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

Abstract

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.

Keywords

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

Abbreviations

3-NP

3-nitropropionic acid

6-OHDA

6-hydroxydopamine

amyloid beta peptide

AD

Alzheimer’s disease

BBB

blood–brain barrier

Bcl2

B-cell CLL/lymphoma 2

BCSFB

blood–cerebrospinal fluid barrier

BRE

brain and reproductive organ expressed gene

CER

cerebellum

CNS

central nervous system

CSF

cerebrospinal fluid

CTX

cortex

DD

death domain

DENN

differentially expressed in normal versus neoplastic

EAE

experimental allergic encephalomyelitis

FADD

Fas-associated death domain

HIP

Hippocampus

HIV

human immunodeficiency virus

MADD

mitogen-activated protein kinase-activating death domain

MCAO

middle cerebral artery occlusion

MDMA

3,4-methylenedioxymethamphetamine

METH

methamphetamine

MHC

major histocompatibility complex

MK-801

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

MnSOD

manganese superoxide dismutase

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS

multiple sclerosis

NFκB

nuclear factor kappa B

NIK

nuclear factor kappa B inducing kinase

NMDA

N-methyl-d-aspartic acid

PD

Parkinson’s disease

RIP

receptor-interacting protein

TACE

TNF-α converting enzyme

TNF

tumor necrosis factor

TNFR

tumor necrosis factor receptor

TNFR-DKO

tumor necrosis factor receptor double knockout

TRADD

TNF receptor-associated death domain

TRAF

TNF receptor-associated factor

TRIP

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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