Tumor necrosis factor alpha but not interleukin 1 beta mediates neuroprotection in response to acute nitric oxide excitotoxicity.
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 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha), 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-alpha or IL-1beta. 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-alpha- and IL-1beta/TNF-alpha-deficient mice compared with IL-1beta-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-1beta knock-out and wild-type groups. This suggests a crucial role for TNF-alpha 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.
Turrin
Nicolas P
NP
Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center, Sainte-Foy, Québec, G1V 4G2, Canada.
Rivest
Serge
S
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009569:Nitric Oxide / Q000633:toxicity*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D007375:Interleukin-1; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide