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- Title
Identification in human airways smooth muscle cells of the prostanoid receptor and signalling pathway through which PGE2 inhibits the release of GM-CSF.
- Authors
Clarke, Deborah L.; Belvisi, Maria G.; Catley, Matthew C.; Yacoub, Magdi H.; Newton, Robert; Giembycz, Mark A.
- Abstract
1: The prostanoid receptor(s) on human airways smooth muscle (HASM) cells that mediates the inhibitory effect of PGE2 on interleukin (IL)-1ß-induced granulocyte/macrophage colony-stimulating factor (GM-CSF) release has been classified. 2: IL-1ß 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-?-trinor PGE2) and EP3-receptor (sulprostone) subtypes as well as cicaprost (IP-selective), PGD2, PGF2a and U-46619 (TP-selective) were poorly active or inactive at concentrations up to 10?µM. 3: 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. 4: 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. 5: 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
- Subjects
GENE expression; PROSTANOIDS; ADENOVIRUSES; INTERLEUKINS; MUSCLE cells; EICOSANOIC acid derivatives; PROSTACYCLIN; CELL metabolism; PROTEIN metabolism; METABOLISM in viruses; CELL physiology; CELL receptors; CELLS; CELLULAR signal transduction; ENZYME inhibitors; GRANULOCYTE-colony stimulating factor; GENES; GRANULOCYTE-macrophage colony-stimulating factor; HETEROCYCLIC compounds; INDOMETHACIN; INTERLEUKIN-1; ISOQUINOLINE; NUCLEOTIDES; PROSTAGLANDINS; PROTEINS; SULFONAMIDES; TRACHEA; TRANSFERASES; VASODILATORS; VIRUSES; MISOPROSTOL; DINOPROSTONE; CHEMICAL inhibitors; PHARMACODYNAMICS
- Publication
British Journal of Pharmacology, 2004, Vol 141, Issue 7, p1141
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1038/sj.bjp.0705716