活化的Toll样受体对人内皮（祖）细胞生物学功能的影响及其机制研究
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摘要
第一章聚肌胞(PolyⅠ:C)对人脐血内皮祖细胞增殖的影响及其机制研究
第一节人脐血内皮祖细胞表达Toll样受体的研究
目的：分离纯化人脐静脉血来源的单个核细胞并诱导培养为内皮祖细胞,观察Toll样受体在人脐血内皮祖细胞中的表达情况。
方法：采用密度梯度离心法分离人脐静脉血中的单个核细胞,用含多种生长因子的内皮祖细胞专用EBM-2培养基诱导培养,诱导单个核细胞向内皮祖细胞分化,通过形态学、免疫荧光及逆转录多聚酶链反应(RT-PCR)检测并鉴定细胞的生物学特性；采用RT-PCR法检测静息状态下人内皮祖细胞(EPCs)表达的Toll样受体亚型；检测不同浓度的PolyⅠ:C对内皮祖细胞表达TLR3受体、炎性细胞因子的影响。
结果：
1.分离培养的内皮祖细胞早期以集落为中心呈放射状生长,晚期形成典型的“铺路石”样改变。荧光染色示DiL-acLDL和FITC-UEA-I双染色阳性；RT-PCR法检测示细胞表达干细胞表面标志物CD34、CD133、KDR,证明为内皮祖细胞。
2.静息状态下,内皮祖细胞表达较高水平的TLR1、TLR3、TLR4、TLR6,表达较低水平的TLR2、TLR5、TLR7、TLR8、TLR10,不表达TLR9。而PolyⅠ:C能上调TLR3的mRNA及蛋白表达,并呈量效关系。
3. PolyⅠ:C通过活化TLR3剂量依赖性上调炎性细胞因子IL-1p、IL-6、IL-8、TNF-α、IFN-p的基因表达。
结论：EPCs表达功能性TLR3；PolyⅠ:C能呈剂量依赖性上调TLR3在EPCs的mRNA及蛋白表达,并通过活化TLR3剂量依赖性上调炎性细胞因子的mRNA表达。
第二节PolyⅠ:C对人脐血内皮祖细胞增殖、凋亡的影响
目的：观察TLR3的配体PolyⅠ:C对人脐血内皮祖细胞增殖、凋亡的影响。
方法：采用不同浓度的PolyⅠ:C持续干预人脐血内皮祖细胞(EPCs),通过CCK-8细胞增殖试验检测其对EPCs增殖的影响及时间效应；通过流式细胞术检测不同浓度的PolyⅠ:C对EPCs细胞周期时相分布及细胞凋亡的影响。
结果：
1.与对照组相比,较高浓度PolyⅠ:C(1,10μg/m1)持续作用于脐血内皮祖细胞3天后显著抑制内皮祖细胞增殖；终浓度10μg/ml的PolyⅠ:C呈时间依赖性抑制内皮祖细胞增殖。
2.较高浓度的PolyⅠ:C(1,10μg/m1)显著减少S期和G2/M期细胞比例,并通过下调细胞周期素A,B1,D1,E的表达阻滞细胞周期于G0/G1期而改变细胞周期的时相分布,从而抑制EPCs的增殖。
3. PolyⅠ:C呈剂量依赖性诱导内皮祖细胞凋亡。
结论：高浓度的PolyⅠ:C通过将细胞周期阻滞于G0/G1期并诱导细胞凋亡从而抑制EPCs增殖。
第三节PolyⅠ:C诱导人脐血内皮祖细胞凋亡的机制研究
目的：阐明PolyⅠ:C诱导人脐血内皮祖细胞凋亡的具体机制。
方法：利用Caspase8的抑制剂和Caspase9的抑制剂抑制相应的信号分子,分析其对PolyⅠ:C诱导细胞凋亡的作用。以不同浓度的TNF-α及IL-1β干预EPCs24h后,CCK-8细胞增殖试验分别检测TNF-α和IL-1β对细胞凋亡的影响。利用IL-1β受体的中和抗体Anti-IL-1R1预先封闭IL-1β的结合位点,分析其对PolyⅠ:C诱导细胞凋亡的作用。
结果：
1. Caspase8和9的抑制剂并不能抑制PolyⅠ:C诱导的细胞凋亡。
2.随着TNF-α作用浓度的增高,EPCs的细胞凋亡率并无明显增加。
3.随着IL-1p作用浓度的增高,EPCs的细胞凋亡率逐步增加,并呈剂量依赖性。使用IL-1p受体的中和抗体Anti-IL-1R1预先封闭IL-1p的结合位点后,再加入PolyⅠ:C干预24h,结果显示高浓度的Anti-IL-1R1可以部分抑制PolyⅠ:C诱导的细胞凋亡。
结论：PolyⅠ:C活化TLR3后通过上调IL-1p的表达诱导EPCs凋亡,而内、外源性细胞凋亡途径及TNF-a不参与PolyⅠ:C诱导的细胞凋亡
第二章Pam3CSK4在人脐静脉内皮细胞中诱导非耐受性的细胞因子表达
第一节Pam3CSK4对人脐静脉内皮细胞表达炎症因子的影响及其可能机制
目的：阐明TLR1/2激动剂Pam3CSK4对人脐静脉内皮细胞表达炎症因子的影响及其可能机制。
方法：以不同浓度的Pam3CSK4干预人脐静脉内皮细胞(HUVECs), RT-PCR法检测Pam3CSK4对TLR1、TLR2mRNA表达的影响。用RT-PCR法、Real-time RT-PCR法、ELISA法检测Pam3CSK4对HUVECs分泌TNF-α、IL-6的时间效应及剂量效应。分别用TLR1、TLR2及TLR1阻断剂阻断相应受体的表达,观察其对Pam3CSK4诱导HUVECs分泌TNF-α、IL-6的影响。用Western-blot法检测Pam3CSK4对MAPK家族及NF-κB信号转导通路的活化情况。
结果：Pam3CSK4呈剂量依赖性上调TLR2的mRNA表达,而对TLR1mRNA表达的影响不明显。Pam3CSK4呈剂量依赖性上调TNF-α、IL-6的基因及蛋白表达量。加入TLR1、TLR2、TLR1/2受体阻断剂后均能明显抑制Pam3CSK4诱导的TNF-a、IL-6的基因表达上调,其中以TLR1/2受体阻断剂的阻断作用最明显。Pam3CSK4与TLR2结合后可以不同程度活化MAPK家族和NF-κB信号传导通路。
结论：HUVECs表达功能性TLR2；Pam3CSK4与TLR2结合后活化MAPK家族和NF-κB信号传导通路,从而诱导炎症因子TNF-α、IL-6的分泌,且TNF-α、IL-6的分泌依赖于TLR1及TLR2的表达。
第二节Pam3CSK4在人脐静脉内皮细胞中诱导非耐受性的IL-6表达
目的：阐明预处理的TLR1/2激动剂Pam3CSK4重复刺激对人脐静脉内皮细胞表达炎症因子的影响及其可能机制。
方法：以不同浓度的Pam3CSK4预处理人脐静脉内皮细胞(HUVECs)后,再用Pam3CSK4重复刺激HUVECs,用RT-PCR法、Real-time RT-PCR法、ELISA法检测Pam3CSK4对HUVECs分泌TNF-α、IL-6的影响。用不同TLR受体的配体预处理HUVECs后,再用Pam3CSK4重复刺激HUVECs,以观察不同TLR受体之间的耐受情况。Western-blot法检测Pam3CSK4重复刺激对MAPK家族及NF-κB信号传导通路的活化情况。RT-PCR法检测Pam3CSK4对负性调节蛋白锌指蛋白A20基因表达的影响,然后用质粒转染试验检测A20的过度表达对Pam3CSK4及LPS诱导的IL-6分泌的影响。用Notch信号通路抑制剂抑制相关分子,观察其对Pam3CSK4诱导HUVECs分泌IL-6的影响。
结果：给予HUVECsPam3CSK4预处理后,再给予Pam3CSK4重复刺激可以下调TNF-a的基因及蛋白表达,而对IL-6表达无影响。LPS预处理可以使Pam3CSK4诱导的TNF-α表达下降,而对IL-6表达无影响。Pam3CSK4重复刺激HUVECs能抑制JNK通路的活化,而对p38、ERK、NF-κB信号通路的活化无影响。Pam3CSK4呈剂量依赖性上调负性调节蛋白锌指蛋白A20的基因表达,A20的过度表达对Pam3CSK4及LPS诱导的IL-6分泌无明显影。Notch信号通路抑制剂能部分抑制Pam3CSK4诱导的IL-6分泌。
结论：
1.Pam3CSK4重复刺激可诱导耐受性的TNF-α表达,而诱导非耐受性的IL-6表达。
2.TLR2与TLR4之间存在交叉耐受性。
3.Pam3CSK4可能通过Notch信号通路诱导非耐受性的IL-6表达。
Charpter I The Possible Mechanisms Responsible for the Effects of PolyⅠ:C on the Proliferation of Human Umbilical Cord Blood-Derived Endothelial Progenitor Cells
Part Ⅰ The Expression of Toll-like receptors on the Human Umbilical Cord Blood-Derived Endothelial Progenitor Cells
Objective:To observe the expression of Toll-like receptors on the human umbilical cord blood-derived endothelial progenitor cells (EPCs).
Methods:Mononuclear cells were isolated from fresh cord blood by density gradient centrifugation and cultured in EBM-2medium. The biological features of the isolated cells were observed at different time point and identified by morphology, immunofluorescence staining and RT-PCR. Furthermore, RT-PCR was performed firstly to detect the mRNA expression of Toll-like receptor subtypes in EPCs at rest, secondly the expression of Toll-like receptor3(TLR3)and inflammatory cytokines induced by PolyⅠ:C at different concentrations.
Results:
1. Early EPCs changed from small size round cells to spindle shape cells,Late EPCs formed a typical cobblestone-like cells.Adherent EPCs were characterized by DiLDL uptake and concomitant lectin binding, and by expressing of CD34、CD133and KDR, which are markers of stem cells.
2. RT-PCR results shown that Under basal condition, except TLR9, TLR1～TLR10were expressed in EPCs with high expression levels of TLR1、TLR3、TLR4. TLR6and low expression levels of TLR2、TLR5、 TLR7、TLR8、TLR10. Expression of TLR3was significantly up-regulated by treatment with Poly I:C at both the gene and protein levels and there was dose-effect relationship in experiment range.
3. PolyI:C upregulated the mRNA expression of inflammatory cytokines such as IL-1β、IL-6、IL-8、TNF-α、IFN-β by activating TLR3.
Conclusions:EPCs expressed functional TLR3; PolyI:C can up-regulate the expression of TLR3at both the gene and protein levels and up-regulate the gene expression of inflammatory cytokines in a dose-dependent manner by activating TLR3.
Part Ⅱ The Effect of PolyⅠ:C on the Proliferation and Apoptosis of Human Umbilical Cord Blood-Derived Endothelial Progenitor Cells
Objective:To analyze the effect of TLR3agonist PolyⅠ:C on the proliferation and apoptosis of human umbilical cord blood-derived endothelial progenitor cells.
Methods:EPCs were treated with different concentrations of PolyⅠ: C sequentially for3days, and then cell numbers were measured by CCK-8assay.EPCs were treated with Polyl:C at different concentrations, the phase of cell cycle was tested by PI staining and cell apoptosis was detected by the PI/Annexin V staining.
Results:
1.Compared with the control group, PolyⅠ:C at high concentrations of1and10μg/ml significantly inhibited the proliferation of EPCs after3days treatment, and the inhibition of cell proliferation by Poly I:C was time-dependent.
2. Poly Ⅰ:C at high concentrations of1and10μg/ml significantly decreased the proportion of cells in S phase and G2/M phase. Moreover, Poly Ⅰ:C down-regulated the gene expression of cyclins A, B1, D1, and E, inducing cell cycle arrest in G0/G1phase, thus inhibiting the proliferation of EPCs.
3. PolyI:C induced the apoptosis of EPCs in a dose-dependent manner.
Conclusions:PolyⅠ:C at high concentrations inhibited EPCs proliferation by inducing cell cycle arrest in G0/G1phase and inducing cell anoptosis of EPCs.
Part Ⅲ The Possible Mechanisms Responsible for the Effects of PolyⅠ:C on the Apoptosis of Human Umbilical Cord Blood-Derived Endothelial Progenitor Cells
Objective:To elucidate the mechanism of PolyⅠ:C induced apoptosis in human umbilical cord blood-derived endothelial progenitor cells.
Methods:We used specific inhibitors of Caspase8and Caspase9to inhibit the corresponding signal molecules, then tested the effect of caspase inhibition on Poly Ⅰ:C-induced apoptosis. EPCs were treated with different concentrations of TNF-α and IL-1β for24h respectively,then CCK-8assay was used to detect the apoptosis of EPCs. EPCs were pre-treated with IL-1receptor1neutralizing antibody(Anti-IL-1R1),then re-stimulated with PolyⅠ:C, cell apoptosis was measured by CCK-8assay.
Results:
1.Caspase8and Caspase9inhibitors did not reduce PolyⅠ:C-induced apoptosis of EPCs.
2. When EPCs were treated with increasing concentration of TNF-α, cell apoptosis was not increase in TNF-α-treated groups.
3. IL-1β induced cell apoptosis in a dose-dependent manner. Moreover, when EPCs pre-treated with Anti-IL-1R1, were re-stimulated with PolyⅠ:C, the cell apoptosis induced by Poly Ⅰ:C was decreased.
Conclusions:PolyⅠ:C induced the apoptosis of EPCs through up-regulating the expression of IL-1β via activating TLR3. Endogenous and exogenous apoptosis pathway and TNF-α did not contribute to PolyⅠ:C-induced cell apoptosis.
Charpter II Pam3CSK4Induces a Non-tolerant Up-regulation of Cytokine in Human Umbilical Vein Endothelial Cells
Part I The Possible Mechanism Responsible for the Effect of Pam3CSK4on the Expression of Cytokines in Human Umbilical Vein Endothelial Cells
Objective:To observe the effects of TLR1/TRL2agonist Pam3CSK4on the expression of cytokines in HUVECs and to elucidate the possible mechanism.
Methods:HUVECs were treated with different concentrations of Pam3CSK4, RT-PCR was used to detect the mRNA expression of TLR1and TLR2. Then, RT-PCR、Real-time RT-PCR and ELISA were performed to detect the effect of Pam3CSK4on the expression of TNF-a and IL-6at both mRNA and protein level. We used specific inhibitors of TLR1、TLR2and TLR1/TLR2to inhibit the corresponding receptors, then tested the effect of TLR1、TLR2inhibition on the expression of TNF-a and IL-6induced by Pam3CSK4. In order to elucidate the signaling pathways involving in this process, Western-blot was performed to detect the phosphorylation of MAPK and NF-κB.
Results:
After treated with different concentrations of Pam3CSK4for24h, the RT-PCR results show that Pam3CSK4could significantly up-regulate the mRNA expression of TLR2,the effect of Pam3CSK4on TLR1mRNA expression was not obvious. Pam3CSK4up-regulated the expression of TNF-α and IL-6at both mRNA and protein level in a dose-dependent manner.TLR1、TLR2and TLR1/TLR2inhibitors could significantly inhibit the up-regulation of TNF-α and IL-6induced by Pam3CSK4,and the inhibition induced by TLR1/TLR2inhibitor was most obvious. The Western-blot results showed that Pam3CSK4could induce the phosphorylation of MAPK and NF-κB signal transduction pathways via TLR2activation.
Conclusions:HUVECs expressed functional TLR2.Pam3CSK4induced the phosphorylation of MAPK and NF-κB signal transduction pathways via TLR2activation,thus significantly up-regulate the expression of TNF-a and IL-6at both mRNA and protein level which was TLR1and TLR2dependent.
Part II Pam3csk4Induces a Non-tolerant Up-regulation of Cytokine IL-6in Human Umbilical Vein Endothelial Cells
Objective:To observe the effect of Pam3CSK4pre-treatment on cytokine expression in HUVECs induced by Pam3CSK4re-treatment and to elucidate the possible mechanism.
Methods:HUVECs, pre-treated with1μg/ml Pam3CSK4for indicated hours, were re-treated with1μg/ml Pam3CSK4for1hour. The gene and protein expression of cytokine IL-6and TNF-a were detected by Real-time RT-PCR and ELISA respectively.Then Real-time RT-PCR and ELISA were performed to detect the effect of various PAMP pre-treatment on cytokine gene and protein expression induced by Pam3CSK4re-treatment,observing the cross-tolerance between different TLRs. Then we used western-blot to detect the phosphorylation of MAPK and NF-κB signal transduction pathways after Pam3CSK4repeating stimulation. The effect of Pam3CSK4on the gene expression of ubiquitin-editing enzyme A20was detected by RT-PCR, and the effect of A20over-expression on cytokine IL-6expression induced by Pam3CSK4and LPS was detected by plasmid transfection. We used inhibitors of Notch signal transduction pathway to inhibit the corresponding signal molecules, then tested the effect of Notch signal transduction pathway inhibition on the expression of IL-6induced by Pam3CSK4.
Results:Pam3CSK4pre-treatment could down-regulate the expression of TNF-a induced by Pam3CSK4at both gene and protein level,but had no effect on the expression of IL-6. LPS pre-treatment could down-regulate the expression of TNF-a induced by Pam3CSK4,but had no effect on the expression of IL-6.The Western-blot results showed that Pam3CSK4repeating stimulation inhibited activation of JNK, without influencing the phospholyration of p38、ERK、NF-κB. Pam3CSK4down-regulated the mRNA expression of ubiquitin-editing enzyme A20in a dose-dependent manner,but A20over-expression had no effect on the the expression of IL-6induced by Pam3CSK4and LPS. Inhibitors of Notch signal transduction pathway could partly inhibit the expression of IL-6induced by Pam3CSK4.
Conclusions:Pam3CSK4induced a tolerant up-regulation of cytokine TNF-a, but induced a non-tolerant up-regulation of cytokine IL-6.There was cross-tolerance between TLR2and TLR4. Pam3CSK4probably induced the non-tolerant up-regulation of cytokine IL-6via Notch signal transduction pathway.
第一节人脐血内皮祖细胞表达Toll样受体的研究
目的：分离纯化人脐静脉血来源的单个核细胞并诱导培养为内皮祖细胞,观察Toll样受体在人脐血内皮祖细胞中的表达情况。
方法：采用密度梯度离心法分离人脐静脉血中的单个核细胞,用含多种生长因子的内皮祖细胞专用EBM-2培养基诱导培养,诱导单个核细胞向内皮祖细胞分化,通过形态学、免疫荧光及逆转录多聚酶链反应(RT-PCR)检测并鉴定细胞的生物学特性；采用RT-PCR法检测静息状态下人内皮祖细胞(EPCs)表达的Toll样受体亚型；检测不同浓度的PolyⅠ:C对内皮祖细胞表达TLR3受体、炎性细胞因子的影响。
结果：
1.分离培养的内皮祖细胞早期以集落为中心呈放射状生长,晚期形成典型的“铺路石”样改变。荧光染色示DiL-acLDL和FITC-UEA-I双染色阳性；RT-PCR法检测示细胞表达干细胞表面标志物CD34、CD133、KDR,证明为内皮祖细胞。
2.静息状态下,内皮祖细胞表达较高水平的TLR1、TLR3、TLR4、TLR6,表达较低水平的TLR2、TLR5、TLR7、TLR8、TLR10,不表达TLR9。而PolyⅠ:C能上调TLR3的mRNA及蛋白表达,并呈量效关系。
3. PolyⅠ:C通过活化TLR3剂量依赖性上调炎性细胞因子IL-1p、IL-6、IL-8、TNF-α、IFN-p的基因表达。
结论：EPCs表达功能性TLR3；PolyⅠ:C能呈剂量依赖性上调TLR3在EPCs的mRNA及蛋白表达,并通过活化TLR3剂量依赖性上调炎性细胞因子的mRNA表达。
第二节PolyⅠ:C对人脐血内皮祖细胞增殖、凋亡的影响
目的：观察TLR3的配体PolyⅠ:C对人脐血内皮祖细胞增殖、凋亡的影响。
方法：采用不同浓度的PolyⅠ:C持续干预人脐血内皮祖细胞(EPCs),通过CCK-8细胞增殖试验检测其对EPCs增殖的影响及时间效应；通过流式细胞术检测不同浓度的PolyⅠ:C对EPCs细胞周期时相分布及细胞凋亡的影响。
结果：
1.与对照组相比,较高浓度PolyⅠ:C(1,10μg/m1)持续作用于脐血内皮祖细胞3天后显著抑制内皮祖细胞增殖；终浓度10μg/ml的PolyⅠ:C呈时间依赖性抑制内皮祖细胞增殖。
2.较高浓度的PolyⅠ:C(1,10μg/m1)显著减少S期和G2/M期细胞比例,并通过下调细胞周期素A,B1,D1,E的表达阻滞细胞周期于G0/G1期而改变细胞周期的时相分布,从而抑制EPCs的增殖。
3. PolyⅠ:C呈剂量依赖性诱导内皮祖细胞凋亡。
