Role of TLR signaling and chemokine in liver regeneration, and their application to accelerated regeneration

TLR信号和趋化因子在肝再生中的作用及其在加速再生中的应用

• 批准号: 16390385
• 负责人: IIMURO Yuji
• 金额: $ 9.15万
• 依托单位: HYOGO COLLEGE OF MEDICINE
• 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-16390385/
• 关键词: Toll-like receptor; liver regeneration; MyD88; innate immunity; NF-κB; SDF-1; 骨髄移植; 肝硬変

Toll-like receptors (TLRs) act as innate immune signal sensors and play central roles in host defense. Myeloid differentiation factor (MyD) 88 is a common adaptor molecule required for signaling mediated by TLRs. When the receptors are activated, cells bearing TLRs produce various proinflammatory cytokines in a MyD88-dependent manner. Liver regeneration following partial hepatectomy (PH) requires innate immune responses, particularly interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) production by Kupffer cells, although the recognition and activation processes are still unknown.We investigated whether TLR/MyD88 signaling is critical for induction of innate immune responses after PH. In Myd88-/- mice after PH, induction of expression of immediate early genes involved in hepatocyte replication and phosphorylation of STAT3 in the liver, and production of TNF-α/IL-6 by and activation of NF-κB in the Kupffer cells were grossly subnormal and were associated with impaired liver regeneration. However, TLR2, 4 and 9, which recognize gram-negative and -positive bacterial products, are not essential for NF-κB activation and IL-6 production after PH, which excludes a possible contribution of TLR2/TLR4 or TLR9 to MyD88-mediated pathways.In conclusion, the TLR/MyD88 pathway is essential for incidental liver restoration, particularly its early phase.

Toll样受体（TLR）作为先天免疫信号传感器，在宿主防御中发挥重要作用。髓样分化因子（MyD）88是TLR介导的信号传导所需的常见接头分子。当受体被激活时，携带TLR的细胞以MyD 88依赖性方式产生各种促炎细胞因子。部分肝切除术后的肝再生需要天然免疫应答，特别是枯否细胞产生的白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF-α），尽管识别和激活过程仍然未知。我们研究了TLR/MyD 88信号转导是否是诱导PH后天然免疫应答的关键。在PH后的Myd 88-/-小鼠中，诱导参与肝细胞复制的即刻早期基因表达和肝脏中STAT 3的磷酸化，以及Kupffer细胞中TNF-α/IL-6的产生和NF-κB的活化均严重低于正常，并与受损的肝再生相关。然而，识别革兰氏阴性和阳性细菌产物的TLR 2、4和9对PH后NF-κB活化和IL-6产生不是必需的，这排除了TLR 2/TLR 4或TLR 9对MyD 88介导的通路的可能贡献。

项目成果

Nuclear factor κB inactivation in the rat liver ameliorates short-term warm ischaemia/reperfusion injury.

大鼠肝脏中核因子 κB 失活可改善短期热缺血/再灌注损伤。

• 发表时间: 2005
• 期刊: Gut (in press)
• 作者: Suetsugu H;Iimuro Y 他
• 通讯作者: Iimuro Y 他

Long-term safety of autotransfusion during hepatectomy for hepatocellular carcinoma

• DOI: 10.1007/s00595-005-3082-8
• 发表时间: 2005-12-01
• 期刊: SURGERY TODAY
• 影响因子: 2.5
• 作者: Hirano, T;Yamanaka, J;Fujimoto, J
• 通讯作者: Fujimoto, J

Nuclear factor {kappa}B inactivation in the rat liver ameliorates short term total warm ischaemia/reperfusion injury.

• 发表时间: 2005
• 期刊: Gut
• 影响因子: 24.5
• 作者: H. Suetsugu;Y. Iimuro;T. Uehara;T. Nishio;N. Harada;M. Yoshida;E. Hatano;G. Son;J. Fujimoto

Ameliorating effect of hepatocyte growth factor on inflammatory bowel disease in a murine model.

肝细胞生长因子对小鼠模型炎症性肠病的改善作用。

• 发表时间: 2005
• 期刊: Am. J. Physiol. Gastrointest Liver Physiol 288・4
• 作者: Oh;K.;limuro;Y.;Takeuchi;M.;Kaneda;Y.;Iwasaki;T.;Terada;N.;Matsumoto;T.;Nakanishi;K.;Fujimoto;J.
• 通讯作者: J.

Role of innate immune response in liver regeneration

• DOI: 10.1111/j.1440-1746.2006.04651.x
• 发表时间: 2007-06-01
• 期刊: JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
• 影响因子: 4.1
• 作者: Iimuro, Yuji;Seki, Ekihiro;Fujimoto, Jiro
• 通讯作者: Fujimoto, Jiro