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Published online before print March 5, 2007

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(Journal of Leukocyte Biology. 2007;81:1523-1534.)
© 2007 by Society for Leukocyte Biology

Dissociation between the translocation and the activation of Akt in fMLP-stimulated human neutrophils—effect of prostaglandin E₂

Chantal Burelout^*, Paul H. Naccache^*, and Sylvain G. Bourgoin^*,,1

^* Centre de Recherche en Rhumatologie-Immunologie, Centre de Recherche du CHUL, and Départements de
Médecine et
d’Anatomie-Physiologie, Université Laval, Québec, Canada

¹ Correspondence: Centre de Recherche en Rhumatologie-Immunologie, Centre de Recherche du CHUL, 2705 Boul. Laurier, Room T1-49, Sainte-Foy, Québec, Canada G1V 4G2. E-mail: sylvain.bourgoin{at}crchul.ulaval.ca

PGE₂ and other cAMP-elevating agents are known to down-regulate most functions stimulated by fMLP in human polymorphonuclear neutrophils. We reported previously that the inhibitory potential of PGE₂ resides in its capacity to suppress fMLP-stimulated PI-3K activation via the PGE₂ receptor EP₂ and hence, to decrease phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P₃] formation. Akt activity is stimulated by fMLP through phosphorylation on threonine 308 (Thr308) and serine 473 (Ser473) by 3-phosphoinositide-dependent kinase 1 (PDK1) and MAPK-AP kinase (APK)-APK-2 (MAPKAPK-2), respectively, in a PI-3K-dependent manner. Despite the suppression of fMLP-induced PI-3K activation observed in the presence of PGE₂, we show that Akt is fully phosphorylated on Thr308 and Ser473. However, fMLP-induced Akt translocation is decreased markedly in this context. PGE₂ does not affect the phosphorylation of MAPKAPK-2 but decreases the translocation of PDK1 induced by fMLP. Other cAMP-elevating agents such as adenosine (Ado) similarly block the fMLP-induced PI-3K activation process but do not inhibit Akt phosphorylation. However, Akt activity stimulated by fMLP is down-regulated slightly by agonists that elevate cAMP levels. Whereas protein kinase A is not involved in the maintenance of Akt phosphorylation, it is required for the inhibition of Akt translocation by PGE₂. Moreover, inhibition of fMLP-stimulated PI-3K activity by the selective inhibitor IC87114 only partially affects the late phase of Akt phosphorylation in the presence of PGE₂. Taken together, these results suggest that cAMP-elevating agents, such as PGE₂ or Ado, are able to induce an alternative mechanism of Akt activation by fMLP in which the translocation of Akt to PI(3,4,5)P₃-enriched membranes is not required prior to its phosphorylation.

Key Words: cAMP • PI-3K • adenosine

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