Interleukin-1 inhibits the induction of insulin-like growth factor-I by growth hormone in CWSV-1 hepatocytes.
Interleukin-1 inhibits the induction of insulin-like growth factor-I by growth hormone in CWSV-1 hepatocytes.
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Interleukin-1 抑制 CWSV-1 肝细胞中生长激素诱导的胰岛素样生长因子-I。
DOI：
10.1152/ajpgi.00424.2004
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
Cooney,RobertN
中科院分区：
文献类型：
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作者：
Shumate,MargaretL;Yumet,Gladys;Ahmed,TamerA;Cooney,RobertN
脓毒症导致肝脏“生长激素(GH)抵抗”，尽管循环中的生长激素(GH)增加了两到四倍，但血浆IGF-I减少。在这项研究中，我们检测了IL-1对CWSV-1肝细胞GH受体(GHR)表达、GH信号转导(通过JAK/STAT和MAPK通路)以及GH诱导基因表达[IGF-I mRNA和丝氨酸蛋白酶抑制物(SPI)2.1]的影响。IL-1β(10 ng/ml，24 h)与细胞孵育对细胞裂解物中GHR或信号蛋白JAK2、STAT5b和ERK1/2的相对丰度无影响。GHR、JAK2、STAT5b和ERK1/2的基础磷酸化水平很低。GH刺激后，GHR、JAK2、STAT5b和ERK1/2的酪氨酸磷酸化水平增加2-10倍。但IL-1对GH诱导的GHR、JAK2和ERK1/2磷酸化的时程和幅度均无明显影响。IL-1不能阻止GH诱导的STAT5b向细胞核的移位。虽然GH刺激15分钟后，GH+IL-1细胞核提取液中磷酸化的STAT5比对照组减少了24%，但这并没有导致STAT5-DNA结合活性的降低。IL-1预处理对IGF-I基因的稳定性无明显影响。结论：IL-1对GH介导的JAK2/STAT5和MAPK信号转导过程的影响很小。因此，IL-1对生长激素诱导的IGF-I和SPI2.1mRNA合成的抑制作用是IL-1介导的生长激素抵抗最可能的机制。
Sepsis results in hepatic “growth hormone (GH) resistance” with reductions in plasma IGF-I despite a two- to fourfold increase in circulating GH. In this study, we examine the effects of IL-1 on GH receptor (GHR) expression, GH signaling (via the JAK/STAT and MAPK pathways), and the induction of gene expression [IGF-I mRNA and serine protease inhibitor (Spi) 2.1] by GH in CWSV-1 hepatocytes. Incubation of cells with IL-1β (10 ng/ml, 24 h) had no effect on the relative abundance of GHR or signaling proteins JAK2, STAT5b, and ERK1/2 in cell lysates. Baseline phosphorylation of GHR, JAK2, STAT5b, and ERK1/2 was minimal. After GH stimulation, tyrosine phosphorylation of GHR, JAK2, STAT5b, and ERK1/2 increased 2- to 10-fold. However, neither the time course nor the magnitude of GHR, JAK2, and ERK1/2 phosphorylation by GH were significantly altered by IL-1. The GH-induced translocation of STAT5b to the nucleus was not prevented by IL-1. Although phosphorylated STAT5 in nuclear extracts from GH + IL-1 cells was decreased by 24% (vs. controls) 15 min after GH stimulation, this did not result in reduced STAT5-DNA binding activity. Pretreatment with IL-1 did not significantly decrease IGF-I mRNA stability. We conclude that IL-1 only minimally affects the time course of JAK2/STAT5 and MAPK signaling by GH. Therefore, an inhibitory effect of IL-1 on IGF-I and Spi 2.1 mRNA synthesis by GH represents the most likely mechanism for IL-1-mediated GH resistance.