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

Abstract

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 proliferatoractivated receptors (PPAR) have been demonstrated to be involved in the modulation of nuclear factor (NF)-kB 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-kB activation and is modulated by PPAR-c.MP were generated by stimulation of human monocytes/macrophages with the calcium ionophore, A23187. MP were incubated with human lung epithelial cells. NF-kB 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-kB activation and IL-8 and MCP-1 synthesis that was inhibited by pre-incubation with the PPAR-c agonists, rosiglitazone and 15-deoxy-D 12,14 -prostaglandin-J 2 . Parallel experiments with normal human bronchial epithelial cells largely confirmed the results. The effects of PPAR-c 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-kB activation through a PPAR-c dependent pathway.

Evolving Role of Microparticles in the Pathophysiology of Endothelial Dysfunction

“…Rosiglitazone inhibits leukocyte MP-mediated vascular dysfunction and decreases the release of proinflammatory proteins from isolated murine aortae (69 ). Peroxisome proliferator activated receptor treatment also reduces the ability of MPs to evoke an increase in NFB and subsequently counteracts vascular dysfunction associated with increased release of proinflammatory proteins elicited by MPs in mice (70 ).…”

Alterations of peroxisome proliferator-activated receptor γ and monocyte chemoattractant protein 1 gene expression in the nitrofen-induced hypoplastic lung

“…Monocyte chemotactic protein 1 has been reported to be inhibited by activation of PPARγ [12,16,17]. In the late stages of lung development, increased pulmonary and circulating MCP-1 levels have been associated with the development of PH in animal models as well as human studies [18][19][20][21].…”

Cell-derived microparticles and the lung

“…We investigated the mechanisms leading to increased transcription of pro-inflammatory mediators induced by HMM-derived microparticles. First, we demonstrated that HMM-derived microparticles cause the translocation of NF-κB into the nucleus [36]. We then showed that PPAR-γ agonists, such as rosiglitazone and 15-deoxy-Δ 12,14 -prostaglandin-J 2 , inhibit the phenomenon [36], in keeping with the postulated anti-inflammatory role of these molecules that have in fact been proposed as potential therapeutic targets in lung diseases [37].…”

“…First, we demonstrated that HMM-derived microparticles cause the translocation of NF-κB into the nucleus [36]. We then showed that PPAR-γ agonists, such as rosiglitazone and 15-deoxy-Δ 12,14 -prostaglandin-J 2 , inhibit the phenomenon [36], in keeping with the postulated anti-inflammatory role of these molecules that have in fact been proposed as potential therapeutic targets in lung diseases [37]. Microparticles with a similar pro-inflammatory potential on lung epithelial cells are also generated by HMMs exposed to cigarette smoke extract [24].…”