Periapical and marginal periodontitis are infections with pathogenic bacteria such asFusobacterium nucleatumandPorphyromonas gingivalisthat result in the loss of bony support of the teeth. We have previously reported that the pro-inflammatory cytokine interleukin-1 (IL-1) is a prominent mediator that elicits bone loss in these diseases. The secretion of IL-1 in periapical and periodontal tissue is regulated innate and adaptive immune responses. The Sasaki laboratory explores the molecular mechanisms of host defense and bone loss in these dental diseases utilizing genetically engineered gene knockout and transgenic mice.
The functional role of regulatory cytokines in periapical and marginal periodontitis.
We are exploring the functional role of the cytokines that mediate Th1 and Th2 type immune responses in periapical and marginal periodontitis. To date, we have reported that gene knockouts of Th2 type anti-inflammatory cytokines interleukin-10 (IL-10) and to a lesser extent IL-6, but not IL-4, resulted in enhanced infection-stimulated periapical and marginal bone loss. In contrast, the Th1 type cytokine IFNg, or its inducers IL-12 and IL-18, have no significant effects in these models, suggesting that pro-inflammatory pathways are highly redundant. Additional cytokines with the potential to regulate inflammation and immunity are being evaluated. The ultimate goal is to define the cytokine network that controls infection-stimulated bone resorption, and to identify potential points of therapeutic intervention.
Role of Stat3 signaling in periapical and marginal periodontitis.
Stat3 is the most important signal transduction molecule for IL-10 responses. The Stat3 knockout mouse is early embryonic lethal; however the importance of Stat3 in dental and other diseases can be assessed using cell-specific Stat3 knockout mice generated via the Cre-loxP system. In this project, the cell type that is most important for IL-10 mediated reduction of alveolar bone loss will be assessedin vivousing macrophage-, T cell-, and keratinocyte-specific Stat3 knockout mice.
Establishment of novel animal models of periapical and marginal periodontitis.
Our laboratory recently established the IL-10 knockout mouse as a novel animal model of marginal periodontitis, in which alveolar bone loss is absolutely dependent upon infection with pathogens such asP. gingivalis. This model will be utilized in the research and development of vaccines and novel therapeutics for this disease.
Selected Publications
Leshem O, Kashino SS, Goncalves RB, Suzuki N, Onodera M, Fujimura A, Sasaki H, Stashenko P, Campos-Neto A. 2008. Th1 biased response to novelPorphyromonas gingivalisprotein aggravates bone resorption caused by this oral pathofen. Microbes Infect. 10(6):664-72.
Sasaki H, Suzuki N, Kent R jr, Kawashima N, Takeda J, Stashenko P. 2008. T Cell response mediated by myeloid cell-derived IL-12 is responsible forPorphyromonas gingivalis-induced periodontitis in IL-10-deficient mice. J. Immunol.
180(9):6193-8.
Kawai T, Paster BJ, Komatsuzawa H, Ernst CW, Goncalves RB, Sasaki H, Ouhara K, Stashenko PP, Sugai M, Taubman MA. 2007. Cross-reactive adaptive immune response to oral commensal bacteria results in an induction of receptor activator of nuclear factor-kappaB ligand (RANKL)-dependent periodontal bone resorption in a mouse model. Oral Microbiol Immunol. 22(3):208-15.
Stashenko P, Goncalves RB, Lipkin B, Ficarelli A, Sasaki H, Campos-Neto A. 2007. Th1 immune response promotes severe bone resorption caused byPorphyromonas gingivalis. Am J Pthol. 170(1):203-13.
Sasaki H, Okamatsu Y, Kawai T, Kent R, Taubman M, Stashenko P. (2004) The interleukin-10 knockout mouse is highly susceptible toPorphyromonas gingivalis-induced alveolar bone loss. J. Perio. Res. (in press)
Okamatsu Y, Kim D, Battaglino R, Sasaki H. Spaete U, Stashenko P. (2004) MIP-1 gamma promotes RANKL-induced osteoclast formation and survival. J. Immunol. (in press)
Sasaki H, Balto K, Kawashima N, Eastcott J, Hoshino K, Akira S, Stashenko P. (2004) Gamma interferon (IFN-g) and IFN-g-inducing cytokines interleukin-12 (IL-12) and IL-18 do not augment infection-stimulated bone resorptionin vivo. Clin. Diagn. Lab Immunol. 11(1): 106-110.
Balto K, Sasaki H, Stashenko P. (2001) Interleukin-6 deficiency increases infection increases bone destruction. Infect. Immun. 69(2): 744-750.
Sasaki H, Hou L, Belani A, Uchiyama T, Mueller R, Stashenko P. (2000) IL-10, but not IL-4, suppresses infection stimulated bone resorptionin vivo. J. Immunol. 165: 3626-3630.