β2-adrenoceptor agonists inhibit release of eosinophil-activating cytokines from human airway smooth muscle cells

1 Airway smooth muscle (ASM) is a potential source of multiple pro-inflammatory cytokines during airway inflammation. beta -Adrenoceptor agonist hyporesponsiveness is a characteristic feature of asthma, and interleukin (IL)-1 beta and tumour necrosis factor (TNF)-alpha are implicated in its cause. Here, the capacity of beta -adrenoceptor agonists to prevent release of GM-CSF, RANTES, eotaxin and IL-8, elicited by IL-1 beta or TNF alpha, was examined in human ASM cells. 2 Isoprenaline (similar to EC50 150 nm), a non-selective beta -adrenoceptor agonist, and salbutamol (similar to EC50 25 nM), a selective beta (2)-adrenoceptor agonist, attenuated release of GM-CSF, RANTES and eotaxin, but not IL-8 (EC50 > 1 muM). The maximum extent of attenuation was RANTES greater than or equal to eotaxin > GMCSF > > IL-8, and was prevented by either propranolol (1 muM), a non-selective beta -adrenoceptor antagonist, or ICI 118511 (IC50 15 nM), a selective beta (2)-adrenoceptor antagonist. 3 The cyclic AMP-elevating agents, dibutyryl cyclic AMP (similar to EC50 135 muM), forskolin (similar to EC50 530 nM) and cholera toxin ( similar to EC50 575 pg ml(-1)) abolished IL-1 beta -induced release of GM-CSF, RANTES and eotaxin, but not IL-8. 4 IL-1 beta (1 ng ml(-1)) attenuated early increases (up to 1 h) in cyclic AMP formation induced by salbutamol (1 muM), but not by forskolin (10 muM). The cyclo-oxygenase inhibitor, indomethacin (1 muM) prevented later increases (3-12 h) in IL-1 beta -stimulated cyclic AMP content, but did not prevent the attenuation by salbutamol of IL-1 beta -induced cytokine release. 5 We conclude in human ASM cells that activation of beta (2)-adrenoceptors and generation of cyclic AMP is negatively-linked to the release, elicited by IL-1 beta or TNF alpha, of eosinophil-activating cytokines such as GM-CSF, RANTES and eotaxin, but not IL-8.