Tumor necrosis factor-alpha induces neuronal death by silencing survival signals generated by the type I insulin-like growth factor receptor

Within the central nervous system, the proinflammatory cytokine tumor necrosis factor (TNF)-alpha is best characterized by its ability to directly foment signals of death. However, recent evidence suggests that TNF-alpha also promotes neurodegeneration through inhibition of a vital survival signal, insulin-like growth factor-I (IGF-I). By inhibiting essential components of the IGF-I survival response, such as phosphatidylinositol 3'-kinase (PI 3-kinase), low nontoxic concentrations of TNF-alpha indirectly trigger the death of neurons. We suggest that this inhibition of survival signaling is a pathophysiologically relevant action of TNF-alpha in the brain. This type of cross-talk by which vastly different receptors utilize shared intracellular substrates is potentially applicable to a broad number of receptors that are coexpressed on the same cell. The use of neuronal growth factors in the treatment of neurodegenerative diseases, such as cerebral ischemia and the AIDS dementia complex, may prove much more effective if the elevated expression of TNF-alpha in these disorders is neutralized.