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Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor

¹Thoracic Medicine and ²Cardiothoracic Surgery (Respiratory Pharmacology Group), National Heart and Lung Institute, Imperial College London, London; ⁴Department of Biological Sciences, Biomedical Research Institute, University of Warwick, Coventry, United Kingdom; and ³Departments of Pharmacology & Therapeutics, and Cell Biology & Anatomy, Respiratory Research Group, University of Calgary, Calgary, Alberta, Canada

Submitted 20 August 2004 ; accepted in final form 21 September 2004

The prostanoid receptors on human airway smooth muscle cells (HASMC) that augment the release by IL-1 of granulocyte colony-stimulating factor (G-CSF) have been characterized and the signaling pathway elucidated. PCR of HASM cDNA identified products corresponding to EP₂, EP₃, and EP₄ receptor subtypes. These findings were corroborated at the protein level by immunocytochemistry. IL-1 promoted the elaboration of G-CSF, which was augmented by PGE₂. Cicaprost (IP receptor agonist) was approximately equiactive with PGE₂, whereas PGD₂, PGF₂, and U-46619 (TP receptor agonist) were over 10-fold less potent. Neither SQ 29,548 nor BW A868C (TP and DP₁ receptor antagonists, respectively) attenuated the enhancement of G-CSF release evoking any of the prostanoids studied. With respect to PGE₂, the EP receptor agonists 16,16-dimethyl PGE₂ (nonselective), misoprostol (EP₂/EP₃ selective), 17-phenyl--trinor PGE₂ (EP₁ selective), ONO-AE1-259, and butaprost (both EP₂ selective) were full agonists at enhancing G-CSF release. AH 6809 (10 µM) and L-161,982 (2 µM), which can be used in HASMC as selective EP₂ and EP₄ receptor antagonists, respectively, failed to displace to the right the PGE₂ concentration-response curve that described the augmented G-CSF release. In contrast, AH 6809 and L-161,982 in combination competitively antagonized PGE₂-induced G-CSF release. Augmentation of G-CSF release by PGE₂ was mimicked by 8-BrcAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). These data demonstrate that PGE₂ facilitates G-CSF secretion from HASMC through a PKA-dependent mechanism by acting through EP₂ and EP₄ prostanoid receptors and that effective antagonism is realized only when both subtypes are blocked concurrently.

cAMP-dependent protein kinase; human airway smooth muscle; granulocyte colony-stimulating factor; prostanoid receptors; airway inflammation

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