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Tumor Necrosis Factor‐α Induces Neuronal Death by Silencing Survival Signals Generated by the Type I Insulin‐Like Growth Factor Receptor
Author(s) -
VENTERS H. D.,
DANTZER R.,
KELLEY K. W.
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb05385.x
Subject(s) - tumor necrosis factor alpha , neurodegeneration , receptor , insulin like growth factor , growth factor , proinflammatory cytokine , cancer research , biology , signal transduction , gene silencing , cytokine , programmed cell death , kinase , endocrinology , microbiology and biotechnology , medicine , immunology , apoptosis , inflammation , biochemistry , disease , gene
A bstract : Within the central nervous system, the proinflammatory cytokine tumor necrosis factor (TNF)‐α is best characterized by its ability to directly foment signals of death. However, recent evidence suggests that TNF‐α 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‐α indirectly trigger the death of neurons. We suggest that this inhibition of survival signaling is a pathophysiologically relevant action of TNF‐α 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‐α in these disorders is neutralized.