Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes

• Published in: The Journal of biological chemistry 2003-04, Vol.278 (16), p.13740-13746
• Main Authors: Senn, Joseph J., Klover, Peter J., Nowak, Irena A., Zimmers, Teresa A., Koniaris, Leonidas G., Furlanetto, Richard W., Mooney, Robert A.
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Northern; Cell Line; Dose-Response Relationship, Drug; Hepatocytes - cytology; Hepatocytes - metabolism; Humans; Insulin Resistance; Interleukin-6 - metabolism; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Precipitin Tests; Protein Binding; Protein-Serine-Threonine Kinases; Proteins - metabolism; Proteins - physiology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Receptor, Insulin - metabolism; Repressor Proteins; RNA, Messenger - metabolism; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Time Factors; Transcription Factors; Transfection; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M210689200

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) Diabetes51, 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.