Inhibition of growth hormone action in models of inflammation
Inhibition of growth hormone action in models of inflammation
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DOI：
10.1152/ajpcell.2000.279.6.c1906
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发表时间：
2000-12-01
影响因子：
5.5
通讯作者：
Berry, SA
中科院分区：
文献类型：
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作者：
Bergad, PL;Schwarzenberg, SJ;Berry, SA
生长激素(GH)的作用在肝脏急性期反应(APR)期间减弱。为了了解这种衰减，我们询问了生长激素和细胞因子信号通路在APR期间是否相交。在给予脂多糖(LPS)处理的去垂体大鼠中，GH反应激活的信号转导和转录激活子5(Stat5)在肝细胞核中的积聚及其与丝氨酸蛋白酶抑制物(SPI)2.1启动子的GH反应元件(GHRE)的结合呈时间依赖性地减少。同样，同时给予生长激素也可减少内毒素在肝细胞核内激活的STAT3的积聚及其与高亲和力SIE的结合。在原代肝细胞的功能分析中，与APR一样，内毒素刺激的单核细胞条件培养液(MoCM)抑制STAT5依赖的SPI2.1报告活性的GH反应，但诱导STAT3依赖的SPI2.2报告活性。当肝细胞被肿瘤坏死因子-α(TNF-α)或白介素1-β(IL-1β)处理时，也得到类似的结果。肿瘤坏死因子α、白介素1β和白介素6也抑制生长激素诱导的肝细胞SPI2.1mRNA表达。因此，在APR期间抑制GH信号通路会导致GH反应基因的表达减少。
Growth hormone (GH) action is attenuated during the hepatic acute-phase response (APR). To understand this attenuation, we asked whether GH and cytokine-signaling pathways intersect during an APR. In hypophysectomized rats treated with lipopolysaccharide (LPS), accumulation of activated signal transducer and transcription activator 5 (Stat5) in hepatic nuclei in response to GH and its binding to a GH response element (GHRE) from the serine protease inhibitor (Spi) 2.1 promoter are diminished in a time-dependent manner. Similarly, accumulation of activated Stat3 in hepatic nuclei in response to LPS and its binding to a high-affinity sis-inducible element (SIE) are also diminished by the simultaneous administration of GH. In functional assays with primary hepatocytes, LPS-stimulated monocyte-conditioned medium (MoCM) inhibits the GH response of Stat5-dependent Spi 2.1 reporter activity but induces Stat3-dependent Spi 2.2 reporter activity, as in an APR. Similar results are obtained when hepatocytes are treated with either tumor necrosis factor-alpha (TNF-alpha) or interleukin (IL)-1 beta. TNF-alpha, IL-1 beta, and IL-6 also inhibit GH-induced Spi 2.1 mRNA expression in hepatocytes. Thus inhibition of the GH signaling pathway during an APR results in reduced expression of GH-responsive genes.