Hong-Brown Ly Q, Brown C Randell, Cooney Robert N, Frost Robert A, Lang Charles H
Department of Cellular and Molecular Physiology, Hershey, Pennsylvania 17033, USA.
Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E63-72. doi: 10.1152/ajpendo.00555.2002. Epub 2003 Mar 18.
Growth hormone (GH) stimulates insulin-like growth factor I (IGF-I) synthesis in both liver and muscle. During sepsis, proinflammatory cytokines inhibit GH action in liver, but it is unknown whether sepsis also produces GH resistance in muscle. Sepsis was induced by cecal ligation and puncture, and 18 h later the effect of GH on signal transducer and activator of transcription (STAT) phosphorylation and IGF-I mRNA content was assessed in rat gastrocnemius and liver. The relative abundance of phosphorylated (p)STAT5a, pSTAT5b, pSTAT3, and pSTAT1 was increased in liver from control rats after GH. Sepsis alone also increased hepatic pSTAT5a, pSTAT3, and pSTAT1. Sepsis dramatically impaired the ability of GH to stimulate the phosphorylation of STAT5a and -5b, as well as to increase IGF-I mRNA in liver. In muscle from control rats, GH increased pSTAT5a and -5b, whereas content of pSTAT3 and pSTAT1 was not affected. Sepsis increased basal content of pSTAT3 but not pSTAT5a, pSTAT5b, or pSTAT1 in muscle. The GH-induced increase of pSTAT5a and -5b in muscle from septic rats was not inhibited, suggesting that muscle was not GH resistant. In contrast to these changes in pSTAT5, the ability of GH to increase IGF-I mRNA was completely absent in muscle from septic rats. Because the suppressor of cytokine signaling (SOCS) proteins may function as negative regulators of GH signaling, we examined the content of these proteins. Sepsis produced small (30-50%), albeit statistically significant, increases in SOCS-1, -2, and -3 protein in muscle. In contrast to muscle, the SOCS proteins in the liver did not change under the various experimental conditions, suggesting that these proteins are not responsible for the impaired phosphorylation of STAT5 by GH. In conclusion, sepsis produces GH resistance in both muscle and liver, with the locus of this impairment in muscle differing from that in liver and being independent of a defect in STAT5 phosphorylation.
生长激素（GH）可刺激肝脏和肌肉中胰岛素样生长因子I（IGF-I）的合成。在脓毒症期间，促炎细胞因子会抑制肝脏中的GH作用，但脓毒症是否也会导致肌肉产生GH抵抗尚不清楚。通过盲肠结扎和穿刺诱导脓毒症，18小时后评估GH对大鼠腓肠肌和肝脏中信号转导和转录激活因子（STAT）磷酸化及IGF-I mRNA含量的影响。给予GH后，对照大鼠肝脏中磷酸化（p）STAT5a、pSTAT5b、pSTAT3和pSTAT1的相对丰度增加。单独的脓毒症也会增加肝脏中的pSTAT5a、pSTAT3和pSTAT1。脓毒症显著损害了GH刺激STAT5a和-5b磷酸化以及增加肝脏中IGF-I mRNA的能力。在对照大鼠的肌肉中，GH增加了pSTAT5a和-5b，而pSTAT3和pSTAT1的含量未受影响。脓毒症增加了肌肉中pSTAT3的基础含量，但未增加pSTAT5a、pSTAT5b或pSTAT1的基础含量。脓毒症大鼠肌肉中GH诱导的pSTAT5a和-5b增加未受到抑制，这表明肌肉不存在GH抵抗。与pSTAT5的这些变化相反，脓毒症大鼠肌肉中GH增加IGF-I mRNA的能力完全丧失。由于细胞因子信号转导抑制因子（SOCS）蛋白可能作为GH信号的负调节因子发挥作用，我们检测了这些蛋白的含量。脓毒症使肌肉中SOCS-1、-2和-3蛋白含量有小幅（30 - 50%）但具有统计学意义的增加。与肌肉不同，在各种实验条件下肝脏中的SOCS蛋白没有变化，这表明这些蛋白不是GH导致STAT5磷酸化受损的原因。总之，脓毒症在肌肉和肝脏中均产生GH抵抗，肌肉中这种损害的位点与肝脏不同，且与STAT5磷酸化缺陷无关。
