title: Role of NF-kappaB and PPAR-gamma 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 proliferator-activated receptors (PPAR) have been demonstrated to be involved in the modulation of nuclear factor (NF)-κB 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-κB activation and is modulated by PPAR-γ. MP were generated by stimulation of human monocytes/macrophages with the calcium ionophore, A23187. MP were incubated with human lung epithelial cells. NF-κB 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-κB activation and IL-8 and MCP-1 synthesis that was inhibited by pre-incubation with the PPAR-γ agonists, rosiglitazone and 15-deoxy-Δ12,14-prostaglandin-J2. Parallel experiments with normal human bronchial epithelial cells largely confirmed the results. The effects of PPAR-γ 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-κB activation through a PPAR-γ dependent pathway.
authors.affiliation: Dipartimento Cardiotoracico e Vascolare, Laboratory of Respiratory Cell Biology, University of Pisa, Via Paradisa, 2 56124 Pisa, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Neri
authors.forename: C
authors.initials: C
authors.lastname: Armani
authors.forename: A
authors.initials: A
authors.lastname: Pegoli
authors.forename: C
authors.initials: C
authors.lastname: Cordazzo
authors.forename: Y
authors.initials: Y
authors.lastname: Carmazzi
authors.forename: S
authors.initials: S
authors.lastname: Brunelleschi
authors.forename: C
authors.initials: C
authors.lastname: Bardelli
authors.forename: M C
authors.initials: MC
authors.lastname: Breschi
authors.forename: P
authors.initials: P
authors.lastname: Paggiaro
authors.forename: A
authors.initials: A
authors.lastname: Celi
mesh_terms: D000813:Anilides / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D055252:Cell-Derived Microparticles / Q000502:physiology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D007476:Ionophores / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D018932:Chemokine CCL2; D016209:Interleukin-8; D007476:Ionophores; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000001:Calcimycin; D015230:Prostaglandin D2