Nuclear transcription factor KB (NF-KB) is a multiprotein complex that regulates a variety of genes important for immunity and inflammation. The present study investigates the silica-induced activation of this transcription factor in mouse macrophage cell line RAW 264.7 cells, the role of free radical reactions in the mechanism of the activation, and its possible inhibition. Tetrandrine, a benzylisoquinoline alka- loid, which has been used as an antifibrotic drug to treat the lesions of silicosis and has been characterized as a hydroxyl radical (OH) scavenger, inhibited the NF-KB activation induced by silica, lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA). Catalase, metal chelator, deferoxamine, and the silanol group (SiOH) blocker, poly(2-vinylpyridine-N-oxide) (PVPNO), also inhibited silica-induced NF-KB activation. Electron spin resonance (ESR) spin trapping measure- ments show that both deferoxamine and PVPNO decreased silica-mediated OH radical generation from H2O2. It is shown that Fe(II) and not Fe(III) is able to cause NF-KB activation. The antioxidant, ascorbate, attenuated the NF-KB activation induced by silica but not by LPS. The OH radical scavenger, sodium formate, inhibited NF-KB activation induced by silica but had only a minor effect on NF-KB activation induced by LPS. The results indicate that silica-mediated free radical generation via the Fenton or Fenton-like reaction (Mn+ + H2O2 --> M(n+l)+ + OH- + OH) and silanol groups on the silica surface play an important role in silica-induced NF-KB activation.
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