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Interleukin-1 Inhibits Insulin Signaling with Phosphorylating Insulin Receptor Substrate-1 on Serine Residues in 3T3-L1 Adipocytes

The First Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan

Address all correspondence and requests for reprints to: Isao Usui, M.D., Ph.D., The First Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. E-mail: isaousui-tym{at}umin.ac.jp.

Proinflammatory cytokines are recently reported to inhibit insulin signaling causing insulin resistance. IL-1 is also one of the proinflammatory cytokines; however, it has not been clarified whether IL-1 may also cause insulin resistance. Here, we investigated the effects of IL-1 treatment on insulin signaling in 3T3-L1 adipocytes. IL-1 treatment up to 4 h did not alter insulin-stimulated insulin receptor tyrosine phosphorylation, whereas tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and the association with phosphatidylinositol 3-kinase were partially inhibited with the maximal inhibition in around 15 min. IRS-1 was transiently phosphorylated on some serine residues around 15 min after IL-1 stimulation, when several serine kinases, IB kinase, c-Jun-N-terminal kinase, ERK, and p70S6K were activated. Chemical inhibitors for these kinases inhibited IL-1-induced serine phosphorylation of IRS-1. Tyrosine phosphorylation of IRS-1 was recovered only by the IKK inhibitor or JNK inhibitor, suggesting specific involvement of these two kinases. Insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake were not inhibited only by IL-1. Interestingly, Akt phosphorylation was synergistically inhibited by IL-1 in the presence of IL-6. Taken together, short-term IL-1 treatment transiently causes insulin resistance at IRS-1 level with its serine phosphorylation. IL-1 may suppress insulin signaling downstream of IRS-1 in the presence of other cytokines, such as IL-6.

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