Thissen J P, Verniers J
Unité de Diabétologie et Nutrition, School of Medicine, University of Louvain, Brussels, Belgium.
Endocrinology. 1997 Mar;138(3):1078-84. doi: 10.1210/endo.138.3.4966.
The cytokines are the putative mediators of the catabolic reaction that accompanies infection and trauma. Evidence suggests that their catabolic actions are indirect and potentially mediated through changes in hormonal axis such as the hypothalamo-pituitary-adrenal axis. Insulin-like growth factor I (IGF-I) is a GH-dependent growth factor that regulates the protein metabolism. To determine whether cytokines can directly inhibit the production of IGF-I by the liver, we investigated the regulation of IGF-I gene expression by interleukin (IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha (10 ng/ml) in a model of rat primary cultured hepatocytes. Hepatocytes were isolated by liver collagenase perfusion and cultured on Matrigel 48 h before experiments. Each experiment was performed in at least three different animals. In the absence of GH, IL-1 beta and TNF-alpha did not affect the IGF-I messenger RNA (mRNA) basal levels, whereas IL-6 increased it by a factor of 2.5 after 24 h (P < 0.05). GH (500 ng/ml) alone stimulated the IGF-I gene expression markedly (5-to 10-fold increase) after 24 h (P < 0.001). IL-1 beta, and TNF-alpha to a lesser extent, dramatically inhibited the IGF-I mRNA response to GH (IL-1 beta: -82%, P < 0.001 and TNF-alpha: -47%, P < 0.01). The half-maximal inhibition of the IGF-I mRNA response to GH was observed for a concentration of IL-1 beta between 0.1 and 1 ng/ml. Moreover, IL-1 beta abolished the IL-6-induced IGF-I mRNA response. In contrast, IL-6 did not impair the IGF-I mRNA response to GH. To determine the potential role of the GH receptor (GHR) and the GH-binding protein (GHBP) in this GH resistance, we assessed the GHR and GHBP mRNAs response to these cytokines. GH alone did not affect the GHR/GHBP mRNA levels. IL-1 beta markedly decreased the GHR and GHBP mRNA levels (respectively, -68% and -60%, P < 0.05). Neither TNF-alpha nor IL-6 affected the GHR/GHBP gene expression. In conclusion, our results show that IL-1 beta, and TNF-alpha to a lesser extent, blunt the IGF-I mRNA response to GH. The resistance to GH induced by IL-1 beta might be mediated by a decrease of GH receptors, as suggested by the marked reduction of GHR mRNA. These findings suggest that decreased circulating IGF-I, in response to infection and trauma, may be caused by a direct effect of cytokines at the hepatocyte level.
细胞因子被认为是伴随感染和创伤的分解代谢反应的介质。有证据表明，它们的分解代谢作用是间接的，可能通过激素轴（如下丘脑 - 垂体 - 肾上腺轴）的变化介导。胰岛素样生长因子I（IGF - I）是一种依赖生长激素（GH）的生长因子，可调节蛋白质代谢。为了确定细胞因子是否能直接抑制肝脏中IGF - I的产生，我们在大鼠原代培养肝细胞模型中研究了白细胞介素（IL）-1β、IL - 6和肿瘤坏死因子（TNF）-α（10 ng/ml）对IGF - I基因表达的调节作用。通过肝脏胶原酶灌注分离肝细胞，并在实验前48小时在基质胶上培养。每个实验至少在三只不同的动物中进行。在没有GH的情况下，IL - 1β和TNF - α不影响IGF - I信使核糖核酸（mRNA）的基础水平，而IL - 6在24小时后使其增加了2.5倍（P < 0.05）。单独使用GH（500 ng/ml）在24小时后显著刺激IGF - I基因表达（增加5至10倍，P < 0.001）。IL - 1β以及程度较轻的TNF - α显著抑制IGF - I mRNA对GH的反应（IL - 1β：-82%，P < 0.001；TNF - α：-47%，P < 0.01）。当IL - 1β浓度在0.1至1 ng/ml之间时，观察到IGF - I mRNA对GH反应的半数最大抑制。此外，IL - 1β消除了IL - 6诱导的IGF - I mRNA反应。相比之下，IL - 6不损害IGF - I mRNA对GH的反应。为了确定生长激素受体（GHR）和生长激素结合蛋白（GHBP）在这种GH抵抗中的潜在作用，我们评估了这些细胞因子对GHR和GHBP mRNA的反应。单独使用GH不影响GHR/GHBP mRNA水平。IL - 1β显著降低GHR和GHBP mRNA水平（分别为-68%和-60%，P < 0.05）。TNF - α和IL - 6均不影响GHR/GHBP基因表达。总之，我们的结果表明，IL - 1β以及程度较轻的TNF - α减弱了IGF - I mRNA对GH的反应。如GHR mRNA的显著减少所示，IL - 1β诱导的对GH的抵抗可能由GH受体的减少介导。这些发现表明，感染和创伤后循环中IGF - I的减少可能是细胞因子在肝细胞水平直接作用的结果。
