Abstract
Background: Secretory phospholipases A<sub>2</sub> (sPLA<sub>2</sub>) are an emerging class of mediators of inflammation. These enzymes are released in vivo in patients with systemic inflammatory diseases and allergic disorders. sPLA<sub>2</sub>s 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 sPLA<sub>2</sub>-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 sPLA<sub>2</sub>s (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 sPLA<sub>2</sub>-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 sPLA<sub>2</sub>-induced arachidonic acid mobilization and exocytosis, assessed as β-glucuronidase release. Suppression of cytokine/chemokine production by budesonide was associated with inhibition of sPLA<sub>2</sub>-induced ERK 1/2 and p38 activation. Conclusions: Budesonide inhibits the production of proinflammatory cytokines/chemokines from human lung macrophages activated by sPLA<sub>2</sub>. Budesonide represents the first example of a drug able to block the nonenzymatic effects of sPLA<sub>2</sub> on human inflammatory cells and, therefore, may provide a useful therapeutic options for diseases associated with enhanced release of sPLA<sub>2</sub>s in vivo.
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