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

Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, New York, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2003; 278(16):13740-6. DOI: 10.1074/jbc.M210689200
Source: PubMed

ABSTRACT 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.

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Available from: Peter J Klover, Apr 02, 2014
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    • "The tyrosine phosphatases, in turn, reduce the level of tyrosine phosphorylation of IRSs and JAK2, which is associated with decreased IRSs recruitment of PI3K and JAK2 tyrosine kinase activity, respectively (Konner and Bruning, 2012). Finally, suppressor cytokine signaling 3 (SOCS3) inhibits phosphorylation of the leptin receptor (Bjorbak et al., 2000; Kievit et al., 2006), decreases IRSs tyrosine phosphorylation and decreases total IRS levels by inducing its proteosomal degradation (Emanuelli et al., 2001; Senn et al., 2003; Ueki et al., 2004; Shi et al., 2004). 4. Cellular and molecular mechanisms of obesity-mediated inflammation Work over the last few decades has established a firm link between obesity and low-grade inflammation (Hotamisligil et al., 1993; Odegaard and Chawla, 2013a, b; Hotamisligil, 2006; Saberi et al., 2009). "
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    • "Moreover, SOCS3 overexpression in cultured cells inhibits IR autophosphorylation . This mechanism is most likely mediated by crosstalk between IR regulators (Senn et al., 2003). In addition, SOCS3 is induced by STAT5B upon insulin stimulation (Emanuelli et al., 2000; Sadowski et al., 2001). "
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    • "This new model suggests that different hits may act in parallel, and that gut-or adipose tissuederived factors may have a key role in the onset of liver inflammation. The cytokines tumor necrosis factor α (TNF-α) and interleukin (IL)-6 represent a link between IR and liver inflammatory process, activating several mechanisms involved in hepatocyte apoptosis and inhibition of insulin signaling [3] [4]. "
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