Role of IL-10 in Periodontal Bone Destruction

描述（由申请人提供）：牙周病是病原细菌的感染，如牙龈卟啉单胞菌（Pg），导致牙槽骨丢失。骨破坏与炎症细胞因子的过度表达有关，特别是白细胞介素(IL)-1。IL-10是一种抗炎细胞因子，由包括巨噬细胞和Th2细胞在内的各种免疫细胞产生，我们之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抑制起作用。最近，我们已经证明IL-10缺乏（IL-10 -/-）的小鼠也非常容易受到pg刺激的牙周骨质流失，而牙龈il -1水平却没有增加。相比之下，Pg感染在相应的野生型（WT）小鼠中未引起明显的骨破坏。在目前的研究中，我们将在T细胞、巨噬细胞和角质形成细胞上使用IL-10 -/-和细胞特异性Stat3缺陷小鼠来验证通过调节IL-10、IL-10受体、它们的信号传导以及IL-10调节的细胞因子网络来改善牙周炎的诱导和进展的假设。与先前描述的模型相比，本研究中描述的IL-10 -/-小鼠具有几个主要优势，特别是疾病发展迅速、疾病严重程度和现有背景口腔菌群的存在。大量试剂和基因工程小鼠菌株的可用性以及产生双重和三重基因敲除的能力使IL-10 -/-小鼠成为了解发病机制的潜在有价值的模型。尽管IL-10信号通路依赖于Stat3信号通路，但细胞特异性Stat3缺陷小鼠提供了直接确定lL-10关键效应细胞类型的优势。在Aim 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质表达。在Aim 2中，将使用T细胞、巨噬细胞和角化细胞特异性Stat3缺陷小鼠在体内对IL-10相关骨吸收减少最重要的细胞类型进行功能评估。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这种疾病的调节剂的开发。

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.