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

Abstract

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.