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