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Diabetes 51:1921-1930, 2002
© 2002 by the American Diabetes Association, Inc.

Differential Effects of Tumor Necrosis Factor-{alpha} on Protein Kinase C Isoforms {alpha} and {delta} Mediate Inhibition of Insulin Receptor Signaling

Tovit Rosenzweig1, Liora Braiman1, Asia Bak1, Addy Alt1, Toshio Kuroki2, and Sanford R. Sampson1

1 Faculty of Life Sciences, Gonda-Goldschmied Center, Bar-Ilan University, Ramat-Gan, Israel
2 Institute of Molecular Oncology, Showa University, Hatanodai, Shinagawa-ku, Tokyo, Japan

Tumor necrosis factor-{alpha} (TNF-{alpha}) is a multifunctional cytokine that interferes with insulin signaling, but the molecular mechanisms of this effect are unclear. Because certain protein kinase C (PKC) isoforms are activated by insulin, we examined the role of PKC in TNF-{alpha} inhibition of insulin signaling in primary cultures of mouse skeletal muscle. TNF-{alpha}, given 5 min before insulin, inhibited insulin-induced tyrosine phosphorylation of insulin receptor (IR), IR substrate (IRS)-1, insulin-induced association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase (PI3-K), and insulin-induced glucose uptake. Insulin and TNF-{alpha} each caused tyrosine phosphorylation and activation of PKCs {delta} and {alpha}, but when TNF-{alpha} preceded insulin, the effects were less than that produced by each substance alone. Insulin induced PKC{delta} specifically to coprecipitate with IR, an effect blocked by TNF-{alpha}. Both PKC{alpha} and -{delta} are constitutively associated with IRS-1. Whereas insulin decreased coprecipitation of IRS-1 with PKC{alpha}, it increased coprecipitation of IRS-1 with PKC{delta}. TNF-{alpha} blocked the effects of insulin on association of both PKCs with IRS-1. To further investigate the involvement of PKCs in inhibitory actions of TNF-{alpha} on insulin signaling, we overexpressed specific PKC isoforms in mature myotubes. PKC{alpha} overexpression inhibited basal and insulin-induced IR autophosphorylation, whereas PKC{delta} overexpression increased IR autophosphorylation and abrogated the inhibitory effect of TNF-{alpha} on IR autophosphorylation and signaling to PI3-K. Blockade of PKC{alpha} antagonized the inhibitory effects of TNF-{alpha} on both insulin-induced IR tyrosine phosphorylation and IR signaling to PI3-K. We suggest that the effects of TNF-{alpha} on IR tyrosine phosphorylation are mediated via alteration of insulin-induced activation and association of PKC{delta} and -{alpha} with upstream signaling molecules.


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