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1 The Department of Pediatrics and Yale Child Health Research Center 06520-8081 and the 2 Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut; 3 The Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; 4 The Departments of Medicine, Cell Biology, and Physiology, University of Alabama at Birmingham, Birmingham, Alabama 35294; and 5 National Hormone and Peptide Program, Harbor-University of California at Los Angeles Medical Center, Torrance, California 90509
Cytokines may cause an acquired
growth hormone (GH) resistance in patients with inflammatory diseases.
Anabolic effects of GH are mediated through activation of STAT5
transcription factors. We have reported that TNF-
suppresses hepatic
GH receptor (GHR) gene expression, whereas the cytokine-inducible
SH2-containing protein 1 (Cis)/suppressors of cytokine signaling
(Socs) genes are upregulated by TNF- and IL-6 and inhibit
GH activation of STAT5. However, the relative importance of these
mechanisms in inflammatory GH resistance was not known. We
hypothesized that IL-6 would prevent GH activation of STAT5 and that
this would involve Cis/Socs protein upregulation. GH ± LPS was
administered to TNF receptor 1 (TNFR1) or IL-6 null mice and wild-type
(WT) controls. STAT5, STAT3, GHR, Socs 1-3, and Cis
phosphorylation and abundance were assessed by using immunoblots, EMSA,
and/or real time RT-PCR. TNF- and IL-6 abundance were assessed by
using ELISA. GH activated STAT5 in WT and TNFR1 or IL-6 null mice. LPS pretreatment prevented STAT5 activation in WT and TNFR1 null mice; however, STAT5 activation was preserved in IL-6 null mice. GHR abundance did not change with LPS administration. Inhibition of STAT5
activation by LPS was temporally associated with phosphorylation of
STAT3 and upregulation of Cis and Socs-3 protein in WT and TNFR1 null
mice; STAT3, Cis, and Socs-3 were not induced in IL-6 null mice. IL-6
inhibits hepatic GH signaling by upregulating Cis and Socs-3, which may
involve activation of STAT3. Therapies that block IL-6 may enhance GH
signaling in inflammatory diseases.
STAT5; STAT3; suppressors of cytokine signaling; endotoxin; cytokines
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