| Heightened expression of both a proinflammatory cytokine, tumor necrosis factor-α (TNFα), and a survival peptide, insulin-like growth factor-I (IGF-I), occurs in diverse diseases of the central nervous system (CNS), including Alzheimer's disease, multiple sclerosis, the AIDS-dementia complex and cerebral ischemia. Conventional roles for these two proteins are neuroprotection by IGF-I and neurotoxicity by TNFα. Although the mechanisms of action for IGF-I and TNFα in the CNS were originally established as disparate and unrelated, we hypothesized that the signaling pathways of these two cytokines may interact during neurodegeneration. Here we show that concentrations of TNFα as low as 10 pg/ml markedly reduce the capacity of IGF-I to promote survival of primary murine cerebellar granule neurons. TNFα suppresses IGF-I-induced tyrosine phosphorylation of insulin receptor substrate-2 (IRS-2) and inhibits IRS-2-precipitable PI 3-kinase activity. These experiments indicate that TNFα promotes IGF-I receptor resistance in neurons and inhibits the ability of the IGF-I receptor to tyrosine phosphorylate the IRS-2 docking molecule and to subsequently activate the critical downstream enzyme PI 3-kinase. This intracellular crosstalk between discrete cytokine receptors reveals a novel pathway that leads to neuronal degeneration whereby a proinflammatory cytokine inhibits receptor signaling by a survival peptide. |
