Role of IL-10 in Periodontal Bone Destruction

IL-10 在牙周骨破坏中的作用

• 批准号: 6790424
• 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/6790424
• 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）：牙周疾病是致病细菌的感染，例如导致肺泡骨质流失的卟啉念珠菌（PG）。骨骼破坏与炎性细胞因子的过度表达有关，尤其是白介素（IL）-1。 IL-10是一种由各种免疫细胞产生的抗炎细胞因子，包括巨噬细胞和Th2细胞，我们以前发现，这是感染感染刺激的体内骨骼骨吸收的关键内生内均匀抑制剂，可能通过IL-1抑制作用。最近，我们表明IL-10缺陷（IL-10 - / - ）小鼠也极易受到PG刺激的牙周骨质流失，而不会增加牙龈IL-I水平。相比之下，在相应的野生型（WT）小鼠中，PG感染不会引起骨骼破坏。在目前的研究中，我们将采用IL-10 - / - 和细胞特异性的STAT3缺乏在T细胞，巨噬细胞和角质形成细胞上，以测试牙周炎诱导和进展的假设，可以通过调节IL-10，IL-10，IL-10受体来改善牙周炎的诱导和进展。该提案中要表征的IL-10 - / - 小鼠比先前描述的模型，特别是疾病的发展，疾病的严重程度和现有背景口服菌群的存在提供了几个主要优势。一系列试剂和基因工程的鼠菌株的可用性以及产生双重基因敲除的能力使IL-10 - / - 小鼠成为理解发病机理的潜在有价值的模型。尽管IL-10信号传导取决于STAT3信号通路，但细胞特异性的STAT3缺陷小鼠提供了直接确定LL-10的关键效应细胞类型的优势。在AIM 1中，在WT和IL-10 - / - 小鼠中，将对骨吸收标记物的组织变化，牙周骨骼流失，全身性骨矿物质密度以及骨吸收标记的基因和蛋白质表达进行动力学表征。在AIM 2中，使用T细胞，巨噬细胞和角质形成细胞特异性STAT3缺陷小鼠在体内评估骨吸收最重要的细胞类型。长期目标是确定LL-10在牙周炎中的预防作用，并将这些信息应用于改善该疾病的调节剂的发展。