T cell response mediated by myeloid cell-derived IL-12 is responsible for Porphyromonas gingivalis-induced periodontitis in IL-10-deficient mice.
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.
Sasaki
Hajime
H
Department of Cytokine Biology, The Forsyth Institute, Boston, MA 02115, USA. hsasaki@forsyth.org
Suzuki
Noriyuki
N
Kent
Ralph
R
Kawashima
Nobuyuki
N
Takeda
Junji
J
Stashenko
Philip
P
D016301:Alveolar Bone Loss / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000382:microbiology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000382:microbiology; D010518:Periodontitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D010641:Phenotype; D016966:Porphyromonas gingivalis / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology
D053762:Interleukin-12 Subunit p40; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10; D023201:CD40 Ligand