Clarification of the mechanism of periodontitis-initiated/accelerated atheroacleicsis and identification of its causal components

新兴的基础科学研究支持感染可能是动脉粥样硬化的危险因素。以牙周致病菌牙龈卟啉单胞菌作为模型病原体，体内研究表明该生物体可加速动物模型中的动脉粥样硬化沉积。在本研究中，我们首先尝试确定牙龈卟啉单胞菌是否可以在体外上调巨噬细胞氧化低密度脂蛋白受体的表达。我们证明，小鼠巨噬细胞系J774.A1细胞在牙龈卟啉单胞菌、热灭活菌及其菌毛突变体的刺激下表达氧化LDL的受体（SR-A、CD 36和Lox-1）。此外，我们发现热休克蛋白（HSP）60也诱导与牙龈卟啉单胞菌刺激在mRNA和蛋白水平。这些数据支持牙龈卟啉单胞菌刺激巨噬细胞分化为泡沫细胞，这是动脉粥样硬化斑块病变发展的必要起始事件。 ...更多信息 研究了重组中间链球菌组蛋白样DNA结合蛋白（rSi-HLP）刺激人单核细胞系（THP-1细胞）产生促炎细胞因子的机制：rSi-HLP刺激诱导的促炎细胞因子（IL-8、IL-1β和TNF-α）的产生具有时间和剂量依赖性。与DNA结合的热稳定活性相反，rSi-HLP的细胞因子诱导活性是热不稳定的。在随后的研究中，rSi-HLP与脂磷壁酸、合成的Toll样受体2激动剂Pam 3CSK 4和胞质核苷酸结合寡聚化结构域2受体激动剂胞壁酰二肽协同作用。Western blot和特异性抑制剂阻断实验表明，rSi-HLP刺激可诱导细胞信号转导通路，细胞外信号调节激酶1/2（ERK 1/2）和c-jun N-末端激酶（JNK）的激活。这些结果表明，口腔，尤其是牙周病，细菌可上调炎症反应，并表明这些细菌的感染加速炎症反应。直接导致动脉粥样硬化少

Emerging basic scientific studies have supported that infection may represent a risk factor for atherosclerosis. With periodotopathogenic bacteria, Porphyromonas gingivalis, as model pathogen, in vivo studies demonstrated that this organism can accelerate atheroma deposition in animal models. In this study, we first try to determine whether P. gingivalis can up-regulate the expression of the receptors for oxidized LDL in macrophage in vitro. We demonstrated that mouse macrophage cell line, J774.A1 cells were induced to express the receptors (SR-A, CD36 and Lox-1) for oxidized LDL by the stimulation with P. gingivalis, heat-killed bacteria or its fimbriae mutants. Moreover, we found that heat shock protein (HSP) 60 was also induced by the stimulation with P. gingivalis at both mRNA and protein levels. These data support that P. gingivalis stimulate macrophage differentiation to foam cells, a necessary initial event in the development of atherosclerotic plaque lesions.In this study, we i … More nvestigated the mechanisms of pro-inflammatory cytokine inductions in human monocytic cell line (THP-1 cells) by stimulation with recombinant histone-like DNA binding protein (HLP) of Streptococcus intermedius (rSi-HLP): rSi-HLP stimulation-induced production of pro-inflammatory cytokines (IL-8, IL-1β and TNF-α) occurred in a time- and dose-dependent manner. In contrast with the heat-stable activity of DNA binding, the cytokine induction activity of rSi-HLP was heat-unstable. In subsequent studies, rSi-HLP acted cooperatively with lipoteichoic acid, the synthetic Toll-like receptor 2 agonist, Pam3CSK4, and the cytosolic nucleotide binding oligomerization domain 2 receptor agonist, muramyldipeptide. Furthermore, Western blot and blocking assays with specific inhibitors showed that rSi-HLP stimulation induced the activation of cell signal transduction pathways, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-jun N-terminal kinase (JNK).Collectively, these results demonstrate oral, especially periodotopathic, bacteria can up-regulate inflammatory response and indicate the infection with these bacteria accelerates inflammatory responses, which directly lead to atherosclerosis. Less