Taxol activates inducible nitric oxide synthase in rat astrocytes: the role of MAP kinases and NF-kappaB.
Taxol is a microtubule-stabilizing agent that has recently been shown effective in the treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. As astrocytes could modulate central nervous system (CNS) autoimmunity through inducible nitric oxide synthase (iNOS)-mediated production of immunoregulatory free radical nitric oxide (NO), we investigated the effect of taxol on NO synthesis in rat astrocytes. Taxol, either alone or in combination with interferon-gamma, induced NO generation in primary astrocytes and astrocytoma C6 cells in a dose- and time-dependent manner. Accordingly, the drug markedly up-regulated the expression of both iNOS mRNA and protein in astrocytes. The observed effect of taxol was mediated through induction of iNOS transcription factors NF-kappaB and IRF-1, and required the activation of p38 MAP kinase and JNK. Finally, NO release by taxol-stimulated astrocytes was blocked with the microtubule-depolymerizing agent colchicine, suggesting the involvement of a microtubule-stabilizing activity of taxol in the observed effect.
Cvetkovic
I
I
Laboratory for Immunology, Institute for Biological Research Sinisa Stankovic, 29. Novembra 142, 11000 Belgrade, Serbia and Montenegro. branicevo@yahoo.com
Miljkovic
D
D
Vuckovic
O
O
Harhaji
L
L
Nikolic
Z
Z
Trajkovic
V
V
Mostarica Stojkovic
M
M
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001253:Astrocytes / Q000201:enzymology*; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D008954:Models, Biological; D016328:NF-kappa B / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D009573:Nitrites; D012333:RNA, Messenger; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D003078:Colchicine