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. 2002;8(6):611–624. doi: 10.1080/13550280290101021

Tumor necrosis factor-alpha in normal and diseased brain: Conflicting effects via intraneuronal receptor crosstalk?

Seth W Perry 1,2,3,4,✉, Stephen Dewhurst 3, Matthew J Bellizzi 1,2,4, Harris A Gelbard 1,2,3,5,✉
PMCID: PMC7094979  PMID: 12476354

Abstract

Tumor necrosis factor-alpha (TNF-α) is pleiotropic mediator of a diverse array of physiological and neurological functions, including both normal regulatory functions and immune responses to infectious agents. Its role in the nervous system is prominent but paradoxical. Studies on uninflamed or “normal” brain have generally attributed TNF-α a neuromodulatory effect. In contrast, in inflamed or diseased brain, the abundance of evidence suggests that TNF-α has an overall neurotoxic effect, which may be particularly pronounced for virally mediated neurological disease. Still others have found TNF-α to be protective under some conditions of neurological insult. It is still uncertain exactly how TNF-α is able to induce these opposing effects through receptor activation of only a limited set of cell signaling pathways. In this paper, we provide support from the literature to advance our hypothesis that one mechanism by which TNF-α can exert its paradoxical effects in the brain is via crosstalk with signaling pathways of growth factors or other cytokines.

Keywords: cytokine, glutamate, human immunodeficiency virus type 1 (HIV-1), inflammation, neurodegenerative, neuron, tumor necrosis factor-alpha

Footnotes

These studies were funded in part by NIH grants T32 AI49815 (SWP and SD); R01 MH56838 (SD and HAG); and P01 MH64570 (SD and HAG).

MJB is a trainee in the Medical Scientist Training Program, NIH T32 GM07356.

Contributor Information

Seth W. Perry, Email: sethperry@urmc.rochester.edu

Harris A. Gelbard, Email: harrisgelbard@urmc.rochester.edu

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