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

免疫活性细胞中牙齿单体的分子机制：抑制 LPS 或 LTA 刺激释放促炎和抗炎细胞因子

• 批准号: 371411317
• 负责人: Professor Dr. Helmut Schweikl
• 金额: --
• 依托单位: Poliklinik für Zahnerhaltung und Parodontologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/371411317?language=en
• 关键词: Molecular; mechanisms; dental; monomers; immuncompetent

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.

龋齿和牙周病是德国最常见的传染病之一。龋齿的发生和发展是基于细菌感染，细菌感染使牙釉质和牙本质脱矿，并可能到达牙髓组织。牙髓的免疫活性细胞如成牙本质细胞和巨噬细胞对从致龋革兰氏阳性和革兰氏阴性细菌释放的LTA（脂磷壁酸）或LPS（脂多糖）作出反应，并引发牙髓组织的炎症。龋齿的去除伴随着用牙齿填充材料修复病变。牙科复合材料和牙科粘合剂经常用于中小型缺损。这些材料由各种单体（甲基丙烯酸酯）组成，包括HEMA（甲基丙烯酸2-羟乙酯）或TEGDMA（三甘醇二甲基丙烯酸酯）。非聚合粘合剂/复合材料的单体可直接接触深腔制备的局部区域中的牙髓细胞或以生理相关浓度通过牙本质小管渗透牙本质。我们以前的工作表明，单体抑制牙髓免疫系统的LPS刺激功能，包括通过氧化还原敏感性转录因子NF-κ B调节的促炎和抗炎细胞因子的释放。这种抑制与免疫活性细胞暴露于单体之间的因果关系尚不清楚，将在本项目中进行分析。有关这一机制的信息将允许开发新的治疗策略，用于深腔的药物治疗，以维持免疫活性细胞的特定功能。该项目的假设是，LPS/LTA刺激的牙髓免疫活性细胞的生理功能的抑制与单体诱导的氧化应激有因果关系，这是因为形成了增强水平的活性氧（ROS），并因此激活了氧化还原敏感性转录因子Nrf 2。这一假设是由于已知的抑制NF-κ B调节功能的免疫活性细胞的单体，如我们以前所示，所描述的功能的Nrf 2作为一种生理调节剂的LPS刺激释放的细胞因子，和激活的氧化还原敏感Nrf 2调节系统的酶抗氧化剂在单体暴露的细胞中发现在我们正在进行的研究项目。因此，将分析ROS与单体HEMA存在下LPS/LTA刺激的免疫活性细胞（成牙本质细胞/巨噬细胞）中促炎或抗炎细胞因子（TNF α、IL-6、IL-10）的抑制动力学和表达程度的相关性。此外，将研究氧化还原敏感性转录因子Nrf 2的激活在抑制LPS/LTA刺激的和HEMA暴露的免疫活性细胞中的细胞因子释放中的功能。