Journal of Neuroimmune Pharmacology

, Volume 2, Issue 2, pp 140–153 | Cite as

Divergent Roles for Tumor Necrosis Factor-α in the Brain

Invited Review


Proinflammatory cytokines and chemokines have been implicated in the pathogenesis of several neurological and neurodegenerative disorders. Prominent among such factors is the pleiotropic cytokine, tumor necrosis factor (TNF)-α. Under normal physiological conditions, TNF-α orchestrates a diverse array of functions involved in immune surveillance and defense, cellular homeostasis, and protection against certain neurological insults. However, paradoxical effects of this cytokine have been observed. TNF-α is elicited in the brain following injury (ischemia, trauma), infection (HIV, meningitis), neurodegeneration (Alzheimer’s, Parkinson’s), and chemically induced neurotoxicity. The multifarious identity for this cytokine appears to be influenced by several mechanisms. Among the most prominent are the regulation of TNFα-induced NF-κB activation by adapter proteins such as TRADD and TRAF, and second, the heterogeneity of microglia and their distribution pattern across brain regions. Here, we review the differential role of TNF-α in response to brain injury, with emphasis on neurodegeneration, and discuss the possible mechanisms for such diverse and region-specific effects.


brain brain injury cytokines microglia neurodegeneration neurotoxicity region specificity TNF-α tumor necrosis factor 



3-nitropropionic acid



amyloid beta peptide


Alzheimer’s disease


blood–brain barrier


B-cell CLL/lymphoma 2


blood–cerebrospinal fluid barrier


brain and reproductive organ expressed gene




central nervous system


cerebrospinal fluid




death domain


differentially expressed in normal versus neoplastic


experimental allergic encephalomyelitis


Fas-associated death domain




human immunodeficiency virus


mitogen-activated protein kinase-activating death domain


middle cerebral artery occlusion






major histocompatibility complex


(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate


manganese superoxide dismutase




multiple sclerosis


nuclear factor kappa B


nuclear factor kappa B inducing kinase


N-methyl-d-aspartic acid


Parkinson’s disease


receptor-interacting protein


TNF-α converting enzyme


tumor necrosis factor


tumor necrosis factor receptor


tumor necrosis factor receptor double knockout


TNF receptor-associated death domain


TNF receptor-associated factor


TRAF-interacting protein


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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.National Institute for Occupational Safety and HealthCenters for Disease Control and Prevention, CDC-NIOSHMorgantownUSA

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