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1 Department of Surgery, The Pennsylvania State University -College of Medicine, Hershey, PA, USA
* To whom correspondence should be addressed. E-mail: rcooney{at}psu.edu.
Sepsis results in hepatic "GH resistance" with reductions in plasma IGF-I despite a 2-
4-fold increase in circulating GH. In this study, we examine the effects of IL-1 on GH
receptor (GHR) expression, GH signaling (via the JAK/STAT and MAP kinase pathways),
and the induction of gene expression (IGF-I mRNA and serine protease inhibitor (Spi 2.1)) by
GH in CWSV-1 hepatocytes. Incubation of cells with IL-1
(10 ng/ml, 24 h) had no effect on
the relative abundance of GHR or signaling proteins JAK2, STAT5b and ERK1/2 in cell
lysates. Baseline phosphorylation of GHR, JAK2, STAT5b, and ERK1/2 was minimal.
Following GH stimulation, tyrosine phosphorylation of GHR, JAK2, STAT5b, and ERK1/2
increased 2-10 -fold. However, neither the time course nor the magnitude of GHR, JAK2,
and ERK1/2 phosphorylation by GH were significantly altered by IL-1. The GH-induced
translocation of STAT5b to the nucleus was not prevented by IL-1. Although phosphorylated
STAT5 in nuclear extracts from GH+IL-1 cells was decreased by 24 % (vs. controls) 15
minutes after GH stimulation, this did not result in reduced STAT5-DNA binding activity.
Pre-treatment with IL-1 did not significantly decrease IGF-I mRNA stability. We conclude
that IL-1 only minimally affects the time course of JAK2/STAT5 and MAP kinase signaling
by GH. Therefore, an inhibitory effect of IL-1 on IGF-I and Spi 2.1 mRNA synthesis by GH
represents the most likely mechanism for IL-1 mediated GH resistance
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