Activation of p38 MAPK induced peroxynitrite generation in LPS plus IFN-γ-stimulated rat primary astrocytes via activation of iNOS and NADPH oxidase

• Published in: Neurochemistry international Vol. 52; no. 6; pp. 1188 - 1197
• Main Authors: Yoo, Byoung Kwon, Choi, Ji Woong, Shin, Chan Young, Jeon, Se Jin, Park, Seo Jin, Cheong, Jae Hoon, Han, Sun Young, Ryu, Jae Ryun, Song, Mi Ryoung, Ko, Kwang Ho
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.05.2008; Elsevier
• Subjects: Animals; Animals, Newborn; Astrocyte; Astrocytes - drug effects; Astrocytes - enzymology; Astrocytes - immunology; Biological and medical sciences; Cells, Cultured; Dominant negative vector of p38α; Down-Regulation - drug effects; Down-Regulation - physiology; Encephalitis - enzymology; Encephalitis - immunology; Encephalitis - physiopathology; Enzyme Activation - drug effects; Enzyme Activation - physiology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; iNOS; Interferon-gamma - immunology; Interferon-gamma - pharmacology; Lipopolysaccharides - pharmacology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; NADPH oxidase; NADPH Oxidases - metabolism; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type II - metabolism; Oxidative Stress - drug effects; Oxidative Stress - physiology; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Peroxynitrite; Peroxynitrous Acid - metabolism; Rats; Rats, Sprague-Dawley; SB203580; Vertebrates: nervous system and sense organs; Peroxynitrite; NADPH oxidase; iNOS; Astrocyte; Dominant negative vector of p38α; SB203580; p38 MAPK; Rat; Enzyme; Neuroglia; Rodentia; Oxidase; Vertebrata; Mammalia; Animal; Lipopolysaccharide; p38 Mitogen activated protein kinase; Oxidoreductases; Dominant negative vector of p38a
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2007.12.009

We have shown that immunostimulated astrocytes produce excess nitric oxide (NO) and eventually peroxynitrite (ONOO −) that was closely associated with the glucose deprivation-potentiated death of astrocytes. The present study shows that activated p38 MAPK regulates ONOO − generation from lipopolysaccharide (LPS) plus interferon-γ (IFN-γ)-stimulated astrocytes. LPS + IFN-γ-induced p38 MAPK activation and ONOO − generation were attenuated by SB203580 or SKF-86002, specific inhibitors of p38 MAPK. ONOO − generation was blocked by NADPH oxidase inhibitor, diphenyleneiodonium chloride, and nitric oxide synthase (NOS) inhibitor, Nω-nitro- l-arginine methyl ester, suggesting both enzymes are involved in ONOO − generation. Inhibition of p38 MAPK suppressed LPS + IFN-γ-induced NO production through down-regulating inducible form of NOS expression. It also suppressed LPS + IFN-γ-induced NADPH oxidase activation and eventually, the inducible form of superoxide production. Transfection with dominant negative vector of p38α reduced LPS + IFN-γ-induced ONOO − generation through blocking both iNOS-derived NO production and NADPH oxidase-derived O 2 − production. Our results suggest that activated p38 MAPK may serve as a potential signaling molecule in ONOO − generation through dual regulatory mechanisms, involving iNOS induction and NADPH oxidase activation.