ToxSci Advance Access originally published online on January 28, 2009
Toxicological Sciences 2009 108(2):356-366; doi:10.1093/toxsci/kfp010
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N-Acetyl Cysteine Mediates Protection from 2-Hydroxyethyl Methacrylate Induced Apoptosis via Nuclear Factor Kappa B–Dependent and Independent Pathways: Potential Involvement of JNK
The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center (JCCC), Dental Research Institute, Division of Oral Biology and Medicine, UCLA School of Dentistry and Medicine, University of California, Los Angeles, California 90095
1 To whom correspondence and reprint requests should be addressed at 10833 Le Conte Ave, UCLA School of Dentistry, Los Angeles, CA 90095. Fax: (310) 794-7109. E-mail: ajewett{at}ucla.edu.
Received October 3, 2008; accepted January 8, 2009
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Abstract |
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The mechanisms by which resin based materials induce adverse effects in patients have not been completely elucidated. Here we show that 2-hydroxyethyl methacrylate (HEMA) induces apoptotic cell death in oral keratinocytes. Functional loss and cell death induced by HEMA was significantly inhibited in the presence of N-acetyl cysteine (NAC) treatment. NAC also prevented HEMA mediated decrease in vascular endothelial growth factor secretion. The protective effect of NAC was partly related to its ability to induce NF-
B in the cells, since HEMA mediated inhibition of nuclear NF-B expression and function was significantly blocked in the presence of NAC treatment. Moreover, blocking of nuclear translocation of NF-B in oral keratinocytes sensitized these cells to HEMA mediated apoptosis. In addition, since NAC was capable of rescuing close to 50% of NF-B knockdown cells from HEMA mediated cell death, there is, therefore, an NF-B independent pathway of protection from HEMA mediated cell death by NAC. NAC mediated prevention of HEMA induced cell death in NF-B knockdown cells was correlated with a decreased induction of c-Jun N-terminal kinase (JNK) activity since NAC inhibited HEMA mediated increase in JNK levels. Furthermore, the addition of a pharmacologic JNK inhibitor to HEMA treated cells prevented cell death and restored NF-B knockdown cell function significantly. Therefore, NAC protects oral keratinocytes from the toxic effects of HEMA through NF-B dependent and independent pathways. Moreover, our data suggest the potential involvement of JNK pathway in NAC mediated protection.
Key Words: HEMA; NF-B; dental pulp stromal cells; apoptosis; VEGF.