title: Role of bioavailable iron in coal dust-induced activation of activator protein-1 and nuclear factor of activated T cells: difference between Pennsylvania and Utah coal dusts.
abstract: Activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT) are two important transcription factors responsible for the regulation of cytokines, which are involved in cell proliferation and inflammation. Coal workers' pneumoconiosis (CWP) is an occupational lung disease that may be related to chronic inflammation caused by coal dust exposure. In the present study, we demonstrate that coal from the Pennsylvania (PA) coalmine region, which has a high prevalence of CWP, can activate both AP-1 and NFAT in JB6 mouse epidermal cells. In contrast, coal from the Utah (UT) coalmine region, which has a low prevalence of CWP, has no such effects. The PA coal stimulates mitogen-activated protein kinase (MAPK) family members of extracellular signal-regulated kinases (ERKs) and p38 MAPK but not c-Jun-NH(2)-terminal kinases, as determined by the phosphorylation assay. The increase in AP-1 by the PA coal was completely eliminated by the pretreatment of cells with PD98059, a specific MAPK kinase inhibitor, and SB202190, a p38 kinase inhibitor, further confirming that the PA coal-induced AP-1 activation is mediated through ERKs and p38 MAPK pathways. Deferoxamine (DFO), an iron chelator, synergistically enhanced the PA coal-induced AP-1 activity, but inhibited NFAT activity. For comparison, cells were treated with ferrous sulfate and/or DFO. We have found that iron transactivated both AP-1 and NFAT, and DFO further enhanced iron-induced AP-1 activation but inhibited NFAT. These results indicate that activation of AP-1 and NFAT by the PA coal is through bioavailable iron present in the coal. These data are in agreement with our previous findings that the prevalence of CWP correlates well with levels of bioavailable iron in coals from various mining regions.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York 10016, USA.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
mesh_terms: D000818:Animals; D001682:Biological Availability; D002478:Cells, Cultured; D003031:Coal / Q000009:adverse effects*; D003032:Coal Mining; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D004391:Dust; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005296:Ferrous Compounds / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007501:Iron / Q000493:pharmacokinetics*; D007502:Iron Chelating Agents / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009930:Organic Chemicals; D010414:Pennsylvania; D011009:Pneumoconiosis / Q000209:etiology; D011725:Pyridines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014589:Utah; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D003031:Coal; D004268:DNA-Binding Proteins; D004391:Dust; D004791:Enzyme Inhibitors; D005296:Ferrous Compounds; D007093:Imidazoles; D007502:Iron Chelating Agents; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009930:Organic Chemicals; C466090:PD 98058; D011725:Pyridines; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D007501:Iron; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003676:Deferoxamine; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole