Innate Immune Mechanisms Involved in P. Gingivalis-Induced Chronic Inflammation

病原菌嗜肺炎衣原体和牙龈卟啉单胞菌引起慢性炎症， 炎症在人类和小鼠模型中的流行病学研究支持C。 肺炎链球菌和牙龈卟啉单胞菌在慢性炎性菌斑积累中的作用。然而，这些 病原体诱导和维持慢性炎症的定义尚不明确。促炎细胞因子 包括IL-1B、TNF和IL-6在慢性炎症中起关键作用。已知人 炎性血管斑块与IL-1受体拮抗剂多态性相关 IL-1在细菌诱导的炎症性血管斑块积聚中起作用， 小鼠IL-1B多态性也与牙龈卟啉单胞菌介导的人类炎症相关。 牙周病本课题主要研究以下假设：1）IL-1B的诱导 在内皮细胞中通过确定的机制发生， 血小板和巨噬细胞的反应;和2）IL-1在慢性口腔炎中起关键作用 与牙龈卟啉单胞菌相关的炎性骨丢失和炎性斑块形成 通过细胞特异性机制慢性感染。为了验证这些假设，我们提出以下建议 目标：目标1。为了确定1 L1-B在牙龈卟啉单胞菌诱导下的机制， 小鼠内皮细胞以及IL-1 B如何调节血小板和巨噬细胞功能。目标二。到 确定IL-1和细胞特异性在牙龈卟啉单胞菌诱导的口腔炎症中的表达中的作用， 在小鼠模型中的骨质流失。目标3.确定IL-1和细胞特异性在表达中的作用， 在牙龈卟啉单胞菌诱导的慢性炎症和牙菌斑积聚的小鼠模型中。项目 4与项目1- 3一起将定义特异性先天免疫信号分子在P. gingivalis和C.肺炎诱导的慢性炎症相关细胞的炎症反应 炎症过程，将表征这些先天性免疫途径的作用， 炎症过程中体内和定义细胞特异性在这些反应。

The pathogenic bacteria Chlamydophila pneumoniae and Porphyromanas gingivalis induce chronic inflammation. Epidemiological studies in humans and mouse models support a role for C. pneumoniae and P. gingivalis in chronic inflammatory plaque accumulation. IHowever, how these pathogens induce and maintain chronic inflammation is not well defined. Proinflammatory cytokines including IL-1B , TNF, and IL-6 play a critical role in chronic inflammation. It is known that human inflammatory vascular plaque is associated with polymorphisms in the IL-1 receptor antagonist gene and that IL-1 plays a role in bacterial induced inflammatory vascular plaque accumulation in mice. IL-1B polymorphisms are also associated with P. gingivalis mediated human inflammatory periodontal disease. In this project we will test the following hypotheses: 1) The induction of IL-1B occurs via a defined mechanism in endothelial cells which leads to stimulation of functional responses in platelets and macrophages; and 2) IL-1 plays a critical role in chronic oral inflammatory bone loss and inflammatory plaque formation that is associated with P. gingivalis chronic infection via cell specific mechanisms. To test these hypotheses we propose the following Aims: Aim 1. To define the mechanism by which 1L1-B is induced in response to P. gingivalis in mouse endothelial cells and how IL-1 B modulates platelet and macrophage function. Aim 2. To define the role of lL-1 and cell specificity in expression in P. gingivalis induced oral inflammatory bone loss in a mouse model. Aim 3. To define the role of IL-1 and cell specificitv in expression in P. gingivalis induced chronic inflammation and plaque accumulation in a mouse model. Project 4 together with Projects 1- 3 will define the role of specific innate immune signaling molecules in P. gingivalis and C. pneumoniae induced inflammatory responses in cells relevant to chronic inflammatory processes, will characterize the roles of these innate immune pathways in inflammatory processes in vivo and define cell specificitv in these responses.