title: Induction of apoptosis by particulate matter: role of TNF-alpha and MAPK.
abstract: Particulate matter (PM) is a major by-product from the combustion of fossil fuels. The biological target of inhaled PM is the pulmonary epithelium and resident macrophages. In this study, we demonstrate that cultured macrophages (RAW 264.7 cells) exposed continously to a well-defined model of PM [benzo[a]pyrene adsorbed on carbon black (CB+BaP)] exhibit a time-dependent expression and release of the cytokine tumor necrosis factor-alpha (TNF-alpha). CB+BaP also evoked programmed cell death or apoptosis in cultured macrophages as assessed by genomic DNA-laddering assays. The CB+BaP-induced apoptosis was inhibited when macrophages were treated with CB+BaP in the presence of a neutralizing antibody to TNF-alpha, suggesting that TNF-alpha plays an important role in mediating CB+BaP-induced apoptosis in macrophages. Interestingly, neither untreated carbon black nor benzo[a]pyrene alone induced apoptosis or caused the release of TNF-alpha in RAW 264.7 cells. Moreover, we observed that TNF-alpha activates mitogen-activated protein kinase (MAPK) activity, the extracellular signal-regulated kinases p42/p44, in a time-dependent manner. RAW 264.7 cells treated with PD-098059, a selective inhibitor of MAPK kinase activity, did not exhibit CB+BaP-induced apoptosis and TNF-alpha secretion. Furthermore, cells treated with the MAPK kinase inhibitor did not undergo TNF-alpha-induced apoptosis. Taken together, our data suggest that TNF-alpha mediates PM-induced apoptosis and that the MAPK pathway may play an important role in regulating this pathway.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors.forename: B Y
authors.initials: BY
authors.lastname: Chin
authors.forename: M E
authors.initials: ME
authors.lastname: Choi
authors.forename: M D
authors.initials: MD
authors.lastname: Burdick
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: T H
authors.initials: TH
authors.lastname: Risby
authors.forename: A M
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000327:Adsorption; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002244:Carbon; D002460:Cell Line; D005579:Fossil Fuels; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
chemical_list: D005579:Fossil Fuels; D014409:Tumor Necrosis Factor-alpha; D001564:Benzo(a)pyrene; D002244:Carbon; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases