RRC ID 65606
Author Nakagawa M, Uno S, Iriyama N, Matsunawa M, Makishima M, Takeuchi J, Tsuboi I, Hatta Y, Takei M.
Title Combined treatment with benzo[a]pyrene and 1α,25-dihydroxyvitamin D3 induces expression of plasminogen activator inhibitor 1 in monocyte/macrophage-derived cells.
Journal Toxicol Appl Pharmacol
Abstract Benzo[a]pyrene (BaP) is an environmental pollutant found in cigarette smoke and is implicated as a causative agent of tobacco-related diseases, such as arteriosclerosis. In contrast, vitamin D signaling, which is principally mediated by conversion of vitamin D to the active form, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], decreases cardiovascular disease risk. However, combined treatment with BaP and 1,25(OH)2D3 enhances BaP toxicity, including BaP-DNA adduct formation. We further investigated the cross-talk between BaP and 1,25(OH)2D3 signaling pathways, and found that combined treatment with these compounds induces mRNA and protein expression of plasminogen activator inhibitor 1 (PAI-1) in monocyte/macrophage-derived THP-1 and U937 cells. Protein synthesis inhibitor treatment did not inhibit induction of the PAI-1 gene (SERPINE1) in these cells. BaP plus 1,25(OH)2D3 induced differentiation markers, inhibited cellular proliferation, and induced apoptosis and oxidative stress in these cells. Reactive oxygen species scavenger treatment suppressed apoptosis but not SERPINE1 induction in cells treated with BaP plus 1,25(OH)2D3. Thus, combined treatment with BaP and 1,25(OH)2D3 induced SERPINE1 mRNA expression in these cells through a mechanism that does not require de novo protein synthesis or reactive oxygen species production. These findings suggest that induction of the proinflammatory factor PAI-1 plays a role in BaP toxicity. Interestingly, PAI-1 knockdown decreased expression of the cell surface antigen CD14, a monocytic differentiation marker, in THP-1 cells treated with BaP plus 1,25(OH)2D3. PAI-1 induction may also be related to a function of monocytes/macrophages in response to xenobiotic and vitamin D signaling.
Volume 345
Pages 48-56
Published 2018-4-15
DOI 10.1016/j.taap.2018.03.003
PII S0041-008X(18)30081-4
PMID 29524502
MeSH Benzo(a)pyrene / administration & dosage* Cell Survival / drug effects Cell Survival / physiology Cholecalciferol / administration & dosage* Drug Combinations Gene Expression Hep G2 Cells Human Umbilical Vein Endothelial Cells / drug effects Human Umbilical Vein Endothelial Cells / metabolism Humans Macrophages / drug effects* Macrophages / metabolism* Plasminogen Activator Inhibitor 1 / biosynthesis* Plasminogen Activator Inhibitor 1 / genetics THP-1 Cells / drug effects THP-1 Cells / metabolism U937 Cells
IF 3.347
Resource
Human and Animal Cells THP-1 U937 HepG2