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First published on November 4, 2004; DOI: 10.1124/mol.104.006486

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Received for publication August 19, 2004.
Revised October 18, 2004.
Accepted for publication November 3, 2004.

E-Ring 8-Isoprostanes are Agonists at EP2- and EP4-Prostanoid Receptors on Human Airways Smooth Muscle Cells and Regulate the Release of Colony-stimulating Factors by Activating cAMP-dependent Protein Kinase

Deborah Clarke 1, Maria G Belvisi 1, Elizabeth Hardaker 1, Robert Newton 2, Mark A Giembycz 2*

1 Imperial College London 2 University of Calgary

* Address correspondence to: E-mail: giembycz{at}ucalgary.ca

Abstract

8-Isoprostanes are bioactive lipid mediators formed via the non-enzymatic peroxidation of arachidonic acid by free radicals and reactive oxygen species. However, their cognate receptors, biological actions and signalling pathways are poorly studied. Here we report the effect of a variety of E- and F{alpha}-ring 8-isoprostanes on the release of granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) from human airways smooth muscle (HASM) cells stimulated with interleukin-1{beta} (IL-1{beta}). The elaboration of GM-CSF and G-CSF by IL-1{beta} 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{alpha}, 8-iso-PGF2{alpha}, and 8-iso-PGF3{alpha}. AH6809, 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 AH6809 and the selective EP4-receptor antagonist, L-161,982. However, when used in combination AH6809 and L-161,982 displaced five-fold to the right the 8-iso-PGE1 and 8-iso-PGE2 concentration-response curves. The opposing effect of E-ring 8-isoprostanes on GM-CSF and G-CSF release was mimicked by 8-Br-cAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). Collectively, 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 while both EP2- and EP4-subtypes positively regulate G-CSF output.


Key words: Prostanoid, Interleukins, cAMP, Protein Kinase A, Oxidative stress




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