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* Department of Cytokine Biology, The Forsyth Institute, Boston, MA 02115;
Pulp Biology and Endodontics, Division of Oral Health Sciences, Department of Restorative Sciences, Tokyo Medical and Dental University Graduate School, Tokyo, Japan;
Department of Biostatistics, The Forsyth Institute, Boston, MA 02115; and
Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
Periodontal disease is a chronic inflammatory disease in the oral cavity, which culminates in alveolar bone loss. Porphyromonas gingivalis is a consensus periodontal pathogen that has been implicated in adult forms of periodontitis. We previously demonstrated that IL-10-deficient mice exhibit a hyperinflammatory phenotype and are highly susceptible to P. gingivalis-induced periodontitis, indicating an important anti-inflammatory effect of IL-10 in suppressing bone loss. In this study, we analyzed the pathway(s) by which IL-10 deficiency leads to severe P. gingivalis-induced periodontitis. Because Stat3 is essential in IL-10 signaling, immune cell-specific Stat3-deficient mice were subjected to P. gingivalis infection to identify the key IL-10-responsive cells in preventing periodontitis. Myeloid cell-specific Stat3-deficient mice exhibited increased periodontal bone loss (p < 0.001), whereas T cell- and B cell-specific Stat3 mice were resistant, suggesting that macrophages (MP) and/or polymorphonuclear leukocytes are the key target cells normally suppressed by IL-10. Myeloid cell-specific Stat3-deficient mice exhibited elevated gingival CD40L gene expression in vivo compared with wild-type controls (p < 0.01), and Stat3-deficient MPs exhibited vigorous P. gingivalis-stimulated IL-12 production in vitro and induced elevated Ag-specific T cell proliferation compared with wild-type MPs (p < 0.01). Of importance, both IL-12p40/IL-10 and T cell/IL-10 double-deficient mice were resistant to P. gingivalis-induced periodontitis, demonstrating roles for both IL-12p40 and T cells in pathogenesis in a hyperinflammatory model of disease. These data demonstrate that P. gingivalis-induced periodontitis in IL-10-deficient mice is dependent upon IL-12p40-mediated proinflammatory T cell responses.
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1 This work was supported by Grants DE-15888 (to H.S.) and DE-09018 (to P.S.) from the National Institute of Dental and Craniofacial Research/National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Hajime Sasaki, The Forsyth Institute, 140 The Fenway, Boston, MA 02115. E-mail address: hsasaki{at}forsyth.org
3 Abbreviations used in this paper: IBD, inflammatory bowel disease; MP, macrophage; PMN, polymorphonuclear neutrophil; CT, cycle threshold; MMC, mitomycin C.
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