ROLE OF CYCLO-OXYGENASE-2 INDUCTION IN INTERLEUKIN-1-BETA INDUCED ATTENUATION OF CULTURED HUMAN AIRWAY SMOOTH-MUSCLE CELL CYCLIC-AMP GENERATION IN RESPONSE TO ISOPRENALINE

1 Airway smooth muscle (ASM) in human asthma shows reduced relaxation and cyclic AMP generation in response to beta-adrenoceptor agonists. I L-beta attenuates cyclic AMP generation but the underlying mechanism i s unclear. We have reported that IL-1 beta induces cyclo-oxygenase-2 ( COX-2) in human ASM cells and results in a marked increase in prostano id generation with PGE(2) and PGI(2) as the major products. 2 We inves tigated the role of COX-2 induction and prostanoid release (measured a s PGE(2)) in IL-1 beta induced attenuation of cyclic AMP generation in response to the beta-adrenoceptor agonist isoprenaline (ISO). 3 Pre-t reatment of human ASM cells with IL-1 beta significantly attenuated cy clic AMP generation in response to high concentrations of ISO (1.0-10. 0 mu M) in a time- and concentration-dependent manner. The effect was accompanied by a high concentration of PGE(2) release. The non-selecti ve COX inhibitor indomethacin (Ind), the selective COX-2 inhibitor NS- 398, the protein synthesis inhibitors cycloheximide (CHX) and actinomy cin D and the steroid dexamethasone (Dex) all abolished the PGE(2) rel ease and prevented the attenuated cyclic AMP generation. 4 COX substra te arachidonic acid time- and concentration-dependently mimicked IL-1 beta induced attenuation and the effect was prevented by the non-selec tive COX inhibitors Ind and flurbiprofen, but not by NS-398, CHX and D ex. 5 In contrast to IL-1 beta, TNF alpha and IFN gamma, which are ine ffective in inducing COX-2 and releasing PGE, from human ASM cells, di d not affect the cyclic AMP formation. 6 Our study demonstrates that C OX-2 induction and the consequent release of prostanoids plays a cruci al role in IL-1 beta induced attenuation of human ASM cell cyclic AMP response to ISO.