结论：高浓度的PolyⅠ:C通过将细胞周期阻滞于G0/G1期并诱导细胞凋亡从而抑制EPCs增殖。
第三节PolyⅠ:C诱导人脐血内皮祖细胞凋亡的机制研究
目的：阐明PolyⅠ:C诱导人脐血内皮祖细胞凋亡的具体机制。
方法：利用Caspase8的抑制剂和Caspase9的抑制剂抑制相应的信号分子,分析其对PolyⅠ:C诱导细胞凋亡的作用。以不同浓度的TNF-α及IL-1β干预EPCs24h后,CCK-8细胞增殖试验分别检测TNF-α和IL-1β对细胞凋亡的影响。利用IL-1β受体的中和抗体Anti-IL-1R1预先封闭IL-1β的结合位点,分析其对PolyⅠ:C诱导细胞凋亡的作用。
结果：
1. Caspase8和9的抑制剂并不能抑制PolyⅠ:C诱导的细胞凋亡。
2.随着TNF-α作用浓度的增高,EPCs的细胞凋亡率并无明显增加。
3.随着IL-1p作用浓度的增高,EPCs的细胞凋亡率逐步增加,并呈剂量依赖性。使用IL-1p受体的中和抗体Anti-IL-1R1预先封闭IL-1p的结合位点后,再加入PolyⅠ:C干预24h,结果显示高浓度的Anti-IL-1R1可以部分抑制PolyⅠ:C诱导的细胞凋亡。
结论：PolyⅠ:C活化TLR3后通过上调IL-1p的表达诱导EPCs凋亡,而内、外源性细胞凋亡途径及TNF-a不参与PolyⅠ:C诱导的细胞凋亡
第二章Pam3CSK4在人脐静脉内皮细胞中诱导非耐受性的细胞因子表达
第一节Pam3CSK4对人脐静脉内皮细胞表达炎症因子的影响及其可能机制
目的：阐明TLR1/2激动剂Pam3CSK4对人脐静脉内皮细胞表达炎症因子的影响及其可能机制。
方法：以不同浓度的Pam3CSK4干预人脐静脉内皮细胞(HUVECs), RT-PCR法检测Pam3CSK4对TLR1、TLR2mRNA表达的影响。用RT-PCR法、Real-time RT-PCR法、ELISA法检测Pam3CSK4对HUVECs分泌TNF-α、IL-6的时间效应及剂量效应。分别用TLR1、TLR2及TLR1阻断剂阻断相应受体的表达,观察其对Pam3CSK4诱导HUVECs分泌TNF-α、IL-6的影响。用Western-blot法检测Pam3CSK4对MAPK家族及NF-κB信号转导通路的活化情况。
结果：Pam3CSK4呈剂量依赖性上调TLR2的mRNA表达,而对TLR1mRNA表达的影响不明显。Pam3CSK4呈剂量依赖性上调TNF-α、IL-6的基因及蛋白表达量。加入TLR1、TLR2、TLR1/2受体阻断剂后均能明显抑制Pam3CSK4诱导的TNF-a、IL-6的基因表达上调,其中以TLR1/2受体阻断剂的阻断作用最明显。Pam3CSK4与TLR2结合后可以不同程度活化MAPK家族和NF-κB信号传导通路。
结论：HUVECs表达功能性TLR2；Pam3CSK4与TLR2结合后活化MAPK家族和NF-κB信号传导通路,从而诱导炎症因子TNF-α、IL-6的分泌,且TNF-α、IL-6的分泌依赖于TLR1及TLR2的表达。
第二节Pam3CSK4在人脐静脉内皮细胞中诱导非耐受性的IL-6表达
目的：阐明预处理的TLR1/2激动剂Pam3CSK4重复刺激对人脐静脉内皮细胞表达炎症因子的影响及其可能机制。
方法：以不同浓度的Pam3CSK4预处理人脐静脉内皮细胞(HUVECs)后,再用Pam3CSK4重复刺激HUVECs,用RT-PCR法、Real-time RT-PCR法、ELISA法检测Pam3CSK4对HUVECs分泌TNF-α、IL-6的影响。用不同TLR受体的配体预处理HUVECs后,再用Pam3CSK4重复刺激HUVECs,以观察不同TLR受体之间的耐受情况。Western-blot法检测Pam3CSK4重复刺激对MAPK家族及NF-κB信号传导通路的活化情况。RT-PCR法检测Pam3CSK4对负性调节蛋白锌指蛋白A20基因表达的影响,然后用质粒转染试验检测A20的过度表达对Pam3CSK4及LPS诱导的IL-6分泌的影响。用Notch信号通路抑制剂抑制相关分子,观察其对Pam3CSK4诱导HUVECs分泌IL-6的影响。
结果：给予HUVECsPam3CSK4预处理后,再给予Pam3CSK4重复刺激可以下调TNF-a的基因及蛋白表达,而对IL-6表达无影响。LPS预处理可以使Pam3CSK4诱导的TNF-α表达下降,而对IL-6表达无影响。Pam3CSK4重复刺激HUVECs能抑制JNK通路的活化,而对p38、ERK、NF-κB信号通路的活化无影响。Pam3CSK4呈剂量依赖性上调负性调节蛋白锌指蛋白A20的基因表达,A20的过度表达对Pam3CSK4及LPS诱导的IL-6分泌无明显影。Notch信号通路抑制剂能部分抑制Pam3CSK4诱导的IL-6分泌。
结论：
1.Pam3CSK4重复刺激可诱导耐受性的TNF-α表达,而诱导非耐受性的IL-6表达。
2.TLR2与TLR4之间存在交叉耐受性。
3.Pam3CSK4可能通过Notch信号通路诱导非耐受性的IL-6表达。
Charpter I The Possible Mechanisms Responsible for the Effects of PolyⅠ:C on the Proliferation of Human Umbilical Cord Blood-Derived Endothelial Progenitor Cells
Part Ⅰ The Expression of Toll-like receptors on the Human Umbilical Cord Blood-Derived Endothelial Progenitor Cells
Objective:To observe the expression of Toll-like receptors on the human umbilical cord blood-derived endothelial progenitor cells (EPCs).
Methods:Mononuclear cells were isolated from fresh cord blood by density gradient centrifugation and cultured in EBM-2medium. The biological features of the isolated cells were observed at different time point and identified by morphology, immunofluorescence staining and RT-PCR. Furthermore, RT-PCR was performed firstly to detect the mRNA expression of Toll-like receptor subtypes in EPCs at rest, secondly the expression of Toll-like receptor3(TLR3)and inflammatory cytokines induced by PolyⅠ:C at different concentrations.
Results:
1. Early EPCs changed from small size round cells to spindle shape cells,Late EPCs formed a typical cobblestone-like cells.Adherent EPCs were characterized by DiLDL uptake and concomitant lectin binding, and by expressing of CD34、CD133and KDR, which are markers of stem cells.
2. RT-PCR results shown that Under basal condition, except TLR9, TLR1～TLR10were expressed in EPCs with high expression levels of TLR1、TLR3、TLR4. TLR6and low expression levels of TLR2、TLR5、 TLR7、TLR8、TLR10. Expression of TLR3was significantly up-regulated by treatment with Poly I:C at both the gene and protein levels and there was dose-effect relationship in experiment range.
3. PolyI:C upregulated the mRNA expression of inflammatory cytokines such as IL-1β、IL-6、IL-8、TNF-α、IFN-β by activating TLR3.
Conclusions:EPCs expressed functional TLR3; PolyI:C can up-regulate the expression of TLR3at both the gene and protein levels and up-regulate the gene expression of inflammatory cytokines in a dose-dependent manner by activating TLR3.
Part Ⅱ The Effect of PolyⅠ:C on the Proliferation and Apoptosis of Human Umbilical Cord Blood-Derived Endothelial Progenitor Cells
Objective:To analyze the effect of TLR3agonist PolyⅠ:C on the proliferation and apoptosis of human umbilical cord blood-derived endothelial progenitor cells.
Methods:EPCs were treated with different concentrations of PolyⅠ: C sequentially for3days, and then cell numbers were measured by CCK-8assay.EPCs were treated with Polyl:C at different concentrations, the phase of cell cycle was tested by PI staining and cell apoptosis was detected by the PI/Annexin V staining.
Results:
1.Compared with the control group, PolyⅠ:C at high concentrations of1and10μg/ml significantly inhibited the proliferation of EPCs after3days treatment, and the inhibition of cell proliferation by Poly I:C was time-dependent.
2. Poly Ⅰ:C at high concentrations of1and10μg/ml significantly decreased the proportion of cells in S phase and G2/M phase. Moreover, Poly Ⅰ:C down-regulated the gene expression of cyclins A, B1, D1, and E, inducing cell cycle arrest in G0/G1phase, thus inhibiting the proliferation of EPCs.
3. PolyI:C induced the apoptosis of EPCs in a dose-dependent manner.
Conclusions:PolyⅠ:C at high concentrations inhibited EPCs proliferation by inducing cell cycle arrest in G0/G1phase and inducing cell anoptosis of EPCs.
Part Ⅲ The Possible Mechanisms Responsible for the Effects of PolyⅠ:C on the Apoptosis of Human Umbilical Cord Blood-Derived Endothelial Progenitor Cells
Objective:To elucidate the mechanism of PolyⅠ:C induced apoptosis in human umbilical cord blood-derived endothelial progenitor cells.
Methods:We used specific inhibitors of Caspase8and Caspase9to inhibit the corresponding signal molecules, then tested the effect of caspase inhibition on Poly Ⅰ:C-induced apoptosis. EPCs were treated with different concentrations of TNF-α and IL-1β for24h respectively,then CCK-8assay was used to detect the apoptosis of EPCs. EPCs were pre-treated with IL-1receptor1neutralizing antibody(Anti-IL-1R1),then re-stimulated with PolyⅠ:C, cell apoptosis was measured by CCK-8assay.
Results:
1.Caspase8and Caspase9inhibitors did not reduce PolyⅠ:C-induced apoptosis of EPCs.
2. When EPCs were treated with increasing concentration of TNF-α, cell apoptosis was not increase in TNF-α-treated groups.
3. IL-1β induced cell apoptosis in a dose-dependent manner. Moreover, when EPCs pre-treated with Anti-IL-1R1, were re-stimulated with PolyⅠ:C, the cell apoptosis induced by Poly Ⅰ:C was decreased.
Conclusions:PolyⅠ:C induced the apoptosis of EPCs through up-regulating the expression of IL-1β via activating TLR3. Endogenous and exogenous apoptosis pathway and TNF-α did not contribute to PolyⅠ:C-induced cell apoptosis.
Charpter II Pam3CSK4Induces a Non-tolerant Up-regulation of Cytokine in Human Umbilical Vein Endothelial Cells
Part I The Possible Mechanism Responsible for the Effect of Pam3CSK4on the Expression of Cytokines in Human Umbilical Vein Endothelial Cells
Objective:To observe the effects of TLR1/TRL2agonist Pam3CSK4on the expression of cytokines in HUVECs and to elucidate the possible mechanism.
Methods:HUVECs were treated with different concentrations of Pam3CSK4, RT-PCR was used to detect the mRNA expression of TLR1and TLR2. Then, RT-PCR、Real-time RT-PCR and ELISA were performed to detect the effect of Pam3CSK4on the expression of TNF-a and IL-6at both mRNA and protein level. We used specific inhibitors of TLR1、TLR2and TLR1/TLR2to inhibit the corresponding receptors, then tested the effect of TLR1、TLR2inhibition on the expression of TNF-a and IL-6induced by Pam3CSK4. In order to elucidate the signaling pathways involving in this process, Western-blot was performed to detect the phosphorylation of MAPK and NF-κB.
