| 19439980 |
Triggiani M, Granata F, Petraroli A, Loffredo S, Frattini A, Staiano RI, Monaco G, Marone G: Inhibition of secretory phospholipase A2-induced cytokine production in human lung macrophages by budesonide. Int Arch Allergy Immunol. 2009;150(2):144-55. Epub 2009 May 11.
BACKGROUND: Secretory phospholipases A (2) (sPLA (2)) are an emerging class of mediators of inflammation. These enzymes are released in vivo in patients with systemic inflammatory diseases and allergic disorders. sPLA (2) 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 (2)-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 (2) s (group IA and group X). At the end of incubation the release of TNF-alpha, 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-alpha, IL-6 and IL-8 from sPLA (2)-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 (2)-induced arachidonic acid mobilization and exocytosis, assessed as beta-glucuronidase release. Suppression of cytokine/chemokine production by budesonide was associated with inhibition of sPLA (2)-induced ERK 1/2 and p38 activation. CONCLUSIONS: Budesonide inhibits the production of proinflammatory cytokines/chemokines from human lung macrophages activated by sPLA (2). Budesonide represents the first example of a drug able to block the nonenzymatic effects of sPLA (2) on human inflammatory cells and, therefore, may provide a useful therapeutic options for diseases associated with enhanced release of sPLA (2) s in vivo. |
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