Role of Hydroxyl Radical in Silica-induced NF-kR Activation in Macrophages*

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 mac­ rophage 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 silicainduced NF-kB activation. Electron spin resonance (ESR) spin trapping measure­ ments show that both deferoxamine and PVPNO decreased silica-mediated -OH radical generation from H20 2. 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 * Send reprint requests to: Laurence M. Demers, Ph.D., Department o f Pathology, The Pennsylvania State University College o f Medicine, The Milton S. Hershey Medical Center, P.O. Box 850, Hershey, PA 17003 or Xianglin Shi, Ph.D., Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Mail Stop B167; Morgantown, WV 26505.