Results:
After treated with different concentrations of Pam3CSK4for24h, the RT-PCR results show that Pam3CSK4could significantly up-regulate the mRNA expression of TLR2,the effect of Pam3CSK4on TLR1mRNA expression was not obvious. Pam3CSK4up-regulated the expression of TNF-α and IL-6at both mRNA and protein level in a dose-dependent manner.TLR1、TLR2and TLR1/TLR2inhibitors could significantly inhibit the up-regulation of TNF-α and IL-6induced by Pam3CSK4,and the inhibition induced by TLR1/TLR2inhibitor was most obvious. The Western-blot results showed that Pam3CSK4could induce the phosphorylation of MAPK and NF-κB signal transduction pathways via TLR2activation.
Conclusions:HUVECs expressed functional TLR2.Pam3CSK4induced the phosphorylation of MAPK and NF-κB signal transduction pathways via TLR2activation,thus significantly up-regulate the expression of TNF-a and IL-6at both mRNA and protein level which was TLR1and TLR2dependent.
Part II Pam3csk4Induces a Non-tolerant Up-regulation of Cytokine IL-6in Human Umbilical Vein Endothelial Cells
Objective:To observe the effect of Pam3CSK4pre-treatment on cytokine expression in HUVECs induced by Pam3CSK4re-treatment and to elucidate the possible mechanism.
Methods:HUVECs, pre-treated with1μg/ml Pam3CSK4for indicated hours, were re-treated with1μg/ml Pam3CSK4for1hour. The gene and protein expression of cytokine IL-6and TNF-a were detected by Real-time RT-PCR and ELISA respectively.Then Real-time RT-PCR and ELISA were performed to detect the effect of various PAMP pre-treatment on cytokine gene and protein expression induced by Pam3CSK4re-treatment,observing the cross-tolerance between different TLRs. Then we used western-blot to detect the phosphorylation of MAPK and NF-κB signal transduction pathways after Pam3CSK4repeating stimulation. The effect of Pam3CSK4on the gene expression of ubiquitin-editing enzyme A20was detected by RT-PCR, and the effect of A20over-expression on cytokine IL-6expression induced by Pam3CSK4and LPS was detected by plasmid transfection. We used inhibitors of Notch signal transduction pathway to inhibit the corresponding signal molecules, then tested the effect of Notch signal transduction pathway inhibition on the expression of IL-6induced by Pam3CSK4.
Results:Pam3CSK4pre-treatment could down-regulate the expression of TNF-a induced by Pam3CSK4at both gene and protein level,but had no effect on the expression of IL-6. LPS pre-treatment could down-regulate the expression of TNF-a induced by Pam3CSK4,but had no effect on the expression of IL-6.The Western-blot results showed that Pam3CSK4repeating stimulation inhibited activation of JNK, without influencing the phospholyration of p38、ERK、NF-κB. Pam3CSK4down-regulated the mRNA expression of ubiquitin-editing enzyme A20in a dose-dependent manner,but A20over-expression had no effect on the the expression of IL-6induced by Pam3CSK4and LPS. Inhibitors of Notch signal transduction pathway could partly inhibit the expression of IL-6induced by Pam3CSK4.
Conclusions:Pam3CSK4induced a tolerant up-regulation of cytokine TNF-a, but induced a non-tolerant up-regulation of cytokine IL-6.There was cross-tolerance between TLR2and TLR4. Pam3CSK4probably induced the non-tolerant up-regulation of cytokine IL-6via Notch signal transduction pathway.
引文
[1]R. Ross, "Atherosclerosis—an inflammatory disease," New England Journal of Medicine, vol.340, no.2, pp.115-126,1999.
[2]HristovM,Weber C. Endothelial progenitor cells:haracterization, pathophy-iology, and possible clinical relevance[J]. Cell.Mol. Med,2004,8(4),498-508.
[3]Urbich C, Dimmeler S. Endothelial progenitor cells:characterization and role in vascular biology. Circ Res 2004;95:343-53.
[4]Dzau VD, Gnecchi M, Pachori AS, et al. Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases. Hypertension 2005;46;7.
[5]Kong D, Melo LG, Mangi AA, et al. Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells. Circulation.2004; 109:1769-1775.
[6]Andreou I, Tousoulis D, Tentolouris C, et al. Potential role of endothelial progenitor cells in the pathophysiology of heart failure:Clinical implications and perspectives. Atherosclerosis 2006; 189:247-54.
[7]Nusslein-Volhard C, Lohs-Schardin M, Sander K, et al. A dorso-ventral shift of embryonic primordia in a new maternal-effect mutant of Drosophila. Nature.1980 Jan 31;283(5746):474-6.
[8]Hashimoto C, Hudson KL, Anderson KV.The Toll gene of Drosophila,required for dorsal-ventral embryonic polarity,appears to encode a transmembrane protein. Cell,1988,52:269-279.
[9]Medzhitov R, Preston HP, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature,1997, 388 (6640):394-397.
[10]MakelaSM, Strenge llM, Pietil a TE, et al. Multiple signa ling pathways contribute to synerg-istic TLR ligand dependent cytok ine gene expression in hum an monocyte derived macrophages and dendritic cells [J]. J Leukoc Biol, 2009,85(4):664-672.
[11]Zhu J, Nieto FJ, Home BD,et al. Prospective study of pathogen burden and risk of myocardial infarction or death.Circulation.2001;103(1):45-51.
[12]Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science.1997;275:964-967.
[13]Jin Hur, Chang-Hwan Yoon, Hyo-Soo Kim, et al.Characterization of Two Types of Endothelial Progenitor Cells and Their Different Contributions to Neovasculogenesis. Arterioscler Thromb Vasc Biol 2004,24:288-293.
[14]Keun-Hwa Jung, Jae-Kyu Roh. Circulating Endothelial Progenitor Cells in Cerebrovascular Disease[J]. Journal of Clinical Neurology,2008,4(4):139-147.
[15]J. Nilsson, G. K. Hansson. Autoimmunity in atherosclerosis:a protective response losing control? [J].Journal of Internal Medicine,2008, 263(5):464-478.
[16]Muhlestein JB,Hammond EH,Carlquist JF.et al. Increased incidence of atherosckerotic versus other forms of cardiovascular disease[J]. J Am Coll Cardiol,1996,27:1555-1561.
[17]Mehta JL,Saldeen TGP,Rand K.Interactive role of infection:inflammation and traditional risk factors in atheroslerosis and coronary heart disease[J].J Am Coll Cardial,2001,31:1217-1219.
[18]Joseph A. Vita, Joseph Loscalzo. Shouldering the Risk Factor Burden: Infection, Atherosclerosis, and the Vascular Endothelium [J]. Circulation,2002, 106(2):164-166.
[19]Prasad A, Zhu J, Mincemoyer R, et al. Cytomegalovirus infection is a determinant of endothelial dysfunction and coronary flow reserve. Circulation. 1998;98(suppl Ⅰ):1-244.Abstract.
[20]Dechend R, MaassM, Gieffers J, et al. Chlamydia pneumoniae infection of vascular smooth muscle and endothelial cells activates NF-kappaB and induces tissue factor and PAI-1 expression:a potential link to accelerated arteriosclerosis[J].Circulation,1999,100(13):1369-1373.
[21]Etingin OR, Silverstein RL, Friedman HM,et al. Viral activation of the coagulation cascade:molecular interactions at the surface of infected endothelial cells. Cell.1990;61:657-662.
[22]Stephen E. Epstein. The multiple mechanisms by which infection may contribute to atherosclerosis development and course [J].Circulation Research, 2002,90(1):2-4.
[23]Aderem A, Ulevitch RJ,et al. Toll-like receptors in the induction of the innate immune response [J].Nature.2000,406(6797):782-7.
[24]Kathrin S. Michelsen, Terence M. Doherty, Prediman K. Shah, et al. TLR signaling:an emerging bridge from innate immunity to atherogenesis[J]. The Journal of Immunology,2004,173(10):5901-5907.
[25]Opitz B, Eitel J, Meixenberger K, et al. Role of Toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections. Thromb Haemost.2009; 102:1103-1109.
[26]De Luca K, Frances-Duvert V, Asensio MJ, et al. The TLR1/2 agonist PAM(3)CSK(4) instructs commitment of human hematopoietic stem cells to a myeloid cell fate [J]. Leukemia,2009,23(11):2063-2074.
[27]Liotta F, Angeli R, Cosmi L, et al. Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling[J].Stem Cells,2008, 26(1):279-289.
[28]Okun E, Griffioen KJ, Son TG, et al. TLR2 activation inhibits embryonic neural progenitor cell proliferation[J]. Journal of Neurochemistry,2010, 114(2):462-474.
[29]Sallustio F, De Benedictis L, Castellano G, et al. TLR2 plays a role in the activation of human resident renal stem/progenitor cells[J].The FASEB Journal, 2010,24(2):514-525.
[30]Xiaoyan Xiao, Peng Zhao, Daniel Rodriguez-Pinto, et al. Inflammatory regulation by TLR3 in acute hepatitis[J].The Journal of Immunology,2009, 183(6):3712-3719.
[31]Shi Yin, Bin Gao. Toll-Like Receptor 3 in Liver Diseases[J]. Gastroenterol Res Pract.2010; 2010:750904.
[32]AssmusB,Urbich C,AicherA, et al. HMG-CoA reductase inhibitors reduce se-nescence and increase proliferation of endothelial p rogenitor cells via regulation of cell cycle regulatory genes[J]. Circ Res,2003,92:104921055.
[33]Bahlmann FH, de Groot K,MuellerO, et al. Stimulation of endothelial p rogenitor cells:A new putative therapeutic effect of angiotensin Ⅱ receptor antagonists[J].Hypertension,2005,45 (4):5262529.
[34]Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res.2001;89:el-e7.
[35]Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med.2003;348:593-600.
[36]Nikos Werner, Sonja Kosiol, Tobias Schiegl, et al. Circulating endothelial progenitor cells and cardiovascular outcomes[J].The New England Journal of Medicine,2005,353(10):999-1007.
[37]Schmidt-Lucke C, Rossig L,Fichtlscherer S,et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events:proof of concept for the clinical importance of endogenous vascular repair[J].Circulation,2005,111(22):2981-2987.
[38]Chironi G, Walch L, Pernollet MG, et al. Decreased number of circulating CD34(+)KDR(+) cells in asymptomatic subjects with preclinical atherosclerosis[J].Atherosclerosis2007,191(1):115-120.
[39]Takeda, K., and S. Akira. TLR signaling pathways. Semin. Immunol.2004.16: 3-9.
[40]Beutler, B., K. Hoebe, X. Du.et al. How we detect microbes and respond to them:the Toll-like receptors and their transducers [J]. Leukocyte Biol.2003,74: 479-485.
[41]Aliprantis, A. O., R. B. Yang, et al. The apoptotic signaling pathway activated by Toll-like receptor-2[J].EMBO.2000,19:3325-3336.
[42]蒋廷旺,熊怀民,盛建华,等.TLR3途径诱导多发性骨髓瘤细胞株增殖抑制和凋亡机制研究[J].中华微生物学和免疫学杂志,2011,31(9).
[43]Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T. TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells.J Immunol.2006 Apr 15;176(8):4894-901.
[44]Qun Jiang, Haiming Wei, and Zhigang Tian. Poly Ⅰ:C enhances cycloheximide-induced apoptosis of tumor cells through TLR3 pathway. BMC Cancer.2008; 8:12.
[45]Stephen E. Epstein. The multiple mechanisms by which infection may contribute to atherosclerosis development and course [J]. Circulation Research, 2002,90(1):2-4.
[46]H ansson GK. Inflammation, atherosclerosis, and coronary artery disease[J]. N Eng 1 JM ed,2005,352(16):1685-1695.
[47]Shishido, T., N. Nozaki, S. Yamaguchi,et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction.Circulation. 2003,108:2905-2910.
[48]Hamann L, Gomma A, Schroder NW, et al. A frequent Toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. J Mol Med.2005;83:478-485.
[49]J. Nilsson, G. K. Hansson. Autoimmunity in atherosclerosis:a protective response losing control? [J]. Journal of Internal Medicine,2008, 263(5):464-478.
[50]Keun-Hwa Jung, Jae-Kyu Roh. Circulating Endothelial Progenitor Cells in Cerebrovascular Disease[J].Journal of Clinical Neurology,2008,4(4):139-147.
[51]Jacobson, M. D., Weil, M.& Raff, M. C. Programmed cell death in animal development. Cell,1997,88,347-354.
[52]Yuan, J.& Yankner, B. A. Apoptosis in the nervous system.Nature,2000,407, 802-809.
[53]Danial, N. N.& Korsmeyer, S. J. Cell death:critical control points. Cell,2004,116,205-219.
[54]Kerr JF, Wyllie AH, Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics[J]. Cancer 1972,26:239-257.
[55]Shi, Y. Mechanisms of caspase inhibition and activation during apoptosis. Mol. Cell,2002,9,459-470.
[56]Earnshaw, W. C., Martins, L. M.& Kaufmann, S. H.Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem.1999,68,383-424.
[57]Nagata, S. Fas ligand-induced apoptosis. Annu. Rev. Genet.1999,33,29-55.
[58]Peter, M. E,Krammer, P. H. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ.2003,10,26-35.
[59]Wang, X. The expanding role of mitochondria in apoptosis.Genes Dev.2001,15, 2922-2933.
[60]Matsumoto, M., S. Kikkawa, M. Kohase, et al. Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling. Biochem. Biophys. Res. Commun.2002,293:1364.
[61]Oshiumi, H., M. Matsumoto, K. Funami, et al. TICAM-1, an adapter molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat. Immun.2003,4:161
[62]Matsumoto M, Funami K, Tanabe M, et al. Subcellular Localization of Toll-Like Receptor 3 in Human Dendritic Cells. J Immunol. 2003;171(6):3154-62.
[63]Yan MH, Zhu SY, Duan CL, et al. Expression of TLR3 and IL-8, Eotaxin in the airway smooth muscle cells induced by PolyI:C[J].Chinese Journal of Cellular And Molecular Immunology,2010,26(10):966-968.
[64]Guillot L, Le Goffic R, Bloch S, et al. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus[J].The Journal of Biological Chemistry,2005,280(7):5571-5580.
[65]Scarim, A. L., M. Arnush, et al.Mechanisms of β-cell death in response to double-stranded (ds) RNA and interferon-y. dsRNA-dependent protein kinase apoptosis and nitric oxide-dependent necrosis. Am. J. Pathol.2001,159: 273-283.
[66]Robbins, M. A., L. Maksumova, et al. Nuclear factor-kB translocation mediates double-stranded ribonucleic acid-induced NIT-1β-cell apoptosis and up-regulates caspase-12 and tumor necrosis factor receptorassociated ligand (TRAIL). Endocrinology.2003,144:4616-4625.
[67]Sun R, Zhang Y, Lv Q,et al. Toll-like receptor 3 (TLR3) induces apoptosis via death receptors and mitochondria by up-regulating the transactivating p63 isoform alpha (TAP63alpha). J Biol Chem.2011;286(18):15918-28.
[68]Bruno Salaun, Isabelle Coste, Marie-Clotilde Rissoan, et al. TLR3 can directly trigger apoptosis in human cancer cells[J].The Journal of Immunology,2006, 176(8):4894-4901.
[69]Nystrom T, Nygren A, Sjoholm A. Increased levels of tumour necrosis factor-alpha (TNF-alpha) in patients with type Ⅱ diabetes mellitus after myocardial infarction are related to endothelial dysfunction. Clin Sci (Lond). 2006;110:673-681.
[70]Csiszar A, Ungvari Z. Endothelial dysfunction and vascular inflammation in type 2 diabetes:interaction of AGE/RAGE and TNF-alpha signaling. Am J Physiol Heart Circ Physiol.2008; 295:H475-H476.
[71]Zhang Y, Herbert BS, Rajashekhar G, et al. Premature senescence of highly proliferative endothelial progenitor cells is induced by tumor necrosis factoralpha via the p38 mitogen-activated protein kinase pathway[J].FASEB. 2009;23:1358-1365.
[72]Henrich D, Seebach C, Wilhelm K, et al. High dosage of simvastatin reduces TNF-alpha-induced apoptosis of endothelial progenitor cells but fails to prevent apoptosis induced by IL-lbeta in vitro[J]. Surg Res.2007;142:13-19.
[73]Shengjie Xu, Yanbo Zhao, Lu Yu,et al. Rosiglitazone Attenuates Endothelial Progenitor Cell Apoptosis Induced by TNF-α via ERK/MAPK and NF-κB Signal Pathways [J]. Pharmacol Sci,2011,117,265-274.
[74]Siedlar, M., M. Frankenberger, E. Benkhart,et al. Tolerance induced by the lipopeptide Pam3Cys is due to ablation of IL-1R-associated kinase-1[J].Immunol.2004.173:2736-2745.
[75]Sato, S., F. Nomura, T. Kawai, at al. Synergy and cross-tolerance between toll-like receptor (TLR) 2-and TLR4-mediated signaling pathways[J]. Immunol. 2000.165:7096-7101.
[76]崔新华,王竫华,王大博TNF-a诱导大鼠视网膜神经节细胞凋亡的研究[J].眼科2008,2,108-112.
[77]Siedlar, M., M. Frankenberger, E. Benkhart,et al. Tolerance induced by the lipopeptide Pam3Cys is due to ablation of IL-1R-associated kinase-1[J].Immunol.2004.173:2736-2745.
[78]Jacinto, R., T. Hartung, C. McCall, et al. Lipopolysaccharide- and lipoteichoic acid-induced tolerance and cross-tolerance:distinct alterations in IL-1 receptor-associated kinase[J]. Immunol.2002.168:6136-6141.
[79]Scarim, A. L., M. Arnush, et al.Mechanisms of β-cell death in response to double-stranded (ds) RNA and interferon-y. dsRNA-dependent protein kinase apoptosis and nitric oxide-dependent necrosis. Am. J. Pathol.2001,159: 273-283.
[80]Luscher TF, Barton M. Biology of the endothelium[J]. Clin Cardiol. 1997;20(suppl Ⅱ):Ⅱ-3-Ⅱ-10.
[81]Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis[J]. Circulation.2004; 109:Ⅲ27-32.
[82]H ansson GK. Inflammation, atherosclerosis, and coronary artery disease[J]. N Eng 1 JMed,2005,352(16):1685-1695.
[83]Reiss A B, Glass A D. Atherosclerosis:immune and inflammatory aspects[J]. J Investig Med.2006,54(3):123-131.
[84]Hansson GK, Libby P.The immune response in atherosclerosis:a double-edged sword[J]. Nat Rev Immunol.2006,6(7):508-19.
[85]Edfeldt K, Swedenborg J, Hansson G K, et al. Expression of toll-like receptors in human atherosclerotic lesions:a possible pathway for plaque activation [J]. Circulation.2002,105(10):1158-1161.
[86]Netea MG, van der Graaf C, Van der Meer JW,et al.Toll-like receptors and the host defense against microbial pathogens:bringing specificity to the innate-immune system[J]. Leukoc Biol.2004,75(5):749-55.
[87]Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol.2000,20,197-216.
[88]Kurt-Jones, E. A. Cutting edge:heat shock protein (HSP) 60 activates the innate immune response:CD 14 is an essential receptor for HSP60 activation of mononuclear cells[J]. Immunol.2000,164,13-17.
[89]Shishido, T., N. Nozaki, S. Yamaguchi,et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation. 2003,108:2905-2910.
[90]Favre, J., and J-P. Henry. Role of toll-like receptor 2 and toll like receptor 4 in postischemic coronary endothelial dysfunction in mice (Abstract).Circulation. 2004.110:111-34.
[91]Schoneveld, A. H., D. P. de Kleijn, B. J. Van Middelaar,et al.In vivo evidence for involvement of toll-like receptor 2 in arterial occlusive disease (Abstract).Circulation.2004,110:111-219.
[92]Laman, J. D., A. H. Schoneveld, F. L. Moll, et al. Significance of peptidoglycan, a proinflammatoary bacterial antigen in atherosclerotic arteries and its association with vulnerable plaques.Am. J. Cardiol.2002,90:119-123.
[93]Nijhuis, M. M., Y. van der Graaf, et al. IgM antibody level against pro inflammatory bacterial peptidoglycan is inversely correlated with extent of atherosclerotic disease. Atherosclerosis.2004,173:245-251.
[94]Schoneveld AH et al. Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development. Cardiovasc Res.2005.66: 162-169.
[95]Shishido T et al. Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury. Biochem Biophys Res Commun.2006.345:1446-1453.
[96]Hamann L, Gomma A, Schroder NW, et al. A frequent Toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. J Mol Med.2005;83:478-485.
[97]Ashida K, Miyazaki K, Takayama E,et al. Characterization of the expression of TLR2 (Toll-like receptor 2) and TLR4 on circulating monocytes in coronary artery disease. JAtheroscler Thromb.2005;12:53-60.
[98]T. Ito, R. Amakawa, T. Kaisho, et al., "Interferon-α and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets," Journal of ExperimentalMedicine, vol.195, no.11, pp. 1507-1512,2002.
[99]G. Wick, M. Romen, A. Amberger, et al., "Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue," FASEB Journal, vol.11, no.13, pp. 1199-1207,1997.
[100]M. P. W. Moos, N. John, R. Grabner, et al., "The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.25, no.11,pp.2386-2391,2005.
[101]M. Komai-Koma, L. Jones, G. S. Ogg, et al., "TLR2 is expressed on activated T cells as a costimulatory receptor," Proceedings of the National Academy of Sciences of the United States of America, vol.101, no.9, pp.3029-3034,2004.
[102]M. Wagner, H. Poeck, B. Jahrsdoerfer, et al., "IL-12p70-dependent Thl induction by human B cells requires combined activation with CD40 ligand and CpG DNA," Journal of Immunology, vol.172, no.2, pp.954-963,2004.
[103]Lehner MD, Morath S, Michelsen KS, et al. Induction of cross-tolerance by lipopolysaccharide and highly purified lipoteichoic acid via different Toll-like receptors independent of paracrine mediators[J]. Immunol.2001; 166(8):5161-7.
[104]F. Cao, A. Castrillo, P. Tontonoz, F. Re, and G. I. Byrne, "Chlamydia pneumoniae-induced macrophage foam cell formation is mediated by Toll-like receptor 2," Infection and Immunity, vol.75, no.2, pp.753-759,2007.
[105]] A. Castrillo, S. B. Joseph, S. A. Vaidya, et al., "Crosstalk between LXR and Toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism," Molecular Cell, vol.12, no.4, pp.805-816,2003.
[106]C. Buono, C. J. Binder, G. Stavrakis, J. L. Witztum, L. H. Glimcher, and A. H. Lichtman, "T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses," Proceedings of the National Academy of Sciences of the United States of America, vol.102, no.5, pp.1596-1601,2005.
[107]Nomura F, Akashi S, Sakao Y.Cutting edge:endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression[J]. Immunol.2000;164(7):3476-9.
[108]Kawai T, Adachi O, Ogawa T,Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity.1999; 11(1):115-22.
[109]Medvedev AE, Kopydlowski KM, Vogel SN.Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages:dysregulation of cytokine, chemokine, and toll-like receptor 2 and 4 gene expression[J]. Immunol.2000; 164(11):5564-74.
[110]Medvedev AE, Henneke P, Schromm A,et al.Induction of tolerance to lipopolysaccharide and mycobacterial components in Chinese hamster ovary/CD14 cells is not affected by overexpression of Toll-like receptors 2 or 4[J]. Immunol.2001;167(4):2257-67.
[111]Wang, J. H., M. Doyle, B. J. Manning, et al. Induction of bacterial lipoprotein tolerance is associated with suppression of Toll-like receptor 2 expression[J]. Biol. Chem. 2002.277:36068-36075.
[112]Nakayama, K., S. Okugawa, S. Yanagimoto,et al. Involvement of IRAK-M in peptidoglycan-induced tolerance in macrophages. J. Biol. Chem. 2004.279:6629-6634.
[113]Siedlar, M., M. Frankenberger, E. Benkhart,et al. Tolerance induced by the lipopeptide Pam3Cys is due to ablation of IL-1R-associated kinase-1[J].Immunol.2004.173:2736-2745.
[114]Mizel, S. B., and J. A. Snipes. Gram-negative flagellin-induced self-tolerance is associated with a block in interleukin-1 receptor-associated kinase release from toll-like receptor 5[J]. Biol. Chem.2002.277:22414-22420.
[115]Yeo, S. J., J. G. Yoon, S. C. Hong, and A. K. Yi. CpG DNA induces self and cross-hyporesponsiveness of RAW264.7 cells in response to CpG DNA and lipopolysaccharide:alterations in IL-1 receptor-associated kinase expression[J]. Immunol.2003.170:1052-1061.
[116]Sato, S., F. Nomura, T. Kawai, at al. Synergy and cross-tolerance between toll-like receptor (TLR) 2-and TLR4-mediated signaling pathways[J]. Immunol. 2000.165:7096-7101.
[117]Li, C. H., J. H. Wang, and H. P. Redmond. Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation[J]. Leukocyte Biol.2006.79: 867-875.
[118]Jacinto, R., T. Hartung, C. McCall, et al. Lipopolysaccharide- and lipoteichoic acid-induced tolerance and cross-tolerance:distinct alterations in IL-1 receptor-associated kinase [J]. Immunol.2002.168:6136-6141.
[119]Mizel, S. B., and J. A. Snipes. Gram-negative flagellin-induced self-tolerance is associated with a block in interleukin-1 receptor-associated kinase release from toll-like receptor 5[J]. Biol. Chem.2002.277:22414-22420.
[120]Frantz S et al. (2001) Role of TLR-2 in the activation of nuclear factor-kappa B by oxidative stress in cardiac myocytes. J Biol Chem 276:5197-5203
[121]Oyama J et al. (2004) Reduced myocardial ischemiareperfusion injury in toll-like receptor 4-deficient mice.Circulation 109:784-789
[122]Kimberly Burns,Sophie Janssens,Brian Brissoni,et al.Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4. J Exp Med.2003; 197(2):263-268.
[123]DixitVM, Green S, SarmaV,et al. Tumor necrosis factor-alpha induction ofnovel gene products in human endothelial cells including amacrophage-specific chemotaxin[J]. J BiolChem,1990,265(5):2973-2978.
[124]EvansP C, OvaaH, HamonM,et al. Zinc-fingerproteinA20, a regulator of inflammation cell surviva.I has de-ubiquitinating activity[J].Biochem J,2004, 387(Pt3):727-734.
[125]ArveloM B, Cooper JT, LongoC,et al. A20 protectsmice from galactosamine/lipopolysaccharide acute toxic lethal hepatitis[J].Hepatoloy, 2002,35(3):535-543.
[126]Zhu X et al. (2006) MyD88 and NOS2 are essential for Toll-like receptor 4-mediated survival effect in cardiomyocytes. Am J Physiol Heart Circ Physiol 291:H1900-H1909
[127]吴丽娟,刘国栋,陈伟等,锌指蛋白A20对人单核细胞LPS应答的影响[J].第三军医大学学报2007,29(14).
[128]Zhao Y, Katzman RB, Delmolino LM, et al. The notch regulator MAML1 interacts with p53 and functions as a coactivator. J Biol Chem,2007, 282(16):11969-11981.
[129]Sundaram MV. The love-hate relationship between Ras and Notch.Genes Dev, 2005,19(16):1825-1839.
[130]Ayyanan A, Civenni G, Ciarloni L, et al. Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. Proc Natl Acad Sci U S A,2006,103(10):3799-3804.
[1]Covacu R, Arvidsson L, Andersson A, et al., TLR activation induces TNF-alpha production from adult neural stem/progenitor cells. J Immunol 182:6889-95,2009.
[2]Jager J, Dekker JM, Kooy A, et al., Endothelial Dysfunction and Low-Grade Inflammation Explain Much of the Excess Cardiovascular Mortality in Individuals With Type 2 Diabetes. Arterioscler Thromb Vasc Biol.26:000-009, 2006.
[3]Hornung V,Rothenfusser S,Britsch S,et al., Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodexynucleotides.J Immunol,168: 4531-4537,2002.
[4][4]Akira S,Takeda K, Kaisho T. Toll-like receptors:critical proteins linking innate and acquired immunity[J]. Nat Immunol,2 (8):6752680,2001.
[5]Akira S, Takeda K:Toll-like receptor signalling. Nat Rev Immunol,4:499-511, 2004.
[6]Palliser D, Huang Q, Hacohen N, et al. A role for Toll-like receptor 4 in dendritic cell activation and cytolytic CD8+T cell differentiation in response to a recombinant heat shock fusion protein. J Immunol,172:2885-93,2004.
[7]R. Ross, "Atherosclerosis—an inflammatory disease," New England Journal of Medicine, vol.340, no.2, pp.115-126,1999.
[8]G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan,"Innate and adaptive immunity in the pathogenesis of atherosclerosis," Circulation Research, vol.91, no.4, pp.281-291,2002.
[9]M. Muzio, D. Bosisio, N. Polentarutti, et al., "Differential expression and regulation of Toll-like receptors (TLR) in human leukocytes:selective expression of TLR3 in dendritic cells," Journal of Immunology, vol.164, no. 11, pp.5998-6004,2000.
[10]N. Kadowaki, S. Ho, S. Antonenko, et al., "Subsets of human dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens," Journal of Experimental Medicine, vol.194, no.6, pp. 863-869,2001.
[11]V. Hornung, S. Rothenfusser, S. Britsch, et al., "Quantitative expression of Toll-like receptor 1-10mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides," Journal of Immunology,vol.168, no.9, pp.4531-4537,2002.
[12]N. Kadowaki, S. Ho, S. Antonenko, et al., "Subsets of human dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens," Journal of Experimental Medicine, vol.194, no.6, pp. 863-869,2001.
[13]H.-L. Geng, H.-Q. Lu, L.-Z. Zhang, et al., "Increased expression of Toll like receptor 4 on peripheral-blood mononuclear cells in patients with coronary arteriosclerosis disease," Clinical and Experimental Immunology, vol.143, no.2, pp.269-273,2006.
[14]S. Kuwahata, S. Fujita, K. Orihara, et al., "High expression level of Toll-like receptor 2 onmonocytes is an important risk factor for arteriosclerotic disease,' Atherosclerosis, vol.209, no.1, pp.248-254,2010.
[15]X. H. Xu, P. K. Shah, E. Faure, et al., "Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL,"Circulation, vol.104, no.25, pp.3103-3108, 2001.
[16]P. Holvoet, P. C. Davey, D. De Keyzer, et al., "Oxidized low-density lipoprotein correlates positively with Toll-like receptor 2 and interferon regulatory factor-1 and inversely with superoxide dismutase-1 expression: studies in hypercholesterolemic swine and THP-1 cells," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.26, no.7, pp.1558-1565,2006.
[17]T. Ito, R. Amakawa, T. Kaisho, et al., "Interferon-a and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets," Journal of ExperimentalMedicine, vol.195, no.11, pp. 1507-1512,2002.
[18]M. Matsumoto, K. Funami, M. Tanabe, et al., "Subcellular localization of Toll-like receptor 3 in human dendritic cells,"Journal of Immunology, vol.171, no.6, pp.3154-3162,2003.
[19]S. Bauer, C. J. Kirschning, H. Hacker, et al., "Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition," Proceedings of the National Academyof Sciences of the United States of America, vol.98, no.16, pp.9237-9242,2001.
[20]T. Ito, R. Amakawa, T. Kaisho, et al., "Interferon-a and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets," Journal of ExperimentalMedicine, vol.195, no.11, pp. 1507-1512,2002.
[21]G. Wick, M. Romen, A. Amberger, et al., "Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue," FASEB Journal, vol.11, no.13, pp. 1199-1207,1997.
[22]G. Millonig, H. Niederegger, W. Rabl, et al., "Network of vascular-associated dendritic cells in intima of healthy young individuals," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.21, no.4, pp.503-508,2001.
[23]J. Jongstra-Bilen, M. Haidari, S.-N. Zhu, M. Chen, D. Guha, and M. I. Cybulsky, "Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis," Journal of Experimental Medicine, vol.203,no.9, pp.2073-2083,2006.
[24]M. P. W. Moos, N. John, R. Grabner, et al., "The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.25, no.11,pp.2386-2391,2005.
[25]S. Stemme, B. Faber, J. Holm, O.Wiklund, J. L.Witztum, and G. K. Hansson, "T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein," Proceedings of the National Academy of Sciences of the United States of America, vol.92, no.9, pp.3893-3897,1995.
[26]X. Zhou, A. Nicoletti, R. Elhage, and G. K. Hansson,"Transfer of CD4+ T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice," Circulation, vol.102, no.24, pp.2919-2922,2000.
