Role of NF-κB and PPAR-γ in lung inflammation induced by monocyte-derived microparticles

Microparticles (MP) are phospholipid vesicles shed by cells upon activation or apoptosis. Monocyte-derived MP upregulate the synthesis of proinflammatory mediators by lung epithelial cells; the molecular bases of such activity are unknown. Peroxisome proliferator-activated receptors (PPAR) have been demonstrated to be involved in the modulation of nuclear factor (NF)-kappa B transcriptional activity and inflammation. We investigated whether the upregulation of the synthesis of proinflammatory cytokines by human lung epithelial cells induced by monocyte/macrophage-derived MP involves NF-kappa B activation and is modulated by PPAR-gamma. MP were generated by stimulation of human monocytes/macrophages with the calcium ionophore, A23187. MP were incubated with human lung epithelial cells. NF-kappa B translocation was assessed by electrophoretic mobility shift assay. Interleukin (IL)-8 and monocyte chemotactic protein (MCP)-1 synthesis was assessed by ELISA and RT-PCR. Stimulation of A549 alveolar cells with monocyte/macrophage-derived MP caused an increase in NF-kappa B activation and IL-8 and MCP-1 synthesis that was inhibited by pre-incubation with the PPAR-gamma agonists, rosiglitazone and 15-deoxy-Delta(12,14)-prostaglandin-J(2). Parallel experiments with normal human bronchial epithelial cells largely confirmed the results. The effects of PPAR-gamma agonists were reversed by the specific antagonist, GW9662. Upregulation of the synthesis of proinflammatory mediators by human lung epithelial cells induced by monocyte/macrophage-derived MP is mediated by NF-kappa B activation through a PPAR- gamma dependent pathway.