Cytokine-mediated neuronal apoptosis.
Cytokines have been reported to induce neuronal injury via the free radical nitric oxide (NO); however, the precise mechanism underlying cytokine-mediated neurotoxicity is unclear. We investigated the hypothesis that cytokine-mediated neurotoxicity in primary cultures of human fetal neurons occurs via an apoptotic mechanism triggered by NO. Treatment of mixed neuronal/glial cell cultures with interferon (IFN)-gamma plus interleukin (IL)-1 beta for 13 days induced a high output of NO accompanied by marked neuronal loss. The NO synthase inhibitor N-monomethyl-L-arginine (NMMA) significantly attenuated cytokine-induced neuronal loss, confirming the involvement of NO. Cytokine-mediated neuronal injury was accompanied by morphologic changes and a DNA fragmentation pattern consistent with apoptosis. Treatment of neuronal cell cultures with NMMA protected against cytokine-mediated apoptotic death. These findings, using primary human neuronal cell cultures, support the hypothesis that cytokine-mediated neurotoxicity involving NO proceeds via an apoptotic mechanism. These findings could lead to the development of new therapies for neurodegenerative diseases involving glia, cytokines, and NO.
Hu
S
S
Neuroimmunobiology and Host Defense Laboratory, Minneapolis Medical Research Foundation, MN 55404, USA.
Peterson
P K
PK
Chao
C C
CC
D017209:Apoptosis; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016207:Cytokines; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase