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J. Biol. Chem., Vol. 281, Issue 11, 7060-7067, March 17, 2006
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From the Department of Internal Medicine, Division of Endocrinology, Metabolism, Pathobiochemistry and Clinical Chemistry, University of Tübingen, D-72076 Germany
The exercise-induced interleukin (IL)-6 production and secretion within skeletal muscle fibers has raised the question of a putative tissue-specific function of IL-6 in the energy metabolism of the muscle during and after the exercise. In the present study, we followed the hypothesis that IL-6 signaling may directly interact with insulin receptor substrate (IRS)-1, a keystone in the insulin signaling cascade. We showed that IL-6 induces a rapid recruitment of IRS-1 to the IL-6 receptor complex in cultured skeletal muscle cells. Moreover, IL-6 induced a rapid and transient phosphorylation of Ser-318 of IRS-1 in muscle cells and in muscle tissue, but not in the liver of IL-6-treated mice, probably via the IL-6-induced co-recruitment of protein kinase C-
. This Ser-318 phosphorylation improved insulin-stimulated Akt phosphorylation and glucose uptake in myotubes since transfection with an IRS-1/Glu-318 mutant simulating a permanent phospho-Ser-318 modification increased Akt phosphorylation and glucose uptake. Noteworthily, two inhibitory mechanisms of IL-6 on insulin action, phosphorylation of the inhibitory Ser-307 residue of IRS-1 and induction of SOCS-3 expression, were only found in liver but not in muscle of IL-6-treated mice. Thus, the data provided evidence for a possible molecular mechanism of the physiological metabolic effects of IL-6 in skeletal muscle, thereby exerting short term beneficial effects on insulin action.
Received for publication, September 6, 2005 , and in revised form, December 23, 2005.
* This study was supported by Deutsche Forschungsgemeinschaft Grants We 4176/1-1 (to C. W.) and Schl 239/9-2 (to E. S.), by Fortune program Grant 1357-0 (to C. W.), and by German Diabetes Association Hagedorn-grants (to C. W. and R. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Dept. of Internal Medicine, Division of Endocrinology, Metabolism, Pathobiochemistry and Clinical Chemistry, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany. Tel.: 49-7071-29-80603; Fax: 49-7071-29 5348; E-mail: caweiger{at}med.uni-tuebingen.de.
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