Immune regulation of oral mucosa and oral mucosal diseases by proteases and their inhibitors

蛋白酶及其抑制剂对口腔粘膜和口腔粘膜疾病的免疫调节

• 批准号: 17390483
• 负责人: SUGAWARA Shunji
• 金额: $ 9.79万
• 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: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390483/
• 关键词: proteases; protease inhibitors; Immune regulation; protease-activated receptors; oral mucosa; saliva; oral mucosal diseases

Research results of this project are as follows,1. Trypsin-like protease produced by periodontopathic bacteria activated human gingival fibroblasts through protease activated receptor (PAR) 1 and PAR2, suggesting that this protease is critically involved in onset of periodontal disease.2. Serum interleukin 18 (IL-18) levels and IL-18-dependent liver injury induced by LPS in Propionibacterium acnes-primed mice were significantly reduced by anti-Gr-1 injection (depletion of neutrophils). The same results were observed by co-administration of a serine protease inhibitor with LPS. A deficiency of PAR2 in mice significantly impaired IL-18 induction by treatment with P. acnes and LPS, and only slight pathological changes in hepatic tissues occurred in the PAR2^<-/-> mice treated with P. acnes and LPS. These results indicate that neutrophil recruitment and PAR2 activation by neutrophil serine proteases are critically involved in the induction of IL-18.3. Lactoferrin (Lf) is an iron-binding an … More tibacterial protein, present in most exocrine secretions, such as saliva. In this study, we identified small Lf peptides in the saliva of chronic periodontitis patients and confirmed them to be fragments of intact Lf. Proteinase 3 (PR3) protein was detected in the saliva of periodontitis patients, and PR3 activity and levels of Lf fragments were correlation to the severity of clinical symptoms. Saliva Lf peptides showed no anti-bacterial activity against Escherichia coil; and had a reduced iron-chelating capacity. Saliva Lf peptides induce the production of pro-inflammatory cytokines in human oral epithelial cells. These results suggest that Lf in the parotid saliva of periodontitis patients was degraded into small peptides by the PR3-like activity with the capability to induce inflammatory mediators.4. We identified soluble form of Toll-like receptor 2 (TLR2) in saliva. As TLR2 is an originally transmembrane receptor, it is suggested that some proteases are involved in the generation of soluble TLR2. We found that saliva modulated the TLR2-mediated immune responses in oral cavity Less

本课题的研究结果如下：1.牙周病细菌产生的类胰蛋白酶通过蛋白水解酶激活受体(PAR)1和PAR2激活人牙龈成纤维细胞，提示该酶在牙周病的发生发展中起重要作用。注射抗Gr-1抗体(去除中性粒细胞)可显著降低痤疮丙酸杆菌诱导的小鼠血清IL-18水平及IL-18依赖性肝损伤。丝氨酸蛋白酶抑制剂与内毒素联合给药也观察到同样的结果。PAR2基因缺失可显著抑制痤疮螺旋体和脂多糖诱导的IL-18的产生，而痤疮螺旋体和脂多糖诱导的小鼠肝组织只有轻微的病理改变。这些结果表明，中性粒细胞募集和中性粒细胞丝氨酸蛋白酶激活PAR2在IL-18.3的诱导中起关键作用。乳铁蛋白(LF)是一种铁结合蛋白(…)更多的细菌蛋白，存在于大多数外分泌物中，如唾液。在这项研究中，我们在慢性牙周炎患者的唾液中鉴定了小的LF多肽，并证实它们是完整的LF片段。牙周炎患者唾液中检测到蛋白酶3(PR3)蛋白，且PR3活性和LF片段水平与临床症状的严重程度相关。唾液中的LF多肽对大肠杆菌无抗菌活性，对铁离子的螯合能力有所降低。唾液LF肽诱导人口腔上皮细胞产生促炎细胞因子。这些结果表明，牙周炎患者腮腺唾液中的LF被PR3样活性降解为小肽，具有诱导炎症介质的能力。我们在唾液中发现了可溶性的Toll样受体2(TLR2)。由于TLR2最初是一种跨膜受体，因此推测某些蛋白酶参与了可溶性TLR2的产生。我们发现唾液对口腔中TLR2介导的免疫反应的调节作用较小

项目成果

Mutual augmentation of the induction of the histamine-forming enzyme, histidine decarboxylase, between alendronate and immuno-stimulants (IL-1, TNF, and LPS), and its prevention by clodronate

• DOI: 10.1016/j.taap.2005.09.005
• 发表时间: 2006-05-15
• 期刊: TOXICOLOGY AND APPLIED PHARMACOLOGY
• 影响因子: 3.8
• 作者: Deng, Xue;Yu, Zhiqian;Endo, Yasuo
• 通讯作者: Endo, Yasuo

Toll-like receptors, NOD1, and NOD2 in oral epithelial cells

• DOI: 10.1177/154405910608500609
• 发表时间: 2006-06-01
• 期刊: JOURNAL OF DENTAL RESEARCH
• 影响因子: 7.6
• 作者: Sugawara, Y.;Uehara, A.;Takada, H.
• 通讯作者: Takada, H.

Involvement of neutrophil recruitment and protease-activated receptor 2 activation in induction of IL-I8 in mice.

中性粒细胞募集和蛋白酶激活受体 2 激活参与小鼠 IL-18 的诱导。

• 发表时间: 2005
• 期刊: J. Leukoc. Biol. 78 (5)
• 作者: Ikawa K;et al.
• 通讯作者: et al.

Involvement of neutrophil recruitment and protease-activated receptor 2 activation in induction of IL-18 in mice

中性粒细胞募集和蛋白酶激活受体 2 激活参与小鼠 IL-18 的诱导

• 发表时间: 2005
• 期刊: J Leukoc Biol 7
• 作者: Ikawa K;Nishioksi T;Yu Z;Sugawara Y;Kawagoe J;TaMzawa T;Prirao V;Nikolic B;Kuroishi T;Sasano T;Shimauchi H;Takada H;Endo Y and Sugawara S.
• 通讯作者: Endo Y and Sugawara S.

Chemically synthesized pathogen-associated molecular patterns increase the expression of peptidoglycan recognition proteins via toll-like recentors, NOD1 and NOD2 in human oral epithelial cells.

化学合成的病原体相关分子模式通过人类口腔上皮细胞中的 Toll 样近期因子 NOD1 和 NOD2 增加肽聚糖识别蛋白的表达。

• 发表时间: 2005
• 期刊: Cell. Microbiol 7・5
• 作者: Uehara;A.
• 通讯作者: A.