ROLE OF HYDROXYL RADICAL IN SILICA-INDUCED NF-KAPPA-B ACTIVATION IN MACROPHAGES

Nuclear transcription factor kappa B (NF-kappa B) is a multiprotein co mplex that regulates a variety of genes important for immunity and inf lammation. The present study investigates the silica-induced activatio n of this transcription factor in mouse macrophage cell line RAW 264.7 cells, the role of free radical reactions in the mechanism of the act ivation, and its possible inhibition. Tetrandrine, a benzylisoquinolin e alkaloid, which has been used as an antifibrotic drug to treat the l esions of silicosis and has been characterized as a hydroxyl radical ( . OH) scavenger, inhibited the NF-kappa B 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-kappa B activation. Electron spin resonance (ESR) spin trap ping measurements show that both deferoxamine and PVPNO decreased sili ca-mediated . OH radical generation from H2O2. It is shown that Fe(II) and not Fe(III) is able to cause NF-kappa B activation. The antioxida nt, ascorbate, attenuated the NF-kappa B activation induced by silica but not by LPS. The . OH radical scavenger, sodium formate, inhibited NF-kappa B activation induced by silica but had only a minor effect on NF-kappa B activation induced by LPS. The results indicate that silic a-mediated free radical generation via the Fenton or Fenton-like react ion (Mn+ + H2O2 --> M(n+1+) + OH- + . OH) and silanol groups on tile s ilica surface play an important role in silica-induced NF-kappa B acti vation.