Shumate Margaret L, Yumet Gladys, Ahmed Tamer A, Cooney Robert N
Dept. of Surgery, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
Am J Physiol Gastrointest Liver Physiol. 2005 Aug;289(2):G227-39. doi: 10.1152/ajpgi.00424.2004. Epub 2005 Apr 14.
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-1beta (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.
脓毒症会导致肝脏出现“生长激素（GH）抵抗”，尽管循环中的GH增加了两到四倍，但血浆胰岛素样生长因子-I（IGF-I）仍会减少。在本研究中，我们检测了白细胞介素-1（IL-1）对CWSV-1肝细胞中生长激素受体（GHR）表达、GH信号传导（通过JAK/STAT和MAPK途径）以及GH诱导的基因表达[IGF-I mRNA和丝氨酸蛋白酶抑制剂（Spi）2.1]的影响。用IL-1β（10 ng/ml，24小时）孵育细胞对细胞裂解物中GHR或信号蛋白JAK2、STAT5b和ERK1/2的相对丰度没有影响。GHR、JAK2、STAT5b和ERK1/2的基线磷酸化水平极低。GH刺激后，GHR、JAK2、STAT5b和ERK1/2的酪氨酸磷酸化增加了2到10倍。然而，IL-1对GH诱导的GHR、JAK2和ERK1/2磷酸化的时间进程和幅度均无显著影响。IL-1并未阻止GH诱导的STAT5b向细胞核的转位。尽管在GH刺激后15分钟，GH + IL-1细胞的核提取物中磷酸化STAT5比对照组减少了24%，但这并未导致STAT5-DNA结合活性降低。用IL-1预处理并未显著降低IGF-I mRNA的稳定性。我们得出结论，IL-1仅对GH介导的JAK2/STAT5和MAPK信号传导的时间进程有最小程度的影响。因此，IL-1对GH诱导的IGF-I和Spi 2.1 mRNA合成的抑制作用是IL-1介导的GH抵抗最可能的机制。
