-4 elevation is still unknown. The aim of this study was to characterize the regulation of IGFBP-4 by proinflammatory cytokines and glucocorticoids. In rat primary cultured hepatocytes, interleukin (IL)-6 strongly stimulated IGFBP-4 messenger RNA (mRNA) and protein levels in a dose- and time-dependent way (mRNA levels: 9-fold, P < 0.01 and protein levels: 3-fold at 24 h, with IL-6 10 ng/ml). Interleukin (IL)-1ß and tumor necrosis factor (TNF)- blunted the IL-6 stimulation of IGFBP-4 mRNA (66% and 46% decrease, respectively) and protein levels (82% and 68% decrease, respectively). In contrast, dexamethasone induced IGFBP-4 mRNA and protein and potentiated the effect of IL-6 on IGFBP-4 mRNA (2.5-fold, P < 0.01 vs. IL-6 alone). Both actinomycin and cycloheximide prevented the IL-6 induction of IGFBP-4 mRNA suggesting that the IL-6 effect on IGFBP-4 gene occurs probably at the transcriptional level and needs an ongoing protein synthesis. Administration of IL-6 to rats caused a 3-fold increase in liver IGFBP-4 mRNA (P < 0.001) reflected in serum levels of IGFBP-4 (P < 0.05). In conclusion, our results show that IL-6 stimulates hepatic IGFBP-4 gene expression and production in vitro and in vivo, thereby suggesting another mechanism by which cytokines could control IGF-I action.

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