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THE STUDY ON THE MECHANISM OF CHRONIC INFLAMMATION BY THE ANALYSIS OF THE CELL FUNCTION MODIFICATION EFFECTS OF PROTEINASES FROM A PERIODONTAL DISEASE BACTERIUM

牙周病菌蛋白酶对细胞功能修饰作用的分析研究慢性炎症机制

基本信息

批准号：
13670221
负责人：
IMAMURA Takahisa
金额：
$ 2.3万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

The periodontal disease is a chronic inflammation caused mainly by Porphyromonas gingivalis infection. The trypsin-like cysteine proteinases produced from the bacterium (gingipains; HRgpA, RgpB and Kgp) are major virulence factors and may be associated the bacterial survival and periodontal tissue breakdown. Hence, the effects of gingipains on the host-defense system and tissue destruction through modulating cell functions. Gingipains destroyed CD4 and CD8 on the human T lymphocytes at 0.1 μM in 30 min. They also cleaved off gingival fibroblast CD14, which recognizes LPS and activates the cells, attenuating the release of IL-8, a neutrophil chemotactic factor. These results indicated that gingipains cleaves receptors of host immune cells, facilitating the escape of the bacterium from these cells. The gingival tissue with periodontitis increased expression matrix metalloproteinase (MMP)-1, -2 and -9. Therefore, the effect of gingipains on cultured gingival cell MMP production was investigated. Gingival fibroblast MMP-1 production increased 2.5 and 2-fold by addition of 1nM HRgpA or RgpB, respectively. Neutrophils released 7 or 1.3-fold more MMP-1 by HRgpA or RgpB, respectively. MMP-2 production by gingival epithelial cells increased 5-fold by 0.1 nM RgpB or 1 nM HRgpA. Taken together, gingipains R stimulate MMP production by gingival cells and neutrophils, which promotes gingival tissue destruction. The fact that factor Xa-specific inhibitor, DX9065a inhibited these gingipain R activities suggested a possible therapeutic effect of proteinase inhibitors on periodontitis.

牙周病是一种慢性炎症，主要由牙龈卟啉单胞菌感染引起。由细菌产生的胰蛋白酶样半胱氨酸蛋白酶（牙龈菌蛋白酶; HRgpA、RgpB和Kgp）是主要的毒力因子，并且可能与细菌存活和牙周组织破坏相关。因此，牙龈卟啉菌蛋白酶通过调节细胞功能而影响宿主防御系统和组织破坏。0.1 μM的牙龈蛋白酶在30分钟内破坏人T淋巴细胞上的CD 4和CD 8。它们还切割牙龈成纤维细胞CD 14，后者识别LPS并激活细胞，减少中性粒细胞趋化因子IL-8的释放。这些结果表明牙龈卟啉菌蛋白酶切割宿主免疫细胞的受体，促进细菌从这些细胞中逃逸。牙周炎患者牙龈组织中MMP-1、MMP-2、MMP-9的表达增加。因此，研究牙龈蛋白酶对培养的牙龈细胞MMP产生的影响。加入1 nM HRgpA或RgpB，牙龈成纤维细胞MMP-1的产生分别增加2.5和2倍。通过HRgpA或RgpB，中性粒细胞分别释放7倍或1.3倍以上的MMP-1。牙龈上皮细胞的MMP-2产量增加5倍，0.1 nM RgpB或1 nM HRgpA。总之，牙龈蛋白酶R刺激牙龈细胞和中性粒细胞产生MMP，这促进牙龈组织破坏。Xa因子特异性抑制剂DX9065 a抑制牙龈菌蛋白酶R活性的事实表明，蛋白酶抑制剂对牙周炎可能有治疗作用。