| Co-Investigator(Kenkyū-buntansha) |
UMEHARA Hisanori Kyoto Univ. Dept of Dent. Associ. Professor, 医学部, 助教授 (70247881)
FUKUSHIMA Hisanori Osaka Dental Univ. Dept of Dent. Professor, 歯学部, 教授 (50103099)
IMAI Hisao Osaka Dental Univ. Dept of Dent. Professor, 歯学部, 教授 (80067024)
MIYAMAE Masami Osaka Dental Univ. Dept of Dent. Assist.Professor, 歯学部, 講師 (20298821)
NAGANO Yutaka Osaka Dental Univ. Dept of Dent. Assist.Professor, 歯学部, 講師 (80228048)
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| Research Abstract |
Periodontitis is the chronic inflammatory disease caused by immunocomponents cells activated by oral pathologic bacteria such as Porphymonas gingivalis in dental plaque. To analyzes the pathogenic mechanisms of the chronic inflammation, we investigated the signaling roles on the activation of immunocomponents cells, such as NK cell, T cell and monocyte, and the roles on these cells-mediated endothelium damage, which may result in vascular injury. Moreover, we investigated the possible involvement of fractalkine and RANKL in the development of periodontitis.
1. The signaling roles in the activation of immunocomponents cells: 1) We analyzed tyrosine phosphorylation and interaction of Cbl with adaptor proteins, Grb2 and CrkL in NK3.3 cells. We revealed that CrkL associates with a large portion of tyrosine phosphorylated Cbl after CD2 stimulation of NK3.3 cells. In contrast to constitutive Cbl association with Grb2, tyrosine phosphorylated Cbl interacted with CrkL via its SH2 domain only af
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ter CD2 stimulation. Their tyrosine phosphorylation strongly suggests that interactions of Cbl with Grb2 and CrkL may play pivotal roles in CD2-mediated NK cell activation. 2) We revealed that tyrosine phosphorylation of adaptor protein LAT and consequent interactions between signaling molecules, Grb2, CrkL, Shc and Cbl might explain that the molecular mechanisms of the additive effects of IL-2 stimulation and CD2 cross-linking on NK cell activation. 3) We found that modulation of lipid raft integrity by aggregation of NK cell activating receptors, which leaded to the formation of complexes of LAT with PI3-K and PLC-γ1, was essential for the NK cell lytic mechanisms. 4) We also revealed that some chemokines, such as MCP-1 and RANTES, had an important role in the adhesion of T cells to fibroblasts, which might be involved in the pathogenesis of periodontitis by enhancing immunologic reaction at the inflammatory sites.
2. The roles of fractalkine in vascular endothelial cell injury by monocytes and NK cells: 1) We revealed that fractalkine might function as an adhesion molecule between monocytes and endothelial cells rather than as a chemotactic factor. 2) We found that fractalkine might induce firm adhesion between monocytes and endothelial cells not only through an intrinsic adhesion function itself, but also through activation of integrin avidity for their ligands. 3) We suggest that fractalkine plays an important role not only in the binding of NK cells to endothelial cells, but also in NK cell-mediated endothelial cell damage, which may result in vascular injury.
3. Expression of fractalkine and RANKL in human periodontitis: Positive immunoreactivities to fractalkine and RANKL have been identified in submucosal vessels of inflammatory human gingival tissue. These results suggest that fractalkine and RANKL are important molecules in the pathogenesis and progression of human periodontitis. Less
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