Interleukin-1α inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes

Proinflammatory cytokines are recently reported to inhibit insulin signaling causing insulin resistance. IL-1 alpha is also one of the proinflammatory cytokines; however, it has not been clarified whether IL-1 alpha may also cause insulin resistance. Here, we investigated the effects of IL-1 alpha treatment on insulin signaling in 3T3-L1 adipocytes. IL-1 alpha 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 alpha stimulation, when several serine kinases, I kappa B kinase, c-Jun-N-terminal kinase, ERK, and p70S6K were activated. Chemical inhibitors for these kinases inhibited IL-1 alpha- 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 alpha. Interestingly, Akt phosphorylation was synergistically inhibited by IL-1 alpha in the presence of IL-6. Taken together, short-term IL-1 alpha treatment transiently causes insulin resistance at IRS-1 level with its serine phosphorylation. IL-1 alpha may suppress insulin signaling downstream of IRS-1 in the presence of other cytokines, such as IL-6.