Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis

被引:52
作者
Yumet, G
Shumate, ML
Bryant, P
Lin, CM
Lang, CH
Cooney, RN [1 ]
机构
[1] Penn State Univ, Coll Med, Dept Surg, Hershey, PA 17033 USA
[2] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2002年 / 283卷 / 03期
关键词
growth hormone/insulin-like growth factor I axis; hepatocytes; janus kinase/signal transducer and activator of transcription signaling; tumor necrosis factor-alpha;
D O I
10.1152/ajpendo.00107.2002
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
During sepsis, growth hormone (GH) resistance contributes to the catabolism of muscle protein. To determine the role of tumor necrosis factor (TNF) as a mediator of GH resistance, we examined the effects of a TNF antagonist [TNF-binding protein (TNFbp)] on the GH/insulin-like growth factor (IGF) I system during abdominal sepsis. To investigate potential mechanisms, the effects of TNF on the IGF-I response to GH and GH signaling were examined in cultured rat hepatocytes (CWSV-1). Three groups of rats were studied: Control, Sepsis, and Sepsis + TNFbp. Liver, gastrocnemius, and plasma were collected on day 5. In gastrocnemius, neither sepsis nor TNFbp altered the abundance of IGF-I mRNA. However, septic rats demonstrated an increase in circulating GH and a reduction in plasma IGF-I concentrations that was ameliorated by pretreatment with TNFbp. Liver from septic rats demonstrated a 50% reduction in GH receptor (GHR) and IGF-I mRNA on day 5 that was attenuated by TNFbp. However, the abundance of GHR protein was not different in liver from Control, Sepsis, or Sepsis + TNFbp rats. Consequently, a decreased amount of hepatic GHR does not explain the GH- resistant septic state. In CWSV-1 hepatocytes, TNF-alpha had no effect on GHR protein level but inhibited the induction of IGF-I mRNA by GH. Nuclear protein from TNF-treated hepatocytes demonstrated similar levels of phosphorylated signal transducer and activator of transcription-5 (STAT5) and DNA binding relative to controls 5 min after GH treatment. However, both of these parameters were decreased (vs. control) in TNF-treated cells 60 min after GH treatment. Collectively, these results suggest that TNF mediates hepatic GH resistance during sepsis by inhibiting the duration of signaling via the janus kinase-2/STAT5 pathway.
引用
收藏
页码:E472 / E481
页数:10
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