title: Role of the suppressor of cytokine signaling-3 in mediating the inhibitory effects of interleukin-1beta on the growth hormone-dependent transcription of the acid-labile subunit gene in liver cells.
abstract: During catabolic diseases such as sepsis, inflammation, and infection, a state of growth hormone (GH) resistance develops in liver. This has been attributed in part to increased production of the proinflammatory cytokine interleukin-1beta (IL-1beta). To determine how IL-1beta induces GH resistance, we studied the acid-labile subunit (ALS) gene whose hepatic transcription is increased by GH via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. IL-1beta reduced the ability of GH to stimulate ALS mRNA in rat primary hepatocytes and ALS promoter activity in H4-II-E rat hepatoma cells. This inhibition was dependent on ALSGAS1, an element resembling a gamma-interferon activated sequence that mediates the transcriptional effects of GH. Inhibition by IL-1beta was also associated with a reduction of GH-dependent binding of STAT5 to this element after chronic (8 and 24 h), but not after acute treatment (15 min). Because these results indicated that the inhibition by IL-1beta was indirect, expression of the recently discovered suppressors of cytokine action (SOCS) was examined in liver cells. IL-1beta did not alter the expression of SOCS1, SOCS2, and CIS, indicating that they are not involved. In contrast, IL-1beta increased SOCS3 mRNA by 8-fold after 24 h of treatment, whereas GH had no effect. Forced expression of SOCS3 was just as effective as IL-1beta in reducing the GH induction of ALS promoter activity in H4-II-E rat hepatoma cells. Similar results were observed in primary rat hepatocytes. We conclude that the induction of SOCS3 by IL-1beta contributes to the development of GH resistance in liver, and represents a mechanism by which cytokines such as IL-1beta cross-talk with cytokines using the JAK-STAT pathway.
authors.affiliation: Department of Animal Science, Cornell University, Ithaca, New York 14853, USA. yrb1@cornell.edu
authors.forename: Y R
authors.initials: YR
authors.lastname: Boisclair
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Shi
authors.forename: K R
authors.initials: KR
authors.lastname: Hurst
authors.forename: G T
authors.initials: GT
authors.lastname: Ooi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics*; D013006:Growth Hormone / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008894:Milk Proteins; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D007375:Interleukin-1; D008894:Milk Proteins; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C491411:Socs3 protein, mouse; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C075944:insulin-like growth factor binding protein, acid labile subunit; D013006:Growth Hormone