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Departments of 1 Surgery, and 2 Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033
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-
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.
growth hormone/insulin-like growth factor I axis; hepatocytes; janus kinase/signal transducer and activator of transcription
signaling; tumor necrosis factor-
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