Apoptosis signal-regulating kinase 1-mediated signaling pathway regulates nitric oxide-induced activator protein-1 activation in human bronchial epithelial cells.
Exhaled nitric oxide (NO) is increased in individuals with bronchial asthma. NO may have antiinflammatory and proinflammatory effects; however, its role in bronchial asthma is unclear. In the present study, to clarify this issue we examined the effect of NO in inducing activator protein-1 (AP-1) activation in human bronchial epithelial cells (BEC) and a role of apoptosis signal-regulating kinase1 (ASK1), an upstream kinase kinase of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in NO-mediated AP-1 activation. The results showed that (1) the reactive nitrogen generating species NOR-1(+/--(E)-methyl-2-[(E)-hydroxykmino]-5-nitro-6-methoxy-3-hexeneamide]) induced AP-1 activation determined by AP-1-dependent luciferase gene activity, and an NO scavenger, carboxyl-PTIO, attenuated NOR-1-induced AP-1 activation; (2) NOR-1 phosphorylated ASK1, JNK, and p38 MAPK; and (3) transient transfection of the dominant negative form of AKS1 attenuated NOR-1-induced AP-1 activation in BEC. To further characterize the role of ASK-1 cascade, the dominant negative form of ASK1-stable transfected porcine artery endothelial (PAE) cells were used. AP-1 activity and JNK and p38 MAPK phosphorylation were depressed in the dominant-negative form of ASK1-stable transfected PAE cells. These results indicate that NO is capable of inducing AP-1 activation, and that ASK1-p38 MAPK/JNK cascade regulates AP-1 activation in NO-stimulated BEC.
Jibiki
Itsuro
I
First Department of Internal Medicine, Nihon University School of Medicine, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan.
Hashimoto
Shu
S
Maruoka
Shuichiro
S
Gon
Yasuhiro
Y
Matsuzawa
Atsushi
A
Nishitoh
Hideki
H
Ichijo
Hidenori
H
Horie
Takashi
T
D001249:Asthma / Q000276:immunology*; D002478:Cells, Cultured; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000276:immunology*; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology*; D010766:Phosphorylation; D026361:Reactive Nitrogen Species / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000737:chemistry / Q000166:cytology / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000276:immunology*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D016166:Free Radical Scavengers; D026361:Reactive Nitrogen Species; D018808:Transcription Factor AP-1; D009569:Nitric Oxide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases