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Inhibition of Secretory Phospholipase A2-Induced Cytokine Production in Human Lung Macrophages by Budesonide

Background: Secretory phospholipases A2 (sPLA2) are an emerging class of mediators of inflammation. These enzymes are released in vivo in patients with systemic inflammatory diseases and allergic disorders. sPLA2s may activate inflammatory cells by both enzymatic and nonenzymatic mechanisms. The aim of this study was to evaluate the effect of the inhaled glucocorticoid budesonide on sPLA2-induced activation of primary human macrophages. Methods: Macrophages isolated from human lung tissue were preincubated (3–18 h) with budesonide (1–1,000 nM) before stimulation with 2 distinct sPLA2s (group IA and group X). At the end of incubation the release of TNF-α, IL-6 and IL-8 was assessed by ELISA. Specific mRNA for these products was determined by quantitative RT-PCR. Activation of mitogen-activated kinases ERK 1/2 and p38 was assessed by Western blot. Results: Budesonide inhibited the release of TNF-α, IL-6 and IL-8 from sPLA2-stimulated macrophages in a concentration-dependent manner. The inhibitory effect of budesonide was due to a reduction of gene expression and was complete after 18 h of preincubation. Budesonide had no effect on sPLA2-induced arachidonic acid mobilization and exocytosis, assessed as β-glucuronidase release. Suppression of cytokine/chemokine production by budesonide was associated with inhibition of sPLA2-induced ERK 1/2 and p38 activation. Conclusions: Budesonide inhibits the production of proinflammatory cytokines/chemokines from human lung macrophages activated by sPLA2. Budesonide represents the first example of a drug able to block the nonenzymatic effects of sPLA2 on human inflammatory cells and, therefore, may provide a useful therapeutic options for diseases associated with enhanced release of sPLA2s in vivo.