AP-1 mediates beta-amyloid-induced iNOS expression in PC12 cells via the ERK2 and p38 MAPK signaling pathways.
Nitrosative stress with subsequent inflammatory cell death has been implicated in some neurodegenerative disorders such as Alzheimer's disease (AD). Expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO) have been frequently elevated in AD. In this study, we have investigated the molecular mechanisms underlying nitrosative stress induced by beta-amyloid (A beta), a neurotoxic peptide associated with senile plaques formed in the brains of patients with AD. Exposure of rat pheochromocytoma (PC12) cells to the A beta resulted in increased mRNA and protein expression of iNOS and generation of NO. NO can rapidly interact with superoxide anion, forming more reactive peroxynitrite. Treatment of PC12 cells with A beta led to increased peroxynitrite production and nitrotyrosine formation. A beta induced activation of redox sensitive transcription factor activator protein-1 (AP-1), and AP-1 antisense oligonucleotide abolished the A beta-induced iNOS expression. Moreover, A beta transiently activated extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) via phosphorylation. Pharmacologic inhibition of both enzymes or dominant-negative mutation of ERK2 or p38 MAPK effectively down-regulated DNA binding as well as transcriptional activity of AP-1 and subsequent iNOS expression and NO production. The above findings suggest that A beta induces iNOS expression in PC12 cells through activation of AP-1 which is regulated by upstream kinases, such as ERK and p38 MAPK.
Jang
Jung-Hee
JH
National Research Laboratory, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Surh
Young-Joon
YJ
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D004790:Enzyme Induction; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D016716:PC12 Cells; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D017931:DNA Primers; D018808:Transcription Factor AP-1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases