Regulation of signal transduction through toll like receptors (interleukin-1 receptor related) by stimulation of live Mycobacterium tuberculosis

通过刺激活结​​核分枝杆菌调节 Toll 样受体（白细胞介素 1 受体相关）的信号转导

• 批准号: 14572111
• 负责人: TAKII Takemasa
• 金额: $ 2.18万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572111/
• 关键词: tuberculosis; interleukin 1; toll like receptor; fibroblast; cytokine; 抗酸菌; IL-1R関連レセプター; toll like reccptors; toll like reseptors; 抗結核薬; スクリーニング

We have previously revealed that live, but not dead, Mycobacterium tuberculosis exhibits cytotoxicity to human lung fibroblast cell line (J. Interferon Cytokine Res., 2001, Antimicrob. Agents Chemother., 2002). In order to investigate the signal transduction from live bacteria to host cell, we studied the expression of toll like receptors (TLRs), which are related to interleukin 1 receptor (IL-1R), and signal transduction from the receptors after stimulation with live bacilli. Lipoproteins which are present in cell wall of mycobacteria are reported as major ligand to TLR2 and induces apoptosis of macrophages. Lipopolysaccharide present in cell wall of gram-negative bacteria, transducer its signal through TLR4. In this study, LPS and transforming growth factor beta are revealed to regulate the expression of TLR2 and TLR4 on mouse hepatocyte (Immunology, 2003, J. Leukocyto Biol., 2004). Human fibroblast cell line, MRC-5, is known to constitutively expresses TLR1-10. The mechanism of activation of NF-kB is closely related to that of IL-1R. Therefore, we have investigated the activation of NF-kB on MRC-5 after stimulation of live M. tuberculosis. Live, but not dead, bacilli strongly induces NF kB and also induce expression of inflammatrical cytokines. Interestingly, the kinetics of induction of NF-kB and cytokines are similar to that of the effect of cytotoxicity of live bacilli. These data suggests that the signaling from TLRs after stimulation of live bacilli would have significance on the cytotoxicity to human cell. Further, we were also successful in applying the cytotoxicity testing for susceptibility test to pyrazinamic acid using clinical isolates of tuberculosis (Antimicrob. Agents Chemother., 2005)

我们先前已经揭示活的而非死的结核分枝杆菌对人肺成纤维细胞系表现出细胞毒性（J. Interferon Cytokine Res.，2001年，Antimicrob.探员Chemother 2002年）。为了研究活菌对宿主细胞的信号转导，我们研究了与白细胞介素1受体（IL-1 R）相关的Toll样受体（TLR）的表达及其在活菌刺激下的信号转导。存在于分枝杆菌细胞壁中的脂蛋白被报道为TLR 2的主要配体并诱导巨噬细胞凋亡。脂多糖存在于革兰氏阴性菌的细胞壁中，通过TLR 4传递其信号。在这项研究中，发现LPS和转化生长因子β可以调节小鼠肝细胞上TLR 2和TLR 4的表达（Immunology，2003，J. Leukocyto Biol.，2004年）。已知人成纤维细胞系MRC-5组成型表达TLR 1 -10。NF-κ B的活化机制与IL-1 R的活化机制密切相关。因此，我们研究了在刺激活M后MRC-5上NF-κ B的活化。结核活的而非死的杆菌强烈地诱导NF kB，并且还诱导炎性细胞因子的表达。有趣的是，NF-kB和细胞因子的诱导动力学与活杆菌的细胞毒性效应相似。这些数据表明，在活杆菌刺激后来自TLR的信号传导对人细胞的细胞毒性具有重要意义。此外，我们还成功地将细胞毒性试验应用于使用结核病临床分离株进行的吡嗪那酸敏感性试验（Antimicrob.探员Chemother（2005年）

项目成果

Multiple mechanisms involved in the inhibition of proinflammatory cytokine production from human monocytes by N-(p-coumaroyl)serotonin and its derivatives

• DOI: 10.1016/s1567-5769(02)00207-2
• 发表时间: 2003-02-01
• 期刊: INTERNATIONAL IMMUNOPHARMACOLOGY
• 影响因子: 5.6
• 作者: Takii, T;Kawashima, S;Onozaki, K
• 通讯作者: Onozaki, K

TRAF6-NF-kappaB pathway is essential for interleukin-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes.

TRAF6-NF-kappaB 通路对于白细胞介素 1 诱导的 TLR2 表达及其对小鼠肝细胞中 TLR2 配体的功能反应至关重要。

• 发表时间: 2003
• 期刊: Immunology 109・1
• 作者: Matsumura T;Degawa T;Takii T;Hayashi H;Okamoto T;Inoue J;Onozaki K
• 通讯作者: Onozaki K

Tamaki A, Hayashi H, Nakajima H, Takii T, Katagiri D, Miyazawa K, Hirose K, Onozaki K.: "Polycyclic aromatic hydrocarbon increases mRNA level for interleukin 1 beta in human fibroblast-like synoviocyte line via aryl hydrocarbon receptor."Biol Pharm Bull.

Tamaki A、Hayashi H、Nakajima H、Takii T、Katagiri D、Miyazawa K、Hirose K、Onozaki K.：“多环芳烃通过芳烃受体增加人成纤维样滑膜细胞系中白细胞介素 1 β 的 mRNA 水平。”Biol

Maeda, Y., Makino, M., Crick, D.C., Mahapatra, S., Srisungnam, S., Takii, T., Kashiwabara, Y., P.J.Brennan: "Novel 33-kilodalton lipoprotein from Mycobacterium leprae"Infection and Immunity. 70(8). 2533-2539 (2002)

Maeda, Y.、Makino, M.、Crick, D.C.、Mahapatra, S.、Srisungnam, S.、Takii, T.、Kashiwabara, Y.、P.J.Brennan：“来自麻风分枝杆菌的新型 33 千道尔顿脂蛋白”感染和免疫

Takii, T., Yamamoto, Y., Chiba, T., Abe, C., Belisle, J.T., Brennan, P.J., K.Onozaki: "Simple fibroblast-based assay for screening of new antimicrobial drugs against Mycobacterium tuberculosis"Antimicrobal Agents and Chemotherapy. 46(8). 2533-2539 (2002)

Takii, T.、Yamamoto, Y.、Chiba, T.、Abe, C.、Belisle, J.T.、Brennan, P.J.、K.Onozaki：“基于简单成纤维细胞的筛选新抗结核药物的测定”