Submitted on January 5, 2006
Accepted on February 15, 2006
Essential Role of ROS-mediated NFAT Activation inTNF-
Induction by Crystalline Silica Exposure
Qingdong Ke1, Jingxia Li1, Jin Ding1, Min Ding2, Liying Wang2, Bingci Liu3, Max Costa1, and Chuanshu Huang1*
1 New York University School of Medicine, Nelson Institute of Environmental Medicine, Tuxedo, NY, USA
2 Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, USA
3 National Institute of Occupational Health and Poisons Control, Chinese Center for Diseases Control and Prevention, Beijing, Beijing, China
* To whom correspondence should be addressed. E-mail: chuanshu{at}env.med.nyu.edu.
Occupational exposure to crystalline silica has been associated with progressive pulmonary silicosis and lung cancer, but the underlying molecular mechanisms are not well understood. Previous studies have shown that crystalline silica exposure can generate reactive oxygen species (ROS) and induce the expression of the inflammatory cytokine tumor necrosis factor 
(TNF-) in cells. TNF-is believed to be critical in the development of silica-related diseases. Thus it will be of significance to understand the mechanisms of TNF- induction by silica exposure. Given the fact that the transcription factor the nuclear factor of activated T cells (NFAT) plays an important role in the regulation of TNF- and it can also be activated by ROS, in this study, we have investigated the potential role of ROS in silica-induced NFAT activity as well as TNF- expression in Cl41 cells. The results showed that exposure of cells to silica led to the NFAT transactivation and TNF- induction, where superoxide anion radicals (O2.-), but not hydrogen peroxide (H2O2), was involved. The knockdown of NFAT3 by its specific siRNA significantly attenuated the silica-induced TNF- transcription. This study demonstrated that silica was able to activate NFAT in an O2.--dependent manner, which was required for TNF- induction.
