Abstract
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.
Highlights
Glass fibers have been popular substitutes for asbestos in the building industry
The results show that glass fibers can induce TNF-␣ production in rat alveolar macrophages and that short and long fibers exhibited different stimulatory potencies (Fig. 1A)
Because Reactive oxygen species (ROS) were involved in glass fiber-induced TNF-␣ production [5], it is possible that the glass fibers activate mitogen-activated protein (MAP) kinases in macrophages
Summary
Glass fibers have been popular substitutes for asbestos in the building industry. The health effects of glass fibers remain to be fully investigated. The major members in the MAP kinase family are extracellular signal-regulated kinase (ERK), p38 kinase, and Jun N-terminal kinase (JNK) (18 –20). Activation of these kinases is marked by phosphorylation of serine/ threonine amino residues in their protein molecule. Activation of ERK, p38, and JNK leads to induction of transcription factors that in turn regulate target gene expression in the nucleus. The nuclear proteins, such as c-Jun, ATF-2, and ElK1, are the major transcription factors that are regulated by the three MAP kinases. Our previous study has demonstrated that fiber-induced ROS were required for TNF-␣ production in a murine macro-
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