Molecular mechanisms of dental monomers in immuncompetent cells: Inhibition of LPS- or LTA-stimulated release pro- and anti-inflammatory cytokines

• Applicant: Professor Dr. Helmut Schweikl
• Subject Area: Dentistry, Oral Surgery
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 371411317

Caries and periodontal diseases are among the most common infectious diseases in Germany. The initiation and progression of caries is based on bacterial infection which demineralizes enamel and dentin and may reach pulp tissues. Immunocompetent cells of the dental pulp like odontoblasts and macrophages respond to LTA (lipoteichoic acid) or LPS (lipopolysaccharide) released from cariogenic Gram-positive and Gram-negative bacteria and initiate inflammation of pulp tissues. Removal of caries is accompanied by restoration of the lesion with dental filling materials. Dental composite materials together with dental adhesives are frequently used in small and middle-sized defects. These materials are composed of various monomers (methacrylates) including HEMA (2-hydroxyethyl methacrylate) or TEGDMA (triethylene glycol dimethacrylate). Monomers of non-polymerized adhesives/composites may directly contact pulp cells in localized areas of deep cavity preparations or penetrate dentin through dentin tubules in physiologically relevant concentrations. Our previous work shows that monomers inhibit LPS-stimulated functions of the immune system of the dental pulp including the release of pro- and anti-inflammatory cytokines regulated through the redoxsensitive transcription factor NF-kB. The causal relationship between this inhibition and the exposure of immunocompetent cells to monomers is unknown and will be analyzed in the present project. Information on this mechanism will allow for the development of new therapeutic strategies for the pharmacological treatment of deep cavities in order to maintain specific functions of immunocompetent cells. It is the hypothesis of this project that inhibition of physiological functions of LPS/LTA-stimulated immunocompetent cells of the dental pulp is causally related to monomer-induced oxidative stress because of the formation of enhanced levels of reactive oxygen species (ROS) and, as a result, the activation of the redoxsensitive transcription factor Nrf2. This hypothesis is a result of the known inhibition of NF-kB-regulated functions of immunocompetent cells by monomers as shown by us previously, the described function of Nrf2 as a physiological regulator of the LPS-stimulated release of cytokines, and the activation of the redoxsensitive Nrf2-regulated system of enzymatic antioxidants in monomer-exposed cells found in our ongoing research project. Therefore, the relevance of ROS for the kinetic of the inhibition and the extent of the expression of pro- or anti-inflammatorischer cytokines (TNFalpha, IL-6, IL-10) in LPS/LTA-stimulated immunocompetent cells (odontoblasts/macrophages) in the presence of the monomer HEMA will be analyzed. Furthermore, the function of the activation of the redoxsensitive transcription factor Nrf2 for in the inhibition of the release of cytokines in LPS/LTA-stimulated and HEMA-exposed immunocompetent cells will be investigated.

• DFG Programme: Research Grants