Role of IL-10 in Periodontal Bone Destruction

描述(申请人提供)：牙周病是感染致病细菌，如牙龈卟啉单胞菌(PG)，导致牙槽骨丢失。骨破坏与炎性细胞因子的过度表达有关，特别是白介素1。IL-10是一种抗炎细胞因子，由巨噬细胞和Th2细胞等多种免疫细胞产生，是体内感染刺激的根尖周骨吸收的内源性关键抑制因子，可能通过抑制IL-1发挥作用。最近，我们发现IL-10缺陷(IL-10-/-)小鼠也非常容易受到PG刺激的牙周骨丢失的影响，而牙周组织中的IL-I水平并没有增加。相反，在相应的野生型(WT)小鼠中，PG感染并没有引起明显的骨破坏。在本研究中，我们将使用T细胞、巨噬细胞和角质形成细胞上的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、它们的信号转导以及IL-10调节的细胞因子网络可以改善牙周炎的诱导和进展的假说。本提案中将描述的IL-10/小鼠与先前描述的模型相比具有几个主要优点，特别是疾病的快速发展、疾病的严重性以及现有的背景口腔菌群的存在。大量试剂和基因工程小鼠品系的可获得性，以及产生双基因和三基因敲除的能力，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IL-10的关键效应细胞类型(S)的优势。在目标1中，动态研究WT和IL-10-/-小鼠的组织病理学改变、牙周骨丢失、全身骨密度以及骨吸收标志物的基因和蛋白表达。在目标2中，对IL-10相关的减少骨吸收最重要的细胞类型(S)将在体内使用T细胞、巨噬细胞和角质形成细胞特异性STAT3缺陷小鼠进行功能评估。长期目标是确定LL-10在牙周炎中的预防作用，并将这一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.