Abstract
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-κB (NF-κB) was found to regulate sPLA2-IIA expression in AMs. Both AA and ETYA inhibited basal activation of NF-κB but had no effect on LPS-induced NF-κB translocation, suggesting that suppression of sPLA2-IIA synthesis by AA in LPS-stimulated cells occurs via a NF-κB–independent pathway. 15-Deoxy-Δ12,14-PGJ2 and ciglitazone, which are, respectively, natural and synthetic ligands for peroxisome proliferator-activated receptor-γ (PPAR-γ), inhibited LPS-induced sPLA2-IIA synthesis, whereas PPAR-α ligands were ineffective. Moreover, electrophoretic mobility shift assay showed PPAR activation by AA and PPAR-γ 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-κB activation. In contrast, the inhibition of LPS-stimulated sPLA2-IIA expression is mediated by cyclooxygenase-derived metabolites of AA and involves a PPAR-γ–dependent pathway. These findings provide new insights for the treatment of ALI.
- The American Society for Pharmacology and Experimental Therapeutics
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