Long-term Interleukin-1α Treatment Inhibits Insulin Signaling via IL-6 Production and SOCS3 Expression in 3T3-L1 Adipocytes

• DOI: 10.1055/s-2007-1004515
• Publication Date: 2008-01-15T10:54:36Z
• Authors: T. Uno; J. He; I. Usui; Y. Kanatani; A. Bukhari; S. Fujisaka; Y. Yamazaki; H. Suzuki; M. Iwata; M. Ishiki; M. Urakaze; T. Haruta; H. Ogawa; M. Kobayashi
• Keywords: STAT3 Transcription Factor; 0301 basic medicine; Time Factors; Interleukin-6; Suppressor of Cytokine Signaling Proteins; Antibodies; Mice; 03 medical and health sciences; Neutralization Tests; Suppressor of Cytokine Signaling 3 Protein; 3T3-L1 Cells; Interleukin-1alpha; Adipocytes; Animals; Humans; Insulin; Phosphorylation; Genes, Dominant; Signal Transduction

Proinflammatory cytokines are well-known to inhibit insulin signaling to result in insulin resistance. IL-1alpha is also one of the proinflammatory cytokines, but the mechanism of how IL-1alpha induces insulin resistance remains unclear. We have now examined the effects of IL-1alpha on insulin signaling in 3T3-L1 adipocytes. Prolonged IL-1alpha treatment for 12 to 24 hours partially decreased the protein levels as well as the insulin-stimulated tyrosine phosphorylation of IRS-1 and Akt phosphorylation. mRNA for SOCS3, an endogenous inhibitor of insulin signaling, was dramatically augmented 4 hours after IL-1alpha treatment. Concomitantly, the level of IL-6 in the medium and STAT3 phosphorylation were increased by the prolonged IL-1alpha treatment. Addition of anti-IL-6 neutralizing antibody to the medium or overexpression of dominant-negative STAT3 decreased the IL-1alpha-stimulated STAT3 activation and SOCS3 induction, and ameliorated insulin signaling. These results suggest that the IL-1alpha-mediated deterioration of insulin signaling is largely due to the IL-6 production and SOCS3 induction in 3T3-L1 adipocytes.