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

基本信息

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

项目摘要

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) 可以被宿主细胞中以 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 NOD1 和NOD2 可识别细菌肽聚糖。我们通过 TLR 和 NOD 在各种细胞中检测先天免疫反应，以阐明先天免疫在口腔粘膜中的作用。这些实验仅使用化学合成的配体来排除细菌制剂中微量成分的影响；细菌脂肽Pam3CSSNA（TLR2配体）、大肠杆菌型脂质A LA-15-PP（TLR4配体）、细菌CpG DNA（我们证明了NOD1-或NOD2-激动剂与各种组合。 TLR 激动剂在培养的人单核 THP-1 细胞中协同诱导炎症细胞因子，同样的组合刺激也在人树突细胞中诱导 Th1 谱系反应，但迄今为止，人口腔上皮细胞也携带所有 TLR 和 NOD 分子。，各个配体的刺激不会诱导炎症细胞因子，但肯定会诱导抗菌因子，例如肽聚糖识别蛋白(PGRP-L,Iα,Iβ,S) 和 β-防御素 2. 考虑到所有这些发现，我们提出一个可行的假设：口腔上皮细胞与正常菌群中的各种细菌相互作用，主动产生抗菌因子然而，这些细胞受到负调控，以防止诱导免疫和炎症反应。当负调控被关闭时，就会发生过度的炎症反应，一旦粘膜屏障被破坏，就会引发组织破坏。巨噬细胞和树突状细胞启动Th1谱系获得性免疫反应，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

期刊论文数量（62）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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。

DOI：
发表时间：
2005
期刊：
Cullular Microbiology 7-5
影响因子：
0
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。

DOI：
发表时间：
2004
期刊：
The Journal of Immunology 173・8
影响因子：
0
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。

DOI：
发表时间：
2004
期刊：
Journal of Experimental Medicine 200(5)
影响因子：
0
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.

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

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

DOI：
发表时间：
2004
期刊：
The Journal of Immunology 173(8)
影响因子：
0
作者：
Ozawa A;Tada H;Sugawara Y;Uehara A;Sasano T;Shimauchi H;Takada H;Sugawara S.
通讯作者：
Sugawara S.

Involvement of Kupffer cells in lipopolysaccharide-induced rapid accumulation of platelets in the liver and the ensuring anaphylaxis-like shock in mice.

库普弗细胞参与脂多糖诱导的血小板在肝脏中的快速积累，并确保小鼠发生过敏反应样休克。

DOI：
发表时间：
2006
期刊：
Biochimica et Biophysica Acta : Molecular Basis of Disease 1762・3
影响因子：
0
作者：
Yamaguchi K;Yu Z;Kumamoto H;Sugawara Y;Kawamura H;Takada H;Yokochi T;Sugawara S;Endo Y
通讯作者：
Endo Y