Essential role of ROS-mediated NFAT activation in TNF-alpha induction by crystalline silica exposure.
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-alpha (TNF-alpha) in cells. TNF-alpha is believed to be critical in the development of silica-related diseases. Thus it will be of significance to understand the mechanisms of TNF-alpha induction by silica exposure. Given the fact that the transcription factor nuclear factor of activated T cells (NFAT) plays an important role in the regulation of TNF-alpha and can also be activated by ROS, in this study we investigated the potential role of ROS in silica-induced NFAT activity as well as TNF-alpha expression in Cl41 cells. The results showed that exposure of cells to silica led to NFAT transactivation and TNF-alpha induction, where superoxide anion radical (O(2)(-).), but not H(2)O(2), was involved. The knockdown of NFAT3 by its specific small interfering RNA significantly attenuated the silica-induced TNF-alpha transcription. This study demonstrated that silica was able to activate NFAT in an O(2)(-).-dependent manner, which was required for TNF-alpha induction.
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, 10987, USA.
Qingdong
Q
Ke
Jingxia
J
Li
Jin
J
Ding
Min
M
Ding
Liying
L
Wang
Bingci
B
Liu
Max
M
Costa
Chuanshu
C
Huang
D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012822:Silicon Dioxide / Q000737:chemistry / Q000494:pharmacology*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D012822:Silicon Dioxide