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

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Abstract
The prostanoid receptors on human airway smooth muscle cells (HASMC) that augment the release by IL-1β 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 EP4receptor subtypes. These findings were corroborated at the protein level by immunocytochemistry. IL-1β promoted the elaboration of G-CSF, which was augmented by PGE2. Cicaprost (IP receptor agonist) was approximately equiactive with PGE2, whereas PGD2, PGF2α, and U-46619 (TP receptor agonist) were over 10-fold less potent. Neither SQ 29,548 nor BW A868C (TP and DP1receptor 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/EP3selective), 17-phenyl-ω-trinor PGE2(EP1selective), ONO-AE1-259, and butaprost (both EP2selective) 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 EP2and EP4receptor antagonists, respectively, failed to displace to the right the PGE2concentration-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 PGE2was 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 PGE2facilitates G-CSF secretion from HASMC through a PKA-dependent mechanism by acting through EP2and EP4prostanoid receptors and that effective antagonism is realized only when both subtypes are blocked concurrently.

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