© 2003 American Thoracic Society DOI: 10.1165/rcmb.2002-0040OC Bradykinin Induces Interleukin-6 Production in Human Airway Smooth Muscle CellsModulation by Th2 Cytokines and DexamethasoneDepartment of Thoracic Medicine II, Chang Gung Memorial Hospital, Taipei, Taiwan; and Department of Medicine, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania Address correspondence to: Dr. Yassine Amrani, University of Pennsylvania Medical Center, Pulmonary and Critical Care Division, 848 Biomedical Research Building II/III, Philadelphia, PA 19104. E-mail: amrani{at}mail.med.upenn.edu Synthetic function of airway smooth muscle (ASM), defined as secretion of cytokines or chemokines, may regulate airway inflammatory responses in chronic obstructive lung diseases. Because bradykinin (BK) and interleukin (IL)-6 may play important roles in the regulation of airway inflammation, we tested whether BK induces IL-6 expression from human ASM cells. BK stimulates IL-6 release in a concentration-dependent (0.001–10 µM) and time-dependent (2–24 h) manner. The increases in IL-6 protein and total mRNA were inhibited by the selective B2 receptor antagonist HOE-140 but not by the selective B1 receptor antagonist desArg9(Leu8)-BK. Actinomycin D (a transcription inhibitor), dexamethasone, indomethacin, IL-4, and IL-13 (Th2 type cytokines) inhibited the expression of IL-6 by BK. In contrast, BK-induced IL-6 secretion was enhanced by exogenous prostaglandin E2 and salmeterol. Using immunoblot analysis, we showed that BK activates ERK1/2 and p38 mitogen-activated protein kinases (MAPK). Blocking ERK1/2 with PD98059 or p38 MAPK with SB203580 reduced BK-induced IL-6 expression. BK also activates luciferase activity in ASM cells transfected with a reporter plasmid containing AP-1 enhancer elements. BK-induced, AP-1–dependent transcription was inhibited by indomethacin and dexamethasone. Curcumin, an inhibitor of AP-1, also reduced BK-induced IL-6 expression. These data show that BK, via the B2 receptor, induces IL-6 expression in ASM cells by involving ERK1/2 and p38 MAPK signaling pathways and the AP-1 transcription factor. Moreover, IL-6 secretion by BK is sensitive to corticosteroids and is regulated by Th2-derived cytokines.
Abbreviations: activator protein-1, AP-1 • airway smooth muscle, ASM • bronchoalveolar fluid, BALF • bradykinin, BK • bovine serum albumin, BSA • cyclic adenosine monophosphate, cAMP • cyclooxygenase, COX • dimethyl sulfoxide, DMSO • extracellular signal-regulated kinase, ERK • glyceraldehyde phosphate dehydrogenase, GAPDH • interleukin, IL • mitogen-activated protein kinase, MAPK • nuclear factor This article has been cited by other articles:
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