title: Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis.
abstract: 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.
authors.affiliation: Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: Yumet
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Shumate
authors.forename: Patrick
authors.initials: P
authors.lastname: Bryant
authors.forename: Cheng-Mao
authors.initials: CM
authors.lastname: Lin
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lang
authors.forename: Robert N
authors.initials: RN
authors.lastname: Cooney
mesh_terms: 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
chemical_list: 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