Objective: Cytotoxicity of dental monomers has been widely investigated but the underlying mechanism(s) and the signal transduction pathways involved are not clear. The aim of our study was to investigated the role of NF-kB in 2-hydroxyethyl methacrylate (HEMA) induced-apoptosis. Methods: Cell death and apoptosis were evaluated quantitatively in human primary fibroblasts by flow cytometry and qualitatively by the activation of procaspases. In order to demonstrate the involvement of NF-kB, we evaluated IkB degradation. In addition, to confirm the protective role of NF-kB we used specific antioxidants inhibitors, and mouse embryonic fibroblasts (MEF) derived from p65 knock-out mice (p65-/-). Results: In the concentration range of 4–10 mM HEMA, the fraction of apoptotic cells increased linearly with the concentration of monomer and reached a plateau level of 30.5% of apoptotic cells at 10 mM HEMA after 24h exposition. The fraction of necrotic cells also increased in a concentration-dependent manner with a maximum of 7.5% at 8 mM HEMA. Caspases –8, -9 and -3 were activated, and the levels of intracellular reactive oxygen species (ROS) also increased during HEMA-induced apoptosis. Blocking of ROS production by antioxidants had no direct influence on apoptosis caused by HEMA. Instead, inhibition of NF-kB significantly increased the fraction of apoptotic cell after HEMA treatment. Accordingly, MEF from p65-/- mice were significantly more susceptible to HEMA-induced apoptosis, than wild type controls. Conclusion: Exposure to HEMA triggers ROS signalling and caspase activation. NF-kB activation counteracts apoptotic signalling induced by HEMA and exerts a protective role, independently on oxidative stress induced by the monomer.

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