[27]S. Babu, C. P. Blauvelt, V. Kumaraswami, and T. B. Nutman,"Cutting edge: diminished T cell TLR expression and function modulates the immune response in human filarial infection," Journal of Immunology, vol.176, no.7, pp.3885-3889,2006.
[28]M. Komai-Koma, L. Jones, G. S. Ogg, et al., "TLR2 is expressed on activated T cells as a costimulatory receptor," Proceedings of the National Academy of Sciences of the United States of America, vol.101, no.9, pp.3029-3034,2004.
[29]V. Hornung, S. Rothenfusser, S. Britsch, et al., "Quantitative expression of Toll-like receptor 1-10mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides," Journal of Immunology, vol.168, no.9, pp.4531-4537,2002.
[30]M. Wagner, H. Poeck, B. Jahrsdoerfer, et al., "IL-12p70-dependent Thl induction by human B cells requires combined activation with CD40 ligand and CpG DNA," Journal of Immunology, vol.172, no.2, pp.954-963,2004.
[31]N. L. Bernasconi, N. Onai, and A. Lanzavecchia, "A role for Toll-like receptors in acquired immunity:up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells," Blood, vol.101, no.11, pp.4500-4504,2003.
[32]M. Kulka, L. Alexopoulou, R. A. Flavell, and D. D. Metcalfe,"Activation of mast cells by double-stranded RNA:evidence for activation through Toll-like receptor 3," Journal of Allergy and Clinical Immunology, vol.114, no.1, pp. 174-182,2004.
[33]M. Kaartinen, A. Penttila, and P. T. Kovanen, "Mast cells of two types differing in neutral protease composition in the human aortic intima: demonstration of tryptase-and tryptase/chymase-containing mast cells in normal intimas, fatty streaks, and the shoulder region of atheromas," Arteriosclerosis and Thrombosis, vol.14, no.6, pp.966-972,1994.
[34]C. Erridge, A. Burdess, A. J. Jackson, et al., "Vascular cell responsiveness to Toll-like receptor ligands in carotid atheroma," European Journal of Clinical Investigation, vol.38, no.10, pp.713-720,2008.
[35]O. Pryshchep,W.Ma-Krupa, B. R. Younge, J. J. Goronzy, and C. M. Weyand, "Vessel-specific Toll-like receptor profiles in human medium and large arteries," Circulation, vol.118, no.12, pp.1276-1284,2008.
[36]K. Edfeldt, J. Swedenborg, G. K. Hansson, and Z.-Q. Yan,"Expression of Toll-like receptors in human atherosclerotic lesions:a possible pathway for plaque activation," Circulation, vol.105, no.10, pp.1158-1161,2002.
[37]X. Yang, D. Coriolan, K. Schultz, D. T. Golenbock, and D.Beasley, "Toll-like receptor 2 mediates persistent chemokine release by Chlamydia pneumoniae-infected vascular smooth muscle cells," Arteriosclerosis, Thrombosis, and Vascular Biology,vol.25, no.11, pp.2308-2314,2005.
[38]T.-J. Hong, J.-E. Ban, K.-H. Choi, et al., "TLR-4 agonistic lipopolysaccharide upregulates interleukin-8 at the transcriptional and post-translational level in vascular smooth muscle cells," Vascular Pharmacology, vol.50, no.1-2, pp. 34-39,2009.
[39]X. Yang, D. Coriolan, K. Schultz, D. T. Golenbock, and D. Beasley, "Toll-like receptor 2 mediates persistent chemokine release by Chlamydia pneumoniae-infected vascular smooth muscle cells," Arteriosclerosis, Thrombosis, and Vascular Biology,vol.25, no.11, pp.2308-2314,2005.
[40]A. E. Mullick, K. Soldau, W. B. Kiosses, T. A. Bell Ⅲ, P. S. Tobias, and L. K. Curtiss, "Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events," Journal of Experimental Medicine, vol.205, no.2, pp.373-383,2008.
[41]C. Erridge, A. Burdess, A. J. Jackson, et al., "Vascular cell responsiveness to Toll-like receptor ligands in carotid atheroma," European Journal of Clinical Investigation, vol.38, no.10, pp.713-720,2008.
[42]M. Zakkar, H. Chaudhury, G. Sandvik, et al., "Increased endothelial mitogen-activated protein kinase phosphatase-1 expression suppresses proinflammatory activation at sites that are resistant to atherosclerosis,' Circulation Research, vol.103, no.7, pp.726-732,2008.
[43]K. S.Michelsen, M. H.Wong, P. K. Shah, et al., "Lack of Toll like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E," Proceedings of the National Academy of Sciences of the United States of America, vol.101, no.29, pp. 10679-10684,2004.
[44]B. Y. Ishida, P. J. Blanche, A. V. Nichols, M. Yashar, and B. Paigen, "Effects of atherogenic diet consumption on lipoproteins in mouse strains C57BL/6 and C3H," Journal of Lipid Research, vol.32, no.4, pp.559-568,1991.
[45]W. Shi, N. J. Wang, D. M. Shih, V. Z. Sun, X. Wang, and A. J. Lusis, "Determinants of atherosclerosis susceptibility in the C3H and C57BL/6 mouse model:evidence for involvement of endothelial cells but not blood cells or cholesterol metabolism," Circulation Research, vol.86, no.10, pp.1078-1084, 2000.
[46]C. Monaco, S. M. Gregan, T. J. Navin, B. M. J. Foxwell, A. H. Davies, and M. Feldmann, "Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis," Circulation, vol.120, no.24, pp.2462-2469,2009.
[47]J.-G. Lee, E.-J. Lim, D.-W. Park, S.-H. Lee, J.-R. Kim, and S.-H. Baek, "A combination of Lox-1 and Noxl regulates TLR9- mediated foam cell formation," Cellular Signalling, vol.20, no.12, pp.2266-2275,2008.
[48]F. Cao, A. Castrillo, P. Tontonoz, F. Re, and G. I. Byrne, "Chlamydia pneumoniae-induced macrophage foam cell formation is mediated by Toll-like receptor 2," Infection and Immunity, vol.75, no.2, pp.753-759,2007.
[49]S. E. Doyle, R. M. O'Connell, G. A. Miranda, et al., "Toll-like receptors induce a phagocytic gene program through p38," Journal of Experimental Medicine, vol.199, no.1, pp.81-90,2004.
[50]P. E. Almeida, A. R. Silva, C. M. Maya-Monteiro, et al., "Mycobacterium bovis bacillus Calmette-Guerin infection induces TLR2-dependent peroxisome proliferator-activated receptor gamma expression and activation:functions in inflammation, lipid metabolism, and pathogenesis," Journal of Immunology, vol.183, no.2, pp.1337-1345,2009.
[51]M. R. Kazemi, C.M.McDonald, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold, "Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by Toll-like receptor agonists," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.25, no.6, pp.1220-1224,2005.
[52]K. R. Feingold, M. R. Kazemi, A. L. Magra, et al., "ADRP/ADFP and Mall expression are increased in macrophages treated with TLR agonists,' Atherosclerosis, vol.209, no.1, pp.81-88,2010.
[53]A. Castrillo, S. B. Joseph, S. A. Vaidya, et al., "Crosstalk between LXR and Toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism," Molecular Cell, vol.12, no.4, pp.805-816,2003.
[54]E. Trogan, J. E. Feig, S. Dogan, et al., "Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficientmice," Proceedings of the National Academy of Sciences of the United States of America, vol.103, no.10, pp.3781-3786,2006.
[55]P. Davenport and P. G. Tipping, "The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice,' American Journal of Pathology, vol.163, no.3, pp.1117-1125,2003.
[56]C. Buono, C. J. Binder, G. Stavrakis, J. L. Witztum, L. H. Glimcher, and A. H. Lichtman, "T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses," Proceedings of the National Academy of Sciences of the United States of America, vol.102, no.5, pp.1596-1601,2005.
[57]S. Potteaux, B. Esposito, O. van Oostrom, et al., "Leukocytederived interleukin 10 is required for protection against atherosclerosis in low-density lipoprotein receptor knockout mice," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.24, no.8, pp.1474-1478,2004.
[58]S. Manicassamy, R. Ravindran, J. Deng, et al., "Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity," Nature Medicine, vol.15, no. 4,pp.401-409,2009.
[59]C. F. Yu, W. M. Peng, J. Oldenburg, et al., "Human plasmacytoid dendritic cells support Th17 cell effector function in response to TLR7 ligation," Journal of Immunology, vol.184,no.3, pp.1159-1167,2010.
[60]M.-Y. Chou, L. Fogelstrand, K.Hartvigsen, et al., "Oxidationspecific epitopes are dominant targets of innate natural antibodies in mice and humans," Journal of Clinical Investigation, vol.119, no.5, pp.1335-1349,2009.
[61]M. J. Lewis, T. H. Malik, M. R. Ehrenstein, J. J. Boyle, M. Botto, and D. O. Haskard, "Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice," Circulation, vol.120, no.5, pp.417-426,2009.
[62]Frantz S et al. (2001) Role of TLR-2 in the activation of nuclear factor-kappa B by oxidative stress in cardiac myocytes. J Biol Chem 276:5197-5203
[63]Zhu X et al. (2006) MyD88 and NOS2 are essential for Toll-like receptor 4-mediated survival effect in cardiomyocytes. Am J Physiol Heart Circ Physiol 291:H1900-H1909
[64]Nemoto S et al. (2002) Escherichia coli LPS-induced LV dysfunction:role of toll-like receptor-4 in the adult heart. Am J Physiol Heart Circ Physiol 282: H2316-H2323
[65]Tavener SA et al. (2004) Immune cell Toll-like receptor 4 is required for cardiac myocyte impairment during endotoxemia. Circ Res 95:700-707
[66]Knuefermann P et al. (2004) Toll-like receptor 2 mediates Staphylococcus aureus-induced myocardial dysfunction and cytokine production in the heart.Circulation 110:3693-3698.
[67]Triantafilou K, Orthopoulos G, Vakakis E, Ahmed MA, Golenbock DT, Lepper PM, Triantafilou M. Human cardiac inflammatory responses triggered by Coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent. Cell Microbiol.2005 Aug;7(8):1117-26.
[68]Fuse K,Chan G,Liu Y et al. Myeloid differentiation factor288 plays a crucial role in the pathogenesis of Coxsackievirus B32induced myocarditis and influences type I interferon production [J]. Circulation,2005; 112(15): 22762-2285.
[69]Hardarson H S,Baker J S,Yang Z et al. Toll21ike receptor 3 is an essential component of the innate stress response in virus2induced cardiac injury[J] AmJ Physiol Heart Circ Physiol,2007;292 (1):H2512H258.
[70]Oyama J et al. (2004) Reduced myocardial ischemiareperfusion injury in toll-like receptor 4-deficient mice.Circulation 109:784-789
[71]Hua F, Ha T, Ma J, Li Y, Kelley J, Gao X, Browder IW, Kao RL, Williams DL, Li C.Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism. J Immunol.2007 Jun 1;178(11):7317-24.
