title: p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation.
abstract: Dendritic cells (DC) play a role in the regulation of immune responses to haptens, which in turn impact DC maturation. Whether beryllium (Be) is able to induce DC maturation and if this occurs via the MAPK pathway is not known. Primary monocyte-derived DCs (moDCs) models were generated from Be non-exposed healthy volunteers as a non-sensitized cell model, while PBMCs from BeS (Be sensitized) and CBD (chronic beryllium disease) were used as disease models. The response of these cells to Be was evaluated. The expression of CD40 was increased significantly (p<0.05) on HLA-DP Glu69+ moDCs after 100 μM BeSO₄-stimulation. BeSO₄ induced p38MAPK phosphorylation, while IκB-α was degraded in Be-stimulated moDCs. The p38 MAPK inhibitor SB203580 blocked Be-induced NF-κB activation in moDCs, suggesting that p38MAPK and NF-κB are dependently activated by BeSO₄. Furthermore, in BeS and CBD subjects, SB203580 downregulated Be-stimulated proliferation in a dose-dependent manner, and decreased Be-stimulated TNF-α and IFNγ cytokine production. Taken together, this study suggests that Be-induces non-sensitized Glu69+ DCs maturation, and that p38MAPK signaling is important in the Be-stimulated DCs activation as well as subsequent T cell proliferation and cytokine production in BeS and CBD. In total, the MAPK pathway may serve as a potential therapeutic target for human granulomatous lung diseases.
authors.affiliation: Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Health, Denver, CO, United States; Division of Pulmonary and Critical Care Sciences, Department of Medicine, School of Medicine, Denver, CO, United States. Electronic address: lili@njhealth.org.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Health, Denver, CO, United States.
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Health, Denver, CO, United States.
authors.forename: M
authors.initials: M
authors.lastname: Gillespie
authors.affiliation: Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Health, Denver, CO, United States.
authors.forename: P M
authors.initials: PM
authors.lastname: Mroz
authors.affiliation: Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Health, Denver, CO, United States; Division of Pulmonary and Critical Care Sciences, Department of Medicine, School of Medicine, Denver, CO, United States; Environmental Occupational Health Department, Colorado School of Public Health, University of Colorado, Denver, CO, United States.
authors.forename: L A
authors.initials: LA
authors.lastname: Maier
mesh_terms: D000368:Aged; D001607:Berylliosis / Q000276:immunology; D001608:Beryllium / Q000494:pharmacology*; D019013:CD40 Antigens / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C020711:beryllium sulfate; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D001608:Beryllium
keywords: CBD; DCs; Lymphocyte proliferation; NF-κB; p38MAPK