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The Journal of Neuroscience, January 4, 2006, 26(1):143-151; doi:10.1523/JNEUROSCI.4032-05.2006

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Neurobiology of Disease
Tumor Necrosis Factor But Not Interleukin 1 Mediates Neuroprotection in Response to Acute Nitric Oxide Excitotoxicity

Nicolas P. Turrin and Serge Rivest

Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center, and Department of Anatomy and Physiology, Laval University, Sainte-Foy, Québec, Canada G1V 4G2

Neurodegenerative processes in the brain are accompanied by activation of innate immunity, which involves the release of proinflammatory cytokines by microglia and infiltrating macrophages. The beneficial or detrimental roles of these cytokines, including interleukin 1 (IL-1) and tumor necrosis factor (TNF-), remain to be clarified. These cytokines have numerous overlapping activities that make it difficult to interpret data generated by mice that have a mutation in the gene encoding either TNF- or IL-1. To remediate the problem, we generated a mouse that bears a mutation in both genes and exposed them to an acute neurotoxic insult. Intracerebral infusion with the nitric oxide donor sodium nitroprusside (SNP) caused neurodegeneration and demyelination that were markedly increased in the brain of TNF-- and IL-1/TNF--deficient mice compared with IL-1-deficient and wild-type mice. Surprisingly, TNF and double mutants exhibited an early (6 h after SNP injections) blunted microglial activation followed by an exaggerated response later on (4 d later). No differences were found in the brain of the IL-1 knock-out and wild-type groups. This suggests a crucial role for TNF- in mediating microglial reactivity to acute injury. An immediate response clearly helps eliminate cell debris, restrict subsequent damages, and restore homeostasis. These findings may have direct implications for the use anti-inflammatory drugs in acute neurodegenerative and demyelinating disorders.

Key words: cytokines; inflammation; innate immunity; microglia; neurodegeneration; NF-B; nitric oxide; TNF-; mutant mice

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Received July 28, 2005; accepted November 6, 2005.

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