title: Fluoride-induced apoptosis in epithelial lung cells involves activation of MAP kinases p38 and possibly JNK.
abstract: Exposure to fluorides can induce inflammatory reactions, cell cycle arrest, and apoptosis in different experimental systems. Fluorides are known G-protein activators, but less is known about fluoride effects downstream of G-protein activation. The aim of this study was to elucidate whether the induction of apoptosis by fluorides and inhibition of proliferation is mediated by MAP kinases in primary rat lung, alveolar type 2 cells and the human epithelial lung cell line A549. Sodium fluoride (NaF) induced apoptosis in both cell types but at different concentrations, with the primary cells being more sensitive to NAF: Proliferation of the type 2 cells and A549 cells was inhibited in the presence of NAF: NaF induced a prolonged activation of MAP kinase ERK. NaF also activated p38 and JNK in A549 cells for several hours (maximally 6-fold and 3-fold increase, respectively). Inhibition of ERK with the MEK1,2 inhibitor PD98059 increased apoptosis 2-fold, whereas the inhibitor of p38, SB202190, decreased the level of apoptotic cells by approximately 40%. SB202190 also inhibited apoptosis by almost 40% when ERK activity was reduced in the presence of PD98059. Neither PD98059 nor SB202190 did affect the NaF-induced inhibition of proliferation. These observations indicate that activation of MAP kinases p38 and possibly JNK are involved in NaF-induced apoptosis of epithelial lung cells, whereas ERK activation seems to counteract apoptosis in epithelial lung cells. In contrast, activation of ERK and p38 are not involved in NaF-induced inhibition of cell proliferation.
authors: Department of Environmental Medicine, National Institute of Public Health, Oslo, Norway.
authors: E V
authors: EV
authors: Thrane
authors: M
authors: M
authors: Refsnes
authors: G H
authors: GH
authors: Thoresen
authors: M
authors: M
authors: Låg
authors: P E
authors: PE
authors: Schwarze
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D001345:Autoradiography; D002455:Cell Division; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005419:Flavonoids / Q000037:antagonists & inhibitors; D005434:Flow Cytometry; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007093:Imidazoles / Q000037:antagonists & inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D011233:Precipitin Tests; D011725:Pyridines / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D012680:Sensitivity and Specificity; D012969:Sodium Fluoride / Q000633:toxicity*; D013045:Species Specificity; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000936:Antigen-Antibody Complex; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D012969:Sodium Fluoride; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one