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1 Department of Pediatrics and Yale Child Health Research Center, Yale University School of Medicine, New Haven, CT, USA; Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA
2 Department of Pediatrics and Yale Child Health Research Center, Yale University School of Medicine, New Haven, CT, USA
3 Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
4 Departments of Medicine, Cell Biology, and Physiology, University of Alabama at Birmingham, Birmingham, AL, USA
5 National Hormone & Peptide Program, Harbor-UCLA Medical Center, Torance, CA, USA
* To whom correspondence should be addressed. E-mail: lee.denson{at}yale.edu.
Background: 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, while the Cis/Socs (suppressors of cytokine signaling) genes are up regulated 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 up regulation. Methods: GH ± lipopolysaccharide (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 using immunoblots (IB), electrophoretic mobility shift assays (EMSA), and/or real time RT-PCR. TNF and IL-6 abundance were assessed using ELISA. Results: GH activated STAT5 in WT and TNFR1 or IL-6 null mice. LPS pre-treatment prevented STAT5 activation in WT and TNFR1 null mice; STAT5 activation was preserved in IL-6 null mice. Ghr abundance was modestly reduced by LPS administration. Inhibition of STAT5 activation by LPS was temporally associated with phosphorylation of STAT3 and up regulation 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. Conclusions: IL-6 inhibits hepatic GH signaling by up regulating Cis and Socs-3; this may involve activation of STAT3. Therapies which block IL-6 may enhance GH signaling in inflammatory diseases.
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