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Molecular and Cellular Biology, March 2007, p. 2372-2383, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01340-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Interleukin-6 Impairs the Insulin Signaling Pathway, Promoting Production of Nitric Oxide in Human Umbilical Vein Endothelial Cells

Department of Clinical and Experimental Medicine, University Magna Græcia of Catanzaro, Catanzaro, Italy,¹ Istituto di Endocrinologia ed Oncologia Sperimentale-CNR, Naples, Italy²

Received 21 July 2006/ Returned for modification 12 October 2006/ Accepted 2 January 2007

Interleukin 6 (IL-6) is an independent predictor of type 2 diabetes and cardiovascular disease and is correlated with insulin resistance. Insulin stimulates nitric oxide (NO) production through the IRS-1/PI3-kinase/Akt/eNOS pathway (where IRS-1 is insulin receptor substrate 1, PI3-kinase is phosphatidylinositol 3-kinase, and eNOS is endothelial NO synthase). We asked if IL-6 affects insulin vasodilator action both in human umbilical vein endothelial cells (HUVEC) and in the aortas of C57BL/6J mice and whether this inhibitory effect was caused by increased Ser phosphorylation of IRS-1. We observed that IL-6 increased IRS-1 phosphorylation at Ser³¹² and Ser⁶¹⁶; these effects were paralleled by increased Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and reversed by JNK and ERK1/2 inhibition. In addition, IL-6 treatment resulted in impaired IRS-1 phosphorylation at Tyr⁶¹², a site essential for engaging PI3-kinase. Furthermore, IL-6 treatment reduced insulin-stimulated phosphorylation of eNOS at the stimulatory Ser¹¹⁷⁷ site and impaired insulin-stimulated eNOS dephosphorylation at the inhibitory Thr⁴⁹⁵ site. Insulin-stimulated eNOS activation and NO production were also inhibited by IL-6; these effects were reversed by inhibition of JNK and ERK1/2. Treatment of C57BL/6J mice with IL-6 resulted in impaired insulin-dependent activation of the Akt/eNOS pathway in the aorta as a result of JNK and ERK1/2 activation. Our data suggest that IL-6 impairs the vasodilator effects of insulin that are mediated by the IRS-1/PI3-kinase/Akt/eNOS pathway through activation of JNK and ERK1/2.

Published ahead of print on 22 January 2007.

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