ToxSci Advance Access originally published online on July 7, 2005
Toxicological Sciences 2005 87(2):483-496; doi:10.1093/toxsci/kfi251
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Induction of Fibroblast Growth Factor-9 and Interleukin-1
Gene Expression by Motorcycle Exhaust Particulate Extracts and Benzo(a)pyrene in Human Lung Adenocarcinoma Cells
* Institute of Toxicology and Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC, and Division of Environmental Health and Occupational Medicine, National Health Research Institute, Kaohsiung, Taiwan, ROC
Received March 22, 2005; accepted June 23, 2005
Motorcycle exhaust particulates (MEP) contain carcinogenic polycyclic aromatic hydrocarbons including benzo(a)pyrene. This study has determined the ability of MEP to alter the expression of select genes from drug metabolism, cytokine, oncogene, tumor suppressor, and estrogen signaling families of human lung adenocarcinoma CL5 cells. cDNA microarray analyses and confirmation studies were performed using CL5 cells treated with 100 µg/ml MEP extract for 6 h. The results showed that MEP increased the mRNA levels of metabolic enzymes CYP1A1 and CYP1B1, proinflammatory cytokines interleukin (IL)-1
, IL-6, and IL-11, fibroblast growth factor (FGF)-6 and FGF-9, vascular endothelial growth factor (VEGF)-D, oncogene fra-1, and tumor suppressor p21. In contrast, MEP decreased tumor suppressor Rb mRNA in CL5 lung epithelial cells. Treatment with 10 µM benzo(a)pyrene for 6 h altered gene expression profiles, in a manner similar to those by MEP. Induction of IL-1, IL-6, IL-11, and FGF-9 mRNA by MEP and benzo(a)pyrene was concentration and time dependent. Cotreatment with 2 mM N-acetylcysteine blocked the MEP- and benzo(a)pyrene-mediated induction. Treatment with MEP or benzo(a)pyrene increased IL-6 and IL-11 releases to CL5 cell medium. Incubation of human lung fibroblast WI-38 with MEP- or benzo(a)pyrene-induced CL5 conditioned medium for 4 days stimulated cell growth of the fibroblasts. Inhalation exposure of rats to 1:10 diluted motorcycle exhaust 2 h daily for 4 weeks increased CYP1A1, FGF-9, and IL-1 mRNA in lung. This present study shows that MEP and benzo(a)pyrene can induce metabolic enzyme, inflammatory cytokine, and growth factor gene expression in CL5 cells and stimulate lung epithelium-fibroblast interaction.
Key Words: motorcycle exhaust particulate; benzo(a)pyrene; fibrobalst growth factor; interleukin; lung epithelial cell.
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