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.