Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis.
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.
Yumet
Gladys
G
Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Shumate
Margaret L
ML
Bryant
Patrick
P
Lin
Cheng-Mao
CM
Lang
Charles H
CH
Cooney
Robert N
RN
D000818:Animals; D001424:Bacterial Infections / Q000235:genetics / Q000503:physiopathology*; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology; D013006:Growth Hormone / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D053614:Janus Kinase 2; D008099:Liver / Q000502:physiology*; D008297:Male; D008894:Milk Proteins; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2