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Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes.

Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. J., Klover, P. J., Nowak, I. A., and Mooney, R. A. (2002) Diabetes 51, 3391-3399). Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. SOCS-3 protein levels were also markedly elevated at 1 h. Transcript and protein levels returned to near basal levels by 2 h. SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance.

Pubmed ID: 12560330

Authors

  • Senn JJ
  • Klover PJ
  • Nowak IA
  • Zimmers TA
  • Koniaris LG
  • Furlanetto RW
  • Mooney RA

Journal

The Journal of biological chemistry

Publication Data

April 18, 2003

Associated Grants

  • Agency: PHS HHS, Id: R01-38138

Mesh Terms

  • Animals
  • Blotting, Northern
  • Cell Line
  • Dose-Response Relationship, Drug
  • Hepatocytes
  • Humans
  • Insulin Resistance
  • Interleukin-6
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger
  • Receptor, Insulin
  • Repressor Proteins
  • Signal Transduction
  • Suppressor of Cytokine Signaling Proteins
  • Time Factors
  • Transcription Factors
  • Transfection
  • Tumor Cells, Cultured