Role of IL-10 in Periodontal Bone Destruction

IL-10 在牙周骨破坏中的作用

• 批准号: 6854560
• 负责人: HAJIME SASAKI
• 金额: $ 8.8万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6854560
• 关键词: Bacteroides gingivalis; T lymphocyte; bacterial disease; biological signal transduction; bone density; cell population study; cytokine receptors; gene expression; genetically modified animals; histopathology; interleukin 10; keratinocyte; laboratory mouse; macrophage; oral bacteria; pathologic bone resorption; periodontium disorder; transcription factor

DESCRIPTION (provided by applicant): Periodontal diseases are infections with pathogenic bacteria such as Porphyromonas gingivalis (Pg) that result in alveolar bone loss. Bone destruction has been linked to excessive expression of inflammatory cytokines, particularly interleukin (IL)-1. IL-10 is an anti-inflammatory cytokine, produced by various immune cells including macrophages and Th2 cells, that we previously found was a key endogeneous inhibitor of infection-stimulated periapical bone resorption in vivo, likely acting via IL-1 inhibition. More recently, we have shown that IL-10 deficient (IL-10 -/-) mice are also extremely susceptible to Pg-stimulated periodontal bone loss, without an increase in gingival IL-I levels. In contrast, no significant bone destruction is induced by the Pg infection in corresponding wild-type (WT) mice. In the present studies, we will employ the IL-10 -/- and cell-specific Stat3 deficient mice on T cell, macrophages, and keratinocytes to test the hypothesis that induction and progression of periodontitis can be ameliorated by modulating IL-10, IL-10 receptors, their signaling, and the cytokine network that IL-10 regulates. The IL-10 -/- mouse to be characterized in this proposal offers several major advantages over previously described models, in particular rapid disease development, the severity of disease, and the presence of an existing background oral flora. The availability of a vast array of reagents and genetically engineered murine strains and the ability to generate double and triple gene knockouts make the IL-10 -/- mouse a potentially valuable model in understanding pathogenesis. Although IL-10 signaling is dependent upon Stat3 signaling pathway, cell-specific Stat3 deficient mice offer the advantage to directly determine the key effector cell type(s) of lL-10. In Aim 1, histopathological changes, periodontal bone loss, systemic bone mineral density, and gene and protein expression of bone resorptive markers will be characterized kinetically in WT and IL-10 -/- mice. In Aim 2, the cell type(s) that is most important for IL-10 associated reduction of bone resorption will be functionally assessed in vivo using T cell-, macrophage-, and keratinocyte specific Stat3 deficient mice. The long-term goal is to determine the preventive role of lL-10 in periodontitis, and to apply this information to the development of modulators that ameliorate this disease.

描述（由申请人提供）：牙周病是由病原菌如牙龈卟啉单胞菌（Pg）感染，导致牙槽骨丢失。骨破坏与炎性细胞因子，特别是白细胞介素（IL）-1的过度表达有关。IL-10是一种抗炎细胞因子，由包括巨噬细胞和Th 2细胞在内的各种免疫细胞产生，我们先前发现它是体内感染刺激的根尖周骨吸收的关键内源性抑制剂，可能通过IL-1抑制作用发挥作用。最近，我们已经表明，IL-10缺陷（IL-10 -/-）小鼠也非常容易受到前列腺素刺激的牙周骨丢失，牙龈IL-1水平没有增加。相比之下，在相应的野生型（WT）小鼠中，Pg感染未诱导显著的骨破坏。在本研究中，我们将采用IL-10 -/-和细胞特异性Stat 3缺陷小鼠T细胞，巨噬细胞和角质形成细胞来测试的假设，牙周炎的诱导和进展可以通过调节IL-10，IL-10受体，它们的信号传导，和IL-10调节的细胞因子网络得到改善。在该提议中待表征的IL-10 -/-小鼠提供了优于先前描述的模型的几个主要优点，特别是快速疾病发展、疾病的严重性和现有背景口腔植物群的存在。大量试剂和基因工程鼠品系的可用性以及产生双重和三重基因敲除的能力使IL-10 -/-小鼠成为理解发病机制的潜在有价值的模型。尽管IL-10信号传导依赖于Stat 3信号传导途径，但细胞特异性Stat 3缺陷型小鼠提供了直接确定IL-10的关键效应细胞类型的优势。在目的1中，将在WT和IL-10 -/-小鼠中动态表征组织病理学变化、牙周骨丢失、全身骨矿物质密度以及骨吸收标志物的基因和蛋白表达。在目的2中，将使用T细胞、巨噬细胞和角质形成细胞特异性Stat 3缺陷小鼠在体内功能性评估对IL-10相关的骨吸收减少最重要的细胞类型。长期目标是确定IL-10在牙周炎中的预防作用，并将该信息应用于开发改善该疾病的调节剂。