Innate Immune Response via Intracellular Receptor NODs and Periodontal Diseases

通过细胞内受体 NOD 的先天免疫反应和牙周病

• 批准号: 16390519
• 负责人: TAKADA Haruhiko
• 金额: $ 9.09万
• 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: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390519/
• 关键词: Toll-like receptors (TLRs); NOD1; NOD2; Innate immunity; Peptidoglycan; PGRPs; Defensins; Epithelial cells; Toll-like receptor(TLR); NOD-1; NOD-2; PGRP; Toll-like receptor; MDP; リピドA; リポペプチド

In innate immunity, common and peculiar structures of microbes, pathogen-associated molecular patterns (PAMPs), are recognized by pattern-recognition molecules (PRMs) represented by Toll-like receptors (TLRs) in host cells. Another intracellular PRM family, NOD1 and NOD2, recognizes bacterial peptidoglycans. We examined innate immune responses through TLRs and NODs in various cells to elucidate the roles of innate immunity in the oral mucosa. In these experiments, only chemically synthesized ligands were used to rule out the influences of minor components in bacterial preparations ; bacterial lipopeptide Pam3CSSNA (TLR2 ligand), E.coli-type lipid A LA-15-PP (TLR4 ligand), bacterial CpG DNA (TLR9 ligand), MDP (NOD2 ligand) and iE-DAP (NOD1 ligand). We demonstrated that NOD1- or NOD2-agonist in combination with various TLR-agonists synergistically induced inflammatory cytokines in human monocytic THP-1 cells in culture. The same combinatory stimulation also induced Th1-lineage responses in human dendritic cells. Human oral epithelial cells also carried all of the TLR and NOD molecules examined to date. However, stimulation by the respective ligands did not induce inflammatory cytokines, but definitely induced anti-bacterial factors such as peptidoglycan recognition proteins (PGRP-L,Iα,Iβ,S) and β-defensin 2. Taking all of these findings in consideration, we postulate a working hypothesis : Oral epithelial cells, which interact with various bacteria in normal flora, actively produce anti-bacterial factors. The cells, however, are negatively controlled to prevent the induction of immune and inflammatory responses. When the negative regulation is turned off, excessive inflammatory responses occur, which in turn initiate tissue destruction. Once the mucosal barrier was broken, accumulated macrophages and dendritic cells initiate Th1-lineage acquired immune responses, which are were typical of oral mucosal disease represented by periodontal diseases.

在先天免疫中，微生物的常见和特殊结构，病原体相关分子模式（PAMP），由宿主细胞中以Toll样受体（TLR）为代表的模式识别分子（PRM）识别。另一个细胞内PRM家族，NOD 1和NOD 2，识别细菌肽聚糖。我们通过各种细胞中的TLR和NOD检测先天免疫应答，以阐明先天免疫在口腔粘膜中的作用。在这些实验中，仅使用化学合成的配体来排除细菌制剂中的次要组分的影响;细菌脂肽Pam 3CSSNA（TLR 2配体）、大肠杆菌型脂质A LA-15-PP（TLR 4配体）、细菌CpG DNA（TLR 9配体）、MDP（NOD 2配体）和iE-DAP（NOD 1配体）。我们证明NOD 1或NOD 2激动剂与各种TLR激动剂联合可协同诱导培养的人单核细胞THP-1细胞中的炎症细胞因子。相同的组合刺激也诱导人树突状细胞中的Th 1-谱系应答。人类口腔上皮细胞也携带了迄今为止检测到的所有TLR和NOD分子。然而，通过相应配体的刺激不诱导炎性细胞因子，但明确诱导抗菌因子，如肽聚糖识别蛋白（PGRP-L，Iα，Iβ，S）和β-防御素2。考虑到所有这些发现，我们提出一个工作假设：口腔上皮细胞，与正常植物群中的各种细菌相互作用，积极产生抗菌因子。然而，这些细胞受到负控制，以防止诱导免疫和炎症反应。当负调节被关闭时，会发生过度的炎症反应，这反过来又会引发组织破坏。一旦粘膜屏障被破坏，积聚的巨噬细胞和树突状细胞启动Th 1谱系获得性免疫应答，这是以牙周病为代表的口腔粘膜疾病的典型特征。

项目成果

Critical roles of platelets in lipopolysaccharide-induced lethality: effects of glycyrrhizin and possible strategy for acute respiratory distress syndrome.

• DOI: 10.1016/j.intimp.2004.11.004
• 发表时间: 2005-03
• 期刊: International immunopharmacology
• 影响因子: 5.6
• 作者: Yu Z;Ohtaki Y;Kai K;Sasano T;Shimauchi H;Yokochi T;Takada H;Sugawara S;Kumagai K;Endo Y
• 通讯作者: Endo Y

Chemically synthesized pathogen-associated molecular patterns increase the expression of peptidoglycan recognition proteins via Toll-like receptors NOD1 and NOD2 in human oral epithelial cell.

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

• 发表时间: 2005
• 期刊: Cullular Microbiology 7-5
• 作者: Uehara A;Sugawara Y;Kurata S;Fujimoto Y;Fukase K;Kusumoto S;Satta Y;Sasano T;Sugawara S;Takada H.
• 通讯作者: Takada H.

Endogenous IL-15 sustains recruitment of IL-2Rβ and common γ and IL-2-mediated chemokine production in normal and inflamed human gingival fibroblasts.

内源性 IL-15 维持正常和发炎的人牙龈成纤维细胞中 IL-2Rβ 的募集以及常见 γ 和 IL-2 介导的趋化因子的产生。

• 发表时间: 2004
• 期刊: The Journal of Immunology 173・8
• 作者: Ozawa A;Tada H;Sugawara Y;Uehara A;Sasano T;Shimauchi H;Takada H;Sugawara S
• 通讯作者: Sugawara S

MyD88 but not TRIF is essential for osteoclastogenes is induced by lipopolysaccharide, diacyl lipopeptide, and IL-1α.

MyD88 而不是 TRIF 对于脂多糖、二酰基脂肽和 IL-1α 诱导的破骨细胞至关重要。

• 发表时间: 2004
• 期刊: Journal of Experimental Medicine 200(5)
• 作者: Sato N;Takahashi N;Suda K;Nakamura M;Yamaki M;Ninomiya T;Kobayashi Y;Takada H;Shibata K;Yamamoto M;Takeda K;Akira S;Noguchi T;Udagawa N.
• 通讯作者: Udagawa N.

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

• DOI: 10.1111/j.1462-5822.2004.00500.x
• 发表时间: 2005-05-01
• 期刊: CELLULAR MICROBIOLOGY
• 影响因子: 3.4
• 作者: Uehara, A;Sugawara, Y;Takada, H
• 通讯作者: Takada, H