title: Inhibition of growth hormone action in models of inflammation.
abstract: Growth hormone (GH) action is attenuated during the hepatic acute-phase response (APR). To understand this attenuation, we asked whether GH and cytokine-signaling pathways intersect during an APR. In hypophysectomized rats treated with lipopolysaccharide (LPS), accumulation of activated signal transducer and transcription activator 5 (Stat5) in hepatic nuclei in response to GH and its binding to a GH response element (GHRE) from the serine protease inhibitor (Spi) 2.1 promoter are diminished in a time-dependent manner. Similarly, accumulation of activated Stat3 in hepatic nuclei in response to LPS and its binding to a high-affinity sis-inducible element (SIE) are also diminished by the simultaneous administration of GH. In functional assays with primary hepatocytes, LPS-stimulated monocyte-conditioned medium (MoCM) inhibits the GH response of Stat5-dependent Spi 2.1 reporter activity but induces Stat3-dependent Spi 2.2 reporter activity, as in an APR. Similar results are obtained when hepatocytes are treated with either tumor necrosis factor-alpha (TNF-alpha) or interleukin (IL)-1beta. TNF-alpha, IL-1beta, and IL-6 also inhibit GH-induced Spi 2.1 mRNA expression in hepatocytes. Thus inhibition of the GH signaling pathway during an APR results in reduced expression of GH-responsive genes.
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Bergad
authors.forename: S J
authors.initials: SJ
authors.lastname: Schwarzenberg
authors.forename: J T
authors.initials: JT
authors.lastname: Humbert
authors.forename: M
authors.initials: M
authors.lastname: Morrison
authors.forename: S
authors.initials: S
authors.lastname: Amarasinghe
authors.forename: H C
authors.initials: HC
authors.lastname: Towle
authors.forename: S A
authors.initials: SA
authors.lastname: Berry
mesh_terms: D000210:Acute-Phase Reaction / Q000276:immunology*; D000818:Animals; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000235:genetics; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D017930:Genes, Reporter; D013006:Growth Hormone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology; D007016:Hypophysectomy; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008894:Milk Proteins; D009000:Monocytes / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000276:immunology; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D015850:Interleukin-6; C091103:LOC299282 protein, rat; D008070:Lipopolysaccharides; D008894:Milk Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D013006:Growth Hormone; D002795:Choline O-Acetyltransferase