Vol. 61, Issue 4, 786-794, April 2002

Arachidonic Acid Differentially Affects Basal and Lipopolysaccharide-Induced sPLA₂-IIA Expression in Alveolar Macrophages through NF-B and PPAR--Dependent Pathways

Mounia Alaoui-El-Azher, Yongzheng Wu, Nathalie Havet, Alain Israël, Alain Lilienbaum, and Lhousseine Touqui

Unité de Défense Innée et Inflammation and Unité de Biologie Moléculaire de l'Expression Génique, Institut Pasteur, Paris, France

Secretory type IIA phospholipase A₂ (sPLA₂-IIA) is a critical enzyme involved in inflammatory diseases. We have previously identified alveolar macrophages (AMs) as the major pulmonary source of lipopolysaccharide (LPS)-induced sPLA₂-IIA expression in a guinea pig model of acute lung injury (ALI). Here, we examined the role of arachidonic acid (AA) in the regulation of basal and LPS-induced sPLA₂-IIA expression in AMs. We showed that both AA and its nonmetabolizable analog, 5,8,11,14-eicosatetraynoic acid (ETYA), inhibited sPLA₂-IIA synthesis in unstimulated AMs. However, only AA inhibited sPLA₂-IIA expression in LPS-stimulated cells, suggesting that this effect requires metabolic conversion of AA. Indeed, cyclooxygenase inhibitors abolished this down-regulation. Prostaglandins PGE₂, PGA₂, and 15d-PGJ₂ also inhibited the LPS-induced sPLA₂-IIA expression. Nuclear factor-B (NF-B) was found to regulate sPLA₂-IIA expression in AMs. Both AA and ETYA inhibited basal activation of NF-B but had no effect on LPS-induced NF-B translocation, suggesting that suppression of sPLA₂-IIA synthesis by AA in LPS-stimulated cells occurs via a NF-B-independent pathway. 15-Deoxy-^12,14-PGJ₂ and ciglitazone, which are, respectively, natural and synthetic ligands for peroxisome proliferator-activated receptor- (PPAR-), inhibited LPS-induced sPLA₂-IIA synthesis, whereas PPAR- ligands were ineffective. Moreover, electrophoretic mobility shift assay showed PPAR activation by AA and PPAR- ligands in LPS-stimulated AMs. Our results suggest that the down-regulation of basal sPLA₂-IIA expression is unrelated to the metabolic conversion of AA but is dependent on the impairment of NF-B activation. In contrast, the inhibition of LPS-stimulated sPLA₂-IIA expression is mediated by cyclooxygenase-derived metabolites of AA and involves a PPAR--dependent pathway. These findings provide new insights for the treatment of ALI.