Freshly fractured crystalline silica induces activator protein-1 activation through ERKs and p38 MAPK.
The transcription factor activator protein-1 (AP-1) reportedly plays an important role in the induction of neoplastic transformation and multiple genes involved in cell proliferation, differentiation, and inflammation. To investigate the mechanisms of silica-induced carcinogenesis, AP-1-luciferase reporter transgenic mice were used as an in vivo model, whereas the JB6 mouse epidermal cell line and a rat lung epithelial cell line were employed as in vitro models to study the effects of silica at the molecular level. Freshly fractured silica caused an 8-fold increase in AP-1 activity in JB6 cells and a 2.5-fold increase in rat lung epithelial cells. The induction of AP-1 activity in cultured cell lines was time- and dose-dependent. Intratracheal administration of silica was also able to induce AP-1 transactivation in transgenic mice. AP-1 activation was first observed at 2 days after silica administration and reached its maximum at 3 days post-exposure of the mice to silica. The signal transduction pathways for AP-1 activation were also investigated using these cell lines. The results demonstrate that freshly fractured silica stimulates mitogen-activated protein kinase (MAPK) family members, as determined by the phosphorylation of p38 MAPK and extracellular signal-regulated protein kinases (ERKs). Inhibition of ERKs with PD98059 or of p38 with SB203580 significantly inhibited silica-induced AP-1 activation. These findings demonstrate for the first time that freshly fractured silica induces AP-1 activation, which may be mediated through p38 MAPK and ERK pathways. Unraveling the complex mechanisms associated with these events may provide insights into the initiation and progression of silica-induced carcinogenesis.
Ding
M
M
Pathology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, West Virginia 26505, USA.
Shi
X
X
Dong
Z
Z
Chen
F
F
Lu
Y
Y
Castranova
V
V
Vallyathan
V
V
D000818:Animals; D002460:Cell Line; D003460:Crystallization; D004817:Epidermis / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D007700:Kinetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012822:Silicon Dioxide / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D012822:Silicon Dioxide; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases