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Amplification Mechanisms of Inflammation: Paracrine Stimulation of Arachidonic Acid Mobilization by Secreted Phospholipase A₂ Is Regulated by Cytosolic Phospholipase A₂-Derived Hydroperoxyeicosatetraenoic Acid¹

Institute of Molecular Biology and Genetics, University of Valladolid School of Medicine, Valladolid, Spain

In macrophages and other major immunoinflammatory cells, two phospholipase A₂ (PLA₂) enzymes act in concert to mobilize arachidonic acid (AA) for immediate PG synthesis, namely group IV cytosolic phospholipase A₂ (cPLA₂) and a secreted phospholipase A₂ (sPLA₂). In this study, the molecular mechanism underlying cross-talk between the two PLA₂s during paracrine signaling has been investigated. U937 macrophage-like cells respond to Con A by releasing AA in a cPLA₂-dependent manner, and addition of exogenous group V sPLA₂ to the activated cells increases the release. This sPLA₂ effect is abolished if the cells are pretreated with cPLA₂ inhibitors, but is restored by adding exogenous free AA. Inhibitors of cyclooxygenase and 5-lipoxygenase have no effect on the response to sPLA₂. In contrast, ebselen strongly blocks it. Reconstitution experiments conducted in pyrrophenone-treated cells to abolish cPLA₂ activity reveal that 12- and 15-hydroperoxyeicosatetraenoic acid (HPETE) are able to restore the sPLA₂ response to levels found in cells displaying normal cPLA₂ activity. Moreover, 12- and 15-HPETE are able to enhance sPLA₂ activity in vitro, using a natural membrane assay. Neither of these effects is mimicked by 12- or 15-hydroxyeicosatetraenoic acid, indicating that the hydroperoxy group of HPETE is responsible for its biological activity. Collectively, these results establish a role for 12/15-HPETE as an endogenous activator of sPLA₂-mediated phospholipolysis during paracrine stimulation of macrophages and identify the mechanism that connects sPLA₂ with cPLA₂ for a full AA mobilization response.

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