Novel bioactivities of neutrophil serine proteases against periodontopathic bacteria in innate immunity

中性粒细胞丝氨酸蛋白酶在先天免疫中对抗牙周病细菌的新生物活性

• 批准号: 15390551
• 负责人: SUGAWARA Shunji
• 金额: $ 8.96万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390551/
• 关键词: periodontopathic bacteria; neutrophils; proteases; protease-activated receptors; innate immunity; oral mucosa; cytokines; 血小板

Research results of this project are as follows,1.Neutrophil serine proteases (elastase, cathepsin G, and proteinase 3 (PR3)) activate human non-epithelial cells (i.e.human gingival fibroblasts (HGF)) through G-protein-coupled protease-activated receptor-2 (PAR-2) and induce cytokine production from the cells. PR3 but not elastase and cathepsin G activates oral epithelial cells, due to secretory leukocyte inhibitor (an inhibitor of elastase and cathepsin G but not PR3) from the epithelial cells.2.Inflamed oral epithelium expresses PR3. Proinflammatory cytokines induce PR3 as membrane-bound and secretory forms with enzymatic activity. Antibodies to PR3 activate the cells through PAR-2 and induce chemokine production from the cells.3.As T cells accumulate in the inflamed lamina propria of gingival tissue from patients with adult periodontitis, immune responses of gingival cells to T cell cytokines, interleukin-2 (IL-2) and IL-15 was investigated. Endogenous IL-15 expressed in HGF sustains recruitment of IL-2/15 receptor β and common γ through nuclear factor-κB activation in normal and inflamed HGF.4.A trypsin-like proteases, gingipains, from periodontopathic bacteria cleave intercellular adhesion molecule-1 (CD54) expressed on oral epithelial cells, and consequently disrupt neutrophil-oral epithelial cell interaction.5.SalivaCD14, an important molecule in innate immunity, promotes the invasion of oral epithelial cells by periodontopathic bacteria and consequently augments the production of chemokine, playing an important role in innate immunity in the oral cavity.

本项目的研究结果如下：1.中性粒细胞丝氨酸蛋白酶（弹性蛋白酶、组织蛋白酶G和蛋白酶3（PR 3））通过G蛋白偶联蛋白酶激活受体2（PAR-2）激活人牙龈成纤维细胞（HGF），诱导细胞产生细胞因子。PR 3而非弹性蛋白酶和组织蛋白酶G激活口腔上皮细胞，这是由于上皮细胞分泌白细胞抑制剂（弹性蛋白酶和组织蛋白酶G的抑制剂，而非PR 3）。促炎细胞因子诱导PR 3作为具有酶活性的膜结合和分泌形式。抗PR 3抗体通过PAR-2激活细胞，诱导细胞产生趋化因子。3.观察T细胞在牙周炎患者牙龈组织固有层中的聚集，以及牙龈细胞对T细胞因子白细胞介素-2（IL-2）和IL-15的免疫应答。HGF中表达的内源性IL-15通过在正常和发炎的HGF中激活核因子-κB来维持IL-2/15受体β和共同γ的募集。4.来自牙周病细菌的胰蛋白酶样蛋白酶gingipains切割口腔上皮细胞上表达的细胞间粘附分子-1（CD 54），从而破坏唾液CD 14，天然免疫中的重要分子，促进牙周病细菌对口腔上皮细胞的侵袭，从而增加趋化因子的产生，在口腔天然免疫中起重要作用。

项目成果

Muramyldipeptide and diaminopimelic acid-containing desmuramylpeptides in combination with chemically synthesized Toll-like receptor agonists synergistically induced production of interleukin-8 in a NOD2-and NOD1-dependent manner, respectively, in human m

胞壁酰二肽和含二氨基庚二酸的去壁酰肽与化学合成的 Toll 样受体激动剂相结合，分别以 NOD2 和 NOD1 依赖性方式协同诱导人白细胞介素 8 的产生。

• 发表时间: 2005
• 期刊: Cell.Microbiol. 7(1)
• 作者: Uehara;A. et al.
• 通讯作者: A. et al.

Proteolysis of ICAM-1 on Human Oral Epithelial Cells by Gingipains

• DOI: 10.1177/154405910308201007
• 发表时间: 2003-10
• 期刊: Journal of Dental Research
• 影响因子: 7.6
• 作者: H. Tada;Shunji Sugawara;Eiji Nemoto;Takahisa Imamura;J. Potempa;J. Travis;H. Shimauchi;Haruhiko T

Muramyldipeptide and diaminopimelic acid-containing desmuramylpeptides in combination with chemically synthesized Toll-like receptor agonists synergistically induced production of interleukin-8 in a NOD2- and NOD1-dependent manner, respectively, in human

含有胞壁酰二肽和二氨基庚二酸的去胞壁酰肽与化学合成的 Toll 样受体激动剂相结合，分别以 NOD2 和 NOD1 依赖性方式协同诱导人体内白细胞介素 8 的产生

• 发表时间: 2005
• 期刊: Cell.Microbiol. 7(1)
• 作者: I.Abe;Y.Utsumi;S.Oguro;H.Morita;Y.Sano;H.Noguchi;A.Uehara
• 通讯作者: A.Uehara

Tada, H.: "Proteolysis of ICAM-1 on human oral epithelial cells by gingipains"J.Dent.Res.. 82・10. 796-801 (2003)

Tada, H.：“牙龈蛋白酶对人口腔上皮细胞上 ICAM-1 的蛋白水解”J.Dent.Res.. 82・10 (2003)。

Ozawa, A.: "Expression of IL-2 receptor β and γ chains by human gingival fibroblasts and up-regulation of adhesion to neutrophils in response to IL-2"J.Leukocyte Biol.. 74・3. 352-359 (2003)

小泽，A.：“人牙龈成纤维细胞的 IL-2 受体 β 和 γ 链的表达以及对 IL-2 的中性粒细胞粘附的上调” J. 白细胞生物学杂志 74・3（2003 年） ）