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ORIGINAL ARTICLE

E-Ring 8-Isoprostanes Are Agonists at EP₂- and EP₄-Prostanoid Receptors on Human Airway Smooth Muscle Cells and Regulate the Release of Colony-Stimulating Factors by Activating cAMP-Dependent Protein Kinase

Thoracic Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom (D.L.C.); Cardiothoracic Surgery (Respiratory Pharmacology Group), National Heart and Lung Institute, Imperial College London, London, United Kingdom (M.G.B., E.H.); and Departments of Cell Biology and Anatomy (R.N.) and Pharmacology and Therapeutics (M.A.G.), Institute of Infection, Immunity, and Inflammation, University of Calgary, Calgary, Alberta, Canada

Abstract

8-Isoprostanes are bioactive lipid mediators formed via the nonenzymatic peroxidation of arachidonic acid by free radicals and reactive oxygen species. However, their cognate receptors, biological actions, and signaling pathways are poorly studied. Here, we report the effect of a variety of E- and F-ring 8-isoprostanes on the release of granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) from human airway smooth muscle (HASM) cells stimulated with interleukin-1 (IL-1). The elaboration of GM-CSF and G-CSF by IL-1 was inhibited and augmented, respectively, in a concentration-dependent manner by 8-iso-prostaglandin (PG) E₁ and 8-iso-PGE₂, but not by 8-iso-PGF₁, 8-iso-PGF₂, and 8-iso-PGF₃. AH 6809 (6-isopropoxy-9-oxoxanthine-2-carboxylic acid), an EP₁-/EP₂-/DP-receptor blocking drug, antagonized the inhibitory effect of 8-iso-PGE₁ and 8-iso-PGE₂ on GM-CSF output with an affinity consistent with an interaction at prostanoid receptors of the EP₂-subtype. In contrast, the facilitation by 8-iso-PGE₁ and 8-iso-PGE₂ of G-CSF release was unaffected by AH 6809 and the selective EP₄-receptor antagonist L-161,982 [4'-[3-butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]. However, when used in combination, AH 6809 and L-161,982 displaced 5-fold to the right the 8-iso-PGE and 8-iso-PGE concentration-response curves. The opposing ¹effect of E-ring ²8-isoprostanes on GM-CSF and G-CSF release was mimicked by 8-bromo-cAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). Together, these data demonstrate that E-ring 8-isoprostanes regulate the secretion of GM-CSF and G-CSF from HASM cells by a cAMP- and PKA-dependent mechanism. Moreover, antagonist studies revealed that 8-iso-PGE₁ and 8-iso-PGE₂ act solely via EP₂ -receptors to inhibit GM-CSF release, whereas both EP₂- and EP₄-receptor subtypes positively regulate G-CSF output.

Address correspondence to: Dr. Mark A. Giembycz, Respiratory Research Group, Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Dr. NW., Calgary, Alberta, Canada T2N 4N1. E-mail: giembycz{at}ucalgary.ca

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