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Identification in human airways smooth muscle cells of the prostanoid receptor and signalling pathway through which PGE 2 inhibits the release of GM‐CSF
Author(s) -
Clarke Deborah L,
Belvisi Maria G,
Catley Matthew C,
Yacoub Magdi H,
Newton Robert,
Giembycz Mark A
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705716
Subject(s) - prostanoid , signalling pathways , identification (biology) , smooth muscle , receptor , microbiology and biotechnology , signalling , signal transduction , biology , chemistry , endocrinology , biochemistry , botany
The prostanoid receptor(s) on human airways smooth muscle (HASM) cells that mediates the inhibitory effect of PGE 2 on interleukin (IL)‐1 β ‐induced granulocyte/macrophage colony‐stimulating factor (GM‐CSF) release has been classified. IL‐1 β evoked the release of GM‐CSF from HASM cells, which was suppressed by PGE 2 , 16,16‐dimethyl PGE 2 (nonselective), misoprostol (EP 2 /EP 3 ‐selective), ONO‐AE1‐259 and butaprost (both EP 2 ‐selective) with pIC 50 values of 8.61, 7.13, 5.64, 8.79 and 5.43, respectively. EP‐receptor agonists that have selectivity for the EP 1 ‐ (17‐phenyl‐ ω ‐trinor PGE 2 ) and EP 3 ‐receptor (sulprostone) subtypes as well as cicaprost (IP‐selective), PGD 2 , PGF 2 α and U‐46619 (TP‐selective) were poorly active or inactive at concentrations up to 10 μ M . AH 6809, a drug that can be used to selectively block EP 2 ‐receptors in HASM cells, antagonised the inhibitory effect of PGE 2 , 16,16‐dimethyl PGE 2 and ONO‐AE1‐259 with apparent p A 2 values of 5.85, 6.09 and 6.1 respectively. In contrast, the EP 4 ‐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 PGE 2 and ONO‐AE1‐259. Inhibition of GM‐CSF release by PGE 2 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 EP 2 ‐subtype mediate the inhibitory effect of PGE 2 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