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

Tumor necrosis factor-alpha (TNF-alpha) 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-alpha a neuromodulatory effect. In contrast, in infl 4med or diseased brain, the abundance of evidence suggests that TNF-alpha has an overall neurotoxic effect, which may be particularly pronounced for virally mediated neurological disease. Still others have found TNF-alpha to be protective u uder some conditions of neurological insult. It is still uncertain exactly how TNF-alpha 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-alpha can exert its paradoxical effects in the brain is via crosstalk with signaling pathways of growth factors or other cytokines.