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 s tudy silica caused a dose-dependent increase in TNF mRNA and the peak response occurred at 3 h following stimulation. A transient transfecti on assay also showed that silica upregulated expression of a TNF CAT c onstruct in THP-1 cells. Furthermore, a nuclear run-on assay demonstra ted that silica particles induce increased TNF gene transcription in e xposed cells. THP-1 cells cultured for various periods of time in the presence of silica released TNF into the cell supernatants. These stud ies show that silica can upregulate the TNF gene, which results in the release of TNF protein from the cells.