© 2003 American Thoracic Society
Apoptosis Signal-Regulating Kinase 1–Mediated Signaling Pathway Regulates Nitric Oxide–Induced Activator Protein-1 Activation in Human Bronchial Epithelial CellsFirst Department of Internal Medicine, and Section of Allergology and Immunology, High-Tech Research Center, Nihon University School of Medicine; and Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan Correspondence and requests for reprints should be addressed to Dr. Shu Hashimoto, First Department of Internal Medicine, Nihon University School of Medicine, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan. E-mail: shuh{at}med.nihon-u.ac.jp 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.
Key Words: mitogen-activated protein kinase • airway inflammation • bronchial epithelium • activator protein-1 • nitric oxide This article has been cited by other articles:
|
|
||||||||||||||||||||||||||||||||||||||||||
