UNSPECIFIED. (2004) Identification in human airways smooth muscle cells of the prostanoid receptor and signalling pathway through which PGE(2) inhibits the release of GM-CSF. BRITISH JOURNAL OF PHARMACOLOGY, 141 (7). pp. 1141-1150. ISSN 0007-1188

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Abstract

1 The prostanoid receptor(s) on human airways smooth muscle (HASM) cells that mediates the inhibitory effect of PGE(2) on interleukin (IL)-1beta-induced granulocyte/macrophage colony-stimulating factor (GM-CSF) release has been classified.

2 IL-1beta evoked the release of GM-CSF from HASM cells, which was suppressed by PGE(2), 16,16-dimethyl PGE(2) (nonselective), misoprostol (EP2/EP3-selective), ONO-AE1-259 and butaprost (both EP2-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 EP1- (17-phenyl-omega-trinor PGE(2)) and EP3-receptor (sulprostone) subtypes as well as cicaprost (IP-selective), PGD(2), PGF(2alpha) and U-46619 (TP-selective) were poorly active or inactive at concentrations up to 10 muM.

3 AH 6809, a drug that can be used to selectively block EP2-receptors in HASM cells, antagonised the inhibitory effect of PGE(2), 16,16-dimethyl PGE(2) and ONO-AE1-259 with apparent pA(2) 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 GMCSF release evoked by PGE(2) and ONO-AE1-259.

4 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.

5 We conclude that prostanoid receptors of the EP2-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.

Item Type:	Journal Article
Subjects:	R Medicine > RS Pharmacy and materia medica
Journal or Publication Title:	BRITISH JOURNAL OF PHARMACOLOGY
Publisher:	NATURE PUBLISHING GROUP
ISSN:	0007-1188
Official Date:	April 2004
Volume:	141
Number:	7
Number of Pages:	10
Page Range:	pp. 1141-1150
Identification Number:	10.1038/sj.bjp.0705716
Publication Status:	Published
URI:	http://wrap.warwick.ac.uk/id/eprint/8489

Data sourced from Thomson Reuters' Web of Knowledge

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