Arachidonic Acid Differentially Affects Basal and Lipopolysaccharide-Induced sPLA 2 -IIA Expression in Alveolar Macrophages through NF-κB and PPAR-γ–Dependent Pathways

Mounia Alaoui-El-Azher (1) , Yongzheng Wu (1) , Nathalie Havet (2) , Alain Israel (2) , Alain Lilienbaum (2) , Lhousseine Touqui (1)

1 Défense innée et inflammation
2 Biologie Moléculaire de l'Expression Génique

Secretory type IIA phospholipase A(2) (sPLA(2)-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 sPLA(2)-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 sPLA(2)-IIA expression in AMs. We showed that both AA and its nonmetabolizable analog, 5,8,11,14-eicosatetraynoic acid (ETYA), inhibited sPLA(2)-IIA synthesis in unstimulated AMs. However, only AA inhibited sPLA(2)-IIA expression in LPS-stimulated cells, suggesting that this effect requires metabolic conversion of AA. Indeed, cyclooxygenase inhibitors abolished this down-regulation. Prostaglandins PGE(2), PGA(2), and 15d-PGJ(2) also inhibited the LPS-induced sPLA(2)-IIA expression. Nuclear factor-kappaB (NF-kappaB) was found to regulate sPLA(2)-IIA expression in AMs. Both AA and ETYA inhibited basal activation of NF-kappaB but had no effect on LPS-induced NF-kappaB translocation, suggesting that suppression of sPLA(2)-IIA synthesis by AA in LPS-stimulated cells occurs via a NF-kappaB-independent pathway. 15-Deoxy-Delta(12,14)-PGJ(2) and ciglitazone, which are, respectively, natural and synthetic ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), inhibited LPS-induced sPLA(2)-IIA synthesis, whereas PPAR-alpha ligands were ineffective. Moreover, electrophoretic mobility shift assay showed PPAR activation by AA and PPAR-gamma ligands in LPS-stimulated AMs. Our results suggest that the down-regulation of basal sPLA(2)-IIA expression is unrelated to the metabolic conversion of AA but is dependent on the impairment of NF-kappaB activation. In contrast, the inhibition of LPS-stimulated sPLA(2)-IIA expression is mediated by cyclooxygenase-derived metabolites of AA and involves a PPAR-gamma-dependent pathway. These findings provide new insights for the treatment of ALI.

Domaines: Biologie moléculaire; Organisation et fonctions cellulaires [q-bio.SC]

Mounia Alaoui-El-Azher, Yongzheng Wu, Nathalie Havet, Alain Israel, Alain Lilienbaum, et al.. Arachidonic Acid Differentially Affects Basal and Lipopolysaccharide-Induced sPLA 2 -IIA Expression in Alveolar Macrophages through NF-κB and PPAR-γ–Dependent Pathways. Molecular Pharmacology, 2002, 61 (4), pp.786-794. ⟨10.1124/mol.61.4.786⟩. ⟨pasteur-02863064⟩