Fernández-Celemín L, Thissen J P
Unité de Diabétologie et Nutrition, Université Catholique de Louvain, 54 B-1200 Brussels, Belgium.
Endocrinology. 2001 Jan;142(1):241-8. doi: 10.1210/endo.142.1.7903.
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: approximately 3-fold at 24 h, with IL-6 10 ng/ml). Interleukin (IL)-1ss and tumor necrosis factor (TNF)-alpha 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.
脓毒症和注射细菌脂多糖(LPS)会降低循环中胰岛素样生长因子(IGF)-I的浓度,并导致IGF结合蛋白(IGFBP)-1和IGFBP-4增加,这可能会影响IGF-I的合成代谢作用。尽管导致LPS刺激后IGFBP-1增加的机制已经阐明,但IGFBP-4升高的原因仍不清楚。本研究的目的是明确促炎细胞因子和糖皮质激素对IGFBP-4的调节作用。在大鼠原代培养肝细胞中,白细胞介素(IL)-6以剂量和时间依赖性方式强烈刺激IGFBP-4信使核糖核酸(mRNA)和蛋白水平(mRNA水平:9倍,P:<0.01;蛋白水平:24小时时约3倍,IL-6为10 ng/ml)。白细胞介素(IL)-1β和肿瘤坏死因子(TNF)-α减弱了IL-6对IGFBP-4 mRNA(分别降低66%和46%)和蛋白水平(分别降低82%和68%)的刺激。相反,地塞米松诱导IGFBP-4 mRNA和蛋白,并增强IL-6对IGFBP-4 mRNA的作用(2.5倍,P:<0.01,与单独使用IL-6相比)。放线菌素和环己酰亚胺均能阻止IL-6对IGFBP-4 mRNA的诱导,提示IL-6对IGFBP-4基因的作用可能发生在转录水平,且需要持续的蛋白质合成。给大鼠注射IL-6导致肝脏IGFBP-4 mRNA增加3倍(P:<0.001),这反映在血清IGFBP-4水平上(P:<0.05)。总之,我们的结果表明,IL-6在体外和体内均能刺激肝脏IGFBP-4基因表达和产生,从而提示细胞因子控制IGF-I作用的另一种机制。