Identification in human airways smooth muscle cells of the prostanoid receptor and signalling pathway through which PGE2 inhibits the release of GM‐CSF

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Abstract
The prostanoid receptor(s) on human airways smooth muscle (HASM) cells that mediates the inhibitory effect of PGE2 on interleukin (IL)‐1β‐induced granulocyte/macrophage colony‐stimulating factor (GM‐CSF) release has been classified. IL‐1β evoked the release of GM‐CSF from HASM cells, which was suppressed by PGE2, 16,16‐dimethyl PGE2 (nonselective), misoprostol (EP2/EP3‐selective), ONO‐AE1‐259 and butaprost (both EP2‐selective) with pIC50 values of 8.61, 7.13, 5.64, 8.79 and 5.43, respectively. EP‐receptor agonists that have selectivity for the EP1‐ (17‐phenyl‐ω‐trinor PGE2) and EP3‐receptor (sulprostone) subtypes as well as cicaprost (IP‐selective), PGD2, PGF2α and U‐46619 (TP‐selective) were poorly active or inactive at concentrations up to 10 μM. AH 6809, a drug that can be used to selectively block EP2‐receptors in HASM cells, antagonised the inhibitory effect of PGE2, 16,16‐dimethyl PGE2 and ONO‐AE1‐259 with apparent pA2 values of 5.85, 6.09 and 6.1 respectively. In contrast, the EP4‐receptor antagonists, AH 23848B and L‐161,982, failed to displace to the right the concentration–response curves that described the inhibition of GM‐CSF release evoked by PGE2 and ONO‐AE1‐259. Inhibition of GM‐CSF release by PGE2 and 8‐Br‐cAMP was abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP‐dependent protein kinase (PKA) but not by H‐89, a purported small molecule inhibitor of PKA. We conclude that prostanoid receptors of the EP2‐subtype mediate the inhibitory effect of PGE2 on GM‐CSF release from HASM cells by recruiting a PKA‐dependent pathway. In addition, the data illustrate that caution should be exercised when using H‐89 in studies designed to assess the role of PKA in biological processes. British Journal of Pharmacology (2004) 141, 1141–1150. doi:10.1038/sj.bjp.0705716

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