Bradykinin stimulates IL-8 production in cultured human airway smooth muscle cells: role of cyclooxygenase products.
IL-8 is an important neutrophil and eosinophil chemoattractant in asthma. A recent report has suggested that bradykinin (BK), an asthmatic mediator, induces the release of IL-8 in nonairway cells. We have recently reported that BK causes cyclooxygenase (COX)-2 induction and PGE2 release in human airway smooth muscle (ASM) cells. In this study, we tested the ability of BK to induce IL-8 from these cells and explored the role of COX products and COX-2 induction in this process. Confluent serum-deprived human ASM cells were studied. IL-8 was assayed by specific ELISA. Unstimulated cells released low levels of IL-8. BK enhanced IL-8 release in a concentration- and time-dependent fashion (maximum 50-fold increase over basal). The nonselective COX inhibitor indomethacin and the selective COX-2 inhibitor NS-398 strongly inhibited BK-stimulated PGE2 and IL-8 production. The COX substrate arachidonic acid also caused PGE2 and IL-8 production, and its effect was inhibited by nonselective COX inhibitors but unaffected by NS-398. Both the BK- and arachidonic acid-induced IL-8 production was inhibited by the protein synthesis inhibitors cycloheximide and actinomycin D and by the steroid dexamethasone. Furthermore, exogenous PGE2 and calcium ionophore A23187 also stimulated IL-8 release. BK-induced IL-8 release was mimicked by the BK B2 receptor agonist (Tyr(Me)8)-BK and was potently inhibited by the selective B2 receptor antagonist HOE-140. These results suggest that human ASM can be a source of IL-8 and also that endogenous prostanoids, involving both COX-1 and COX-2, have a novel role in mediating BK-induced IL-8 production.
Pang
L
L
Division of Respiratory Medicine, City Hospital, University of Nottingham, United Kingdom.
Knox
A J
AJ
D000328:Adult; D016718:Arachidonic Acid / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D000001:Calcimycin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D018002:Receptors, Bradykinin / Q000819:agonists; D013379:Substrate Specificity; D014132:Trachea / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*
D065168:Bradykinin Receptor Antagonists; D016861:Cyclooxygenase Inhibitors; D016209:Interleukin-8; D018002:Receptors, Bradykinin; D016718:Arachidonic Acid; D000001:Calcimycin; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001920:Bradykinin