Effects of TNF-alpha and IFN-gamma on nitric oxide-induced neurotoxicity in the mouse brain.
The present study investigated the interaction between highly reactive gaseous-free radical NO and cytokines that are produced by activated Th-1 cells on the cerebral immune response and neuronal integrity. CD-1 mice received an intrastriatal infusion of different solutions containing the NO synthase inhibitor N(G)-nitro-L-arginine methylester, NO-releasing substance sodium nitroprusside (SNP), IFN-gamma, and/or TNF-alpha. The solution containing both cytokines caused a profound and transient transcriptional activation of numerous genes encoding proinflammatory proteins in microglial/monocytic cells ipsilateral to infusion site. This increase in gene expression peaked 1 day after the cerebral bolus of cytokines and returned to basal levels from 3 to 7 days post administration. N(G)-nitro-L-arginine methylester further stimulated this immune reaction to IFN-gamma and TNF-alpha, but the brain of these mice failed to exhibit signs of neurodegeneration and demyelination. In contrast, a single bolus of SNP in the striatal region caused neuronal death and demyelination as early as 1 to 3 days following the infusion with the NO donor. This phenomenon was greatly exacerbated by the coadministration of both cytokines, although TNF-alpha remained the most critical cytokine to enhance the damage of cerebral elements. These data provide evidence that NO has the ability to modulate the immune response, which is not by itself detrimental for the brain. However, SNP-induced NO production together with TNF-alpha in the cerebral environment are critical events leading to intense neurodegeneration and demyelination in vivo.
Blais
Véronique
V
Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center, and Department of Anatomy and Physiology, Laval University, Québec City, Québec, Canada.
Rivest
Serge
S
D000818:Animals; D001921:Brain / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000633:toxicity*; D009599:Nitroprusside / Q000633:toxicity; D011956:Receptors, Cell Surface / Q000235:genetics; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D018932:Chemokine CCL2; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D009599:Nitroprusside; D009569:Nitric Oxide; D007371:Interferon-gamma; D019331:NG-Nitroarginine Methyl Ester