Activation of Mitogen-activated Protein Kinase p38 and Extracellular Signal-regulated Kinase Is Involved in Glass Fiber-induced Tumor Necrosis Factor-α Production in Macrophages

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)-α and that activation of NF-κB 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-α 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-α 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-α 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-κB pathway for TNF-α production, glass fibers are able to activate c-Jun through MAP kinase pathways that lead to induction of TNF-α expression.