Ye-J; Zeidler-PC; Young-S; Martinez-AB; Robinson-VA; Jones-W; Baron-P; Shi-X; Castranova-V
J Biol Chem 2001 Feb; 276(7):5360-5367
In a previous study, we demonstrated that the length of glass fibers was a critical determinant of fiber potency in induction of tumor necrosis factor (TNF)-alpha and that activation of NF-kappaB was an important factor in this response. In the present study, we analyzed the role of mitogen-activated protein (MAP) kinases in the induction of TNF-alpha by glass fibers. Glass fibers induced phosphorylation of MAP kinases, p38, and ERK in primary rat alveolar macrophages, and this phosphorylation was associated with TNF-alpha gene expression. Long fibers were more potent than short fibers in activation of MAP kinases. Results from mechanistic analysis support that MAP kinases activate transcription factor c-Jun. The activated c-Jun acts on the TNF-alpha gene promoter through two binding sites, the cyclic AMP response element and the activator protein 1-binding site. These results suggest that in addition to the NF-kappaB pathway for TNF-alpha production, glass fibers are able to activate c-Jun through MAP kinase pathways that lead to induction of TNF-alpha expression.
Glass-products; Fiberglass-industry; Genes; Carcinogenicity; Carcinogens; Carcinogenesis; Cell-division; Cell-function; Cell-biology; Cellular-function
HELD; DRDS; DART
Journal of Biological Chemistry