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  • Title: Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling.
    Author: Rosenzweig T, Braiman L, Bak A, Alt A, Kuroki T, Sampson SR.
    Journal: Diabetes; 2002 Jun; 51(6):1921-30. PubMed ID: 12031982.
    Abstract:
    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 PKCdelta specifically to coprecipitate with IR, an effect blocked by TNF-alpha. Both PKCalpha and -delta are constitutively associated with IRS-1. Whereas insulin decreased coprecipitation of IRS-1 with PKCalpha, it increased coprecipitation of IRS-1 with PKCdelta. 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. PKCalpha overexpression inhibited basal and insulin-induced IR autophosphorylation, whereas PKCdelta overexpression increased IR autophosphorylation and abrogated the inhibitory effect of TNF-alpha on IR autophosphorylation and signaling to PI3-K. Blockade of PKCalpha 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 PKCdelta and -alpha with upstream signaling molecules.
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