β 2 ‐Adrenoceptor agonists inhibit release of eosinophil‐activating cytokines from human airway smooth muscle cells

• Published in: British journal of pharmacology Vol. 132; no. 3; pp. 729 - 741
• Main Authors: Hallsworth, Matthew P, Twort, Charles H C, Lee, Tak H, Hirst, Stuart J
• Format: Journal Article
• Language: English
• Published: 29.01.2009
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703866

Airway smooth muscle (ASM) is a potential source of multiple pro‐inflammatory cytokines during airway inflammation. β‐Adrenoceptor agonist hyporesponsiveness is a characteristic feature of asthma, and interleukin (IL)‐1β and tumour necrosis factor (TNF)‐α are implicated in its cause. Here, the capacity of β‐adrenoceptor agonists to prevent release of GM‐CSF, RANTES, eotaxin and IL‐8, elicited by IL‐1β or TNFα, was examined in human ASM cells. Isoprenaline (∼EC 50 150 n M ), a non‐selective β‐adrenoceptor agonist, and salbutamol (∼EC 50 25 n M ), a selective β 2 ‐adrenoceptor agonist, attenuated release of GM‐CSF, RANTES and eotaxin, but not IL‐8 (EC 50 >1 μ M ). The maximum extent of attenuation was RANTES eotaxin > GM‐CSF >> IL‐8, and was prevented by either propranolol (1 μ M ), a non‐selective β‐adrenoceptor antagonist, or ICI 118511 (IC 50 15 n M ), a selective β 2 ‐adrenoceptor antagonist. The cyclic AMP‐elevating agents, dibutyryl cyclic AMP (∼EC 50 135 μ M ), forskolin (∼EC 50 530 n M ) and cholera toxin (∼EC 50 575 pg ml −1 ) abolished IL‐1β‐induced release of GM‐CSF, RANTES and eotaxin, but not IL‐8. IL‐1β (1 ng ml −1 ) attenuated early increases (up to 1 h) in cyclic AMP formation induced by salbutamol (1 μ M ), but not by forskolin (10 μ M ). The cyclo‐oxygenase inhibitor, indomethacin (1 μ M ) prevented later increases (3 – 12 h) in IL‐1β‐stimulated cyclic AMP content, but did not prevent the attenuation by salbutamol of IL‐1β‐induced cytokine release. We conclude in human ASM cells that activation of β 2 ‐adrenoceptors and generation of cyclic AMP is negatively‐linked to the release, elicited by IL‐1β or TNFα, of eosinophil‐activating cytokines such as GM‐CSF, RANTES and eotaxin, but not IL‐8. British Journal of Pharmacology (2001) 132 , 729–741; doi: 10.1038/sj.bjp.0703866