Ding-M; Shi-X; Dong-Z; Chen-F; Lu-Y; Castranova-C; Vallyathan-V
J Biol Chem 1999 Oct; 274(43):30611-30616
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.
Silica-dusts; Silicates; Lung-function; Lung-disease; Inhalants; Dust-exposure; Dust-inhalation; Dust-particles; Cell-damage; Quartz-dust; Fibrosis; Respiratory-system-disorders; Pulmonary-system-disorders; Animal-studies; Animals; Laboratory-animals
V. Vallyathan, Pathology and Physiology Research Branch, NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505
Journal of Biological Chemistry