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B Activation and Cyclooxygenase-2 Expression via the Ras/Raf-1/ERK Pathway in Human Airway Epithelial Cells1
* School of Respiratory Therapy,
Graduate Institutes of Biomedical Technology,
Graduate Institutes of Medical Sciences,
Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan;
¶ Department of Anesthesiology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan; and
|| Department of Pharmacology, National Cardiovascular Center Research Institute, Osaka, Japan
In this study, we investigated the signaling pathways involved in bradykinin (BK)-induced NF-
B activation and cyclooxygenase-2 (COX-2) expression in human airway epithelial cells (A549). BK caused concentration- and time-dependent increase in COX-2 expression, which was attenuated by a selective B2 BK receptor antagonist (HOE140), a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), a MEK inhibitor (PD 098059), an NF-B inhibitor (pyrrolidine dithiocarbate), and an IB protease inhibitor (L-1-tosylamido-2-phenylethyl chloromethyl ketone). The B1 BK receptor antagonist (Lys-(Leu8)des-Arg9-BK) had no effect on COX-2 induction by BK. BK-induced increase in COX-2-luciferase activity was inhibited by cells transfected with the B site deletion of COX-2 construct. BK-induced Ras activation was inhibited by manumycin A. Raf-1 phosphorylation at Ser338 by BK was inhibited by manumycin A and GW 5074. BK-induced ERK activation was inhibited by HOE140, manumycin A, GW 5074, and PD 098059. Stimulation of cells with BK activated IB kinase 
(IKK), IB phosphorylation, IB degradation, p65 and p50 translocation from the cytosol to the nucleus, the formation of an NF-B-specific DNA-protein complex, and B-luciferase activity. BK-mediated increase in IKK activity and formation of the NF-B-specific DNA-protein complex were inhibited by HOE140, a Ras dominant-negative mutant (RasN17), manumycin A, GW 5074, and PD 098059. Our results demonstrated for the first time that BK, acting through B2 BK receptor, induces activation of the Ras/Raf-1/ERK pathway, which in turn initiates IKK and NF-B activation, and ultimately induces COX-2 expression in human airway epithelial cell line (A549).
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