Role of cyclo-oxygenase-2 induction in interleukin-1beta induced attenuation of cultured human airway smooth muscle cell cyclic AMP generation in response to isoprenaline.Br J Pharmacol. 1998 Nov; 125(6):1320-8.BJ
Airway smooth muscle (ASM) in human asthma shows reduced relaxation and cyclic AMP generation in response to beta-adrenoceptor agonists. IL-beta attenuates cyclic AMP generation but the underlying mechanism is unclear. We have reported that IL-1beta induces cyclo-oxygenase-2 (COX-2) in human ASM cells and results in a marked increase in prostanoid generation with PGE2 and PGI2 as the major products. We investigated the role of COX-2 induction and prostanoid release (measured as PGE2) in IL-1beta induced attenuation of cyclic AMP generation in response to the beta-adrenoceptor agonist isoprenaline (ISO). Pre-treatment of human ASM cells with IL-1beta significantly attenuated cyclic AMP generation in response to high concentrations of ISO (1.0-10.0 microM) in a time- and concentration-dependent manner. The effect was accompanied by a high concentration of PGE2 release. The non-selective COX inhibitor indomethacin (Ind), the selective COX-2 inhibitor NS-398, the protein synthesis inhibitors cycloheximide (CHX) and actinomycin D and the steroid dexamethasone (Dex) all abolished the PGE2 release and prevented the attenuated cyclic AMP generation. COX substrate arachidonic acid time- and concentration-dependently mimicked IL-1beta induced attenuation and the effect was prevented by the non-selective COX inhibitors Ind and flurbiprofen, but not by NS-398, CHX and Dex. In contrast to IL-1beta, TNFalpha and IFNgamma, which are ineffective in inducing COX-2 and releasing PGE2 from human ASM cells, did not affect the cyclic AMP formation. Our study demonstrates that COX-2 induction and the consequent release of prostanoids plays a crucial role in IL-1beta induced attenuation of human ASM cell cyclic AMP response to ISO.