SILICA INCREASES TUMOR-NECROSIS-FACTOR (TNF) PRODUCTION, IN PART, BY UP-REGULATING THE TNF PROMOTER

Silica causes release of tumor necrosis factor (TNF) from mononuclear phagocytes. One hypothesis is that silica increases TNF production, in part, by upregulating the TNF gene. To evaluate this hypothesis, THP-1 cells (a myelomortocytic cell line) were exposed to various amounts of silica and then the TNF gene transcription was evaluated. In this study silica caused a dose-dependent increase in TNF mRNA and the peak response occurred at 3 h following stimulation. A transient transfection assay also showed that silica upregulated expression of a TNF CAT construct in THP-1 cells. Furthermore, a nuclear run-on assay demonstrated that silica particles induce increased TNF gene transcription in exposed cells. THP-1 cells cultured for various periods of time in the presence of silica released TNF into the cell supernatants. These studies show that silica can upregulate the TNF gene, which results in the release of TNF protein from the cells.