[72]Farm J, Musette P, Douin Eehinard V, et al. Toll Like receptor 2 deficient mice mprotected against postischemic coronary endothelial dysfunction [J]. Arterioscer Thromb Vasc Biol,2007,27(5):1064-71.
[73]Ha T et al. (2005) Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload. Cardiovasc Res 68:224-234
[74]Ha T et al. (2006) Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo. Am J Physiol Heart Circ Physiol 290:H985-H994
[75]Freund C et al. (2005) Requirement of nuclear factorkappaB in angiotensin Ⅱ-and isoproterenol-induced cardiac hypertrophy in vivo. Circulation 111:2319-2325.
[76]Birks EJ et al. (2004) Increased toll-like receptor 4 in the myocardium of patients requiring left ventricular assist devices. J Heart Lung Transplant 23: 228-235
[77]Shishido T et al. (2003) Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction.Circulation 108:2905-2910
[78]Nozaki N et al. (2004) Modulation of doxorubicininduced cardiac dysfunction in toll-like receptor-2-knockout mice. Circulation 110:2869-2874
[2]HristovM,Weber C. Endothelial progenitor cells:haracterization, pathophy-iology, and possible clinical relevance[J]. Cell.Mol. Med,2004,8(4),498-508.
[3]Urbich C, Dimmeler S. Endothelial progenitor cells:characterization and role in vascular biology. Circ Res 2004;95:343-53.
[4]Dzau VD, Gnecchi M, Pachori AS, et al. Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases. Hypertension 2005;46;7.
[5]Kong D, Melo LG, Mangi AA, et al. Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells. Circulation.2004; 109:1769-1775.
[6]Andreou I, Tousoulis D, Tentolouris C, et al. Potential role of endothelial progenitor cells in the pathophysiology of heart failure:Clinical implications and perspectives. Atherosclerosis 2006; 189:247-54.
[7]Nusslein-Volhard C, Lohs-Schardin M, Sander K, et al. A dorso-ventral shift of embryonic primordia in a new maternal-effect mutant of Drosophila. Nature.1980 Jan 31;283(5746):474-6.
[8]Hashimoto C, Hudson KL, Anderson KV.The Toll gene of Drosophila,required for dorsal-ventral embryonic polarity,appears to encode a transmembrane protein. Cell,1988,52:269-279.
[9]Medzhitov R, Preston HP, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature,1997, 388 (6640):394-397.
[10]MakelaSM, Strenge llM, Pietil a TE, et al. Multiple signa ling pathways contribute to synerg-istic TLR ligand dependent cytok ine gene expression in hum an monocyte derived macrophages and dendritic cells [J]. J Leukoc Biol, 2009,85(4):664-672.
[11]Zhu J, Nieto FJ, Home BD,et al. Prospective study of pathogen burden and risk of myocardial infarction or death.Circulation.2001;103(1):45-51.
[12]Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science.1997;275:964-967.
[13]Jin Hur, Chang-Hwan Yoon, Hyo-Soo Kim, et al.Characterization of Two Types of Endothelial Progenitor Cells and Their Different Contributions to Neovasculogenesis. Arterioscler Thromb Vasc Biol 2004,24:288-293.
[14]Keun-Hwa Jung, Jae-Kyu Roh. Circulating Endothelial Progenitor Cells in Cerebrovascular Disease[J]. Journal of Clinical Neurology,2008,4(4):139-147.
[15]J. Nilsson, G. K. Hansson. Autoimmunity in atherosclerosis:a protective response losing control? [J].Journal of Internal Medicine,2008, 263(5):464-478.
[16]Muhlestein JB,Hammond EH,Carlquist JF.et al. Increased incidence of atherosckerotic versus other forms of cardiovascular disease[J]. J Am Coll Cardiol,1996,27:1555-1561.
[17]Mehta JL,Saldeen TGP,Rand K.Interactive role of infection:inflammation and traditional risk factors in atheroslerosis and coronary heart disease[J].J Am Coll Cardial,2001,31:1217-1219.
[18]Joseph A. Vita, Joseph Loscalzo. Shouldering the Risk Factor Burden: Infection, Atherosclerosis, and the Vascular Endothelium [J]. Circulation,2002, 106(2):164-166.
[19]Prasad A, Zhu J, Mincemoyer R, et al. Cytomegalovirus infection is a determinant of endothelial dysfunction and coronary flow reserve. Circulation. 1998;98(suppl Ⅰ):1-244.Abstract.
[20]Dechend R, MaassM, Gieffers J, et al. Chlamydia pneumoniae infection of vascular smooth muscle and endothelial cells activates NF-kappaB and induces tissue factor and PAI-1 expression:a potential link to accelerated arteriosclerosis[J].Circulation,1999,100(13):1369-1373.
[21]Etingin OR, Silverstein RL, Friedman HM,et al. Viral activation of the coagulation cascade:molecular interactions at the surface of infected endothelial cells. Cell.1990;61:657-662.
[22]Stephen E. Epstein. The multiple mechanisms by which infection may contribute to atherosclerosis development and course [J].Circulation Research, 2002,90(1):2-4.
[23]Aderem A, Ulevitch RJ,et al. Toll-like receptors in the induction of the innate immune response [J].Nature.2000,406(6797):782-7.
[24]Kathrin S. Michelsen, Terence M. Doherty, Prediman K. Shah, et al. TLR signaling:an emerging bridge from innate immunity to atherogenesis[J]. The Journal of Immunology,2004,173(10):5901-5907.
[25]Opitz B, Eitel J, Meixenberger K, et al. Role of Toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections. Thromb Haemost.2009; 102:1103-1109.
[26]De Luca K, Frances-Duvert V, Asensio MJ, et al. The TLR1/2 agonist PAM(3)CSK(4) instructs commitment of human hematopoietic stem cells to a myeloid cell fate [J]. Leukemia,2009,23(11):2063-2074.
[27]Liotta F, Angeli R, Cosmi L, et al. Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling[J].Stem Cells,2008, 26(1):279-289.
[28]Okun E, Griffioen KJ, Son TG, et al. TLR2 activation inhibits embryonic neural progenitor cell proliferation[J]. Journal of Neurochemistry,2010, 114(2):462-474.
[29]Sallustio F, De Benedictis L, Castellano G, et al. TLR2 plays a role in the activation of human resident renal stem/progenitor cells[J].The FASEB Journal, 2010,24(2):514-525.
[30]Xiaoyan Xiao, Peng Zhao, Daniel Rodriguez-Pinto, et al. Inflammatory regulation by TLR3 in acute hepatitis[J].The Journal of Immunology,2009, 183(6):3712-3719.
[31]Shi Yin, Bin Gao. Toll-Like Receptor 3 in Liver Diseases[J]. Gastroenterol Res Pract.2010; 2010:750904.
[32]AssmusB,Urbich C,AicherA, et al. HMG-CoA reductase inhibitors reduce se-nescence and increase proliferation of endothelial p rogenitor cells via regulation of cell cycle regulatory genes[J]. Circ Res,2003,92:104921055.
[33]Bahlmann FH, de Groot K,MuellerO, et al. Stimulation of endothelial p rogenitor cells:A new putative therapeutic effect of angiotensin Ⅱ receptor antagonists[J].Hypertension,2005,45 (4):5262529.
[34]Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res.2001;89:el-e7.
[35]Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med.2003;348:593-600.
[36]Nikos Werner, Sonja Kosiol, Tobias Schiegl, et al. Circulating endothelial progenitor cells and cardiovascular outcomes[J].The New England Journal of Medicine,2005,353(10):999-1007.
[37]Schmidt-Lucke C, Rossig L,Fichtlscherer S,et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events:proof of concept for the clinical importance of endogenous vascular repair[J].Circulation,2005,111(22):2981-2987.
[38]Chironi G, Walch L, Pernollet MG, et al. Decreased number of circulating CD34(+)KDR(+) cells in asymptomatic subjects with preclinical atherosclerosis[J].Atherosclerosis2007,191(1):115-120.
[39]Takeda, K., and S. Akira. TLR signaling pathways. Semin. Immunol.2004.16: 3-9.
[40]Beutler, B., K. Hoebe, X. Du.et al. How we detect microbes and respond to them:the Toll-like receptors and their transducers [J]. Leukocyte Biol.2003,74: 479-485.
[41]Aliprantis, A. O., R. B. Yang, et al. The apoptotic signaling pathway activated by Toll-like receptor-2[J].EMBO.2000,19:3325-3336.
[42]蒋廷旺,熊怀民,盛建华,等.TLR3途径诱导多发性骨髓瘤细胞株增殖抑制和凋亡机制研究[J].中华微生物学和免疫学杂志,2011,31(9).
[43]Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T. TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells.J Immunol.2006 Apr 15;176(8):4894-901.
[44]Qun Jiang, Haiming Wei, and Zhigang Tian. Poly Ⅰ:C enhances cycloheximide-induced apoptosis of tumor cells through TLR3 pathway. BMC Cancer.2008; 8:12.
[45]Stephen E. Epstein. The multiple mechanisms by which infection may contribute to atherosclerosis development and course [J]. Circulation Research, 2002,90(1):2-4.
[46]H ansson GK. Inflammation, atherosclerosis, and coronary artery disease[J]. N Eng 1 JM ed,2005,352(16):1685-1695.
[47]Shishido, T., N. Nozaki, S. Yamaguchi,et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction.Circulation. 2003,108:2905-2910.
[48]Hamann L, Gomma A, Schroder NW, et al. A frequent Toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. J Mol Med.2005;83:478-485.
[49]J. Nilsson, G. K. Hansson. Autoimmunity in atherosclerosis:a protective response losing control? [J]. Journal of Internal Medicine,2008, 263(5):464-478.
[50]Keun-Hwa Jung, Jae-Kyu Roh. Circulating Endothelial Progenitor Cells in Cerebrovascular Disease[J].Journal of Clinical Neurology,2008,4(4):139-147.
[51]Jacobson, M. D., Weil, M.& Raff, M. C. Programmed cell death in animal development. Cell,1997,88,347-354.
[52]Yuan, J.& Yankner, B. A. Apoptosis in the nervous system.Nature,2000,407, 802-809.
[53]Danial, N. N.& Korsmeyer, S. J. Cell death:critical control points. Cell,2004,116,205-219.
[54]Kerr JF, Wyllie AH, Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics[J]. Cancer 1972,26:239-257.
[55]Shi, Y. Mechanisms of caspase inhibition and activation during apoptosis. Mol. Cell,2002,9,459-470.
[56]Earnshaw, W. C., Martins, L. M.& Kaufmann, S. H.Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem.1999,68,383-424.
[57]Nagata, S. Fas ligand-induced apoptosis. Annu. Rev. Genet.1999,33,29-55.
[58]Peter, M. E,Krammer, P. H. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ.2003,10,26-35.
[59]Wang, X. The expanding role of mitochondria in apoptosis.Genes Dev.2001,15, 2922-2933.
[60]Matsumoto, M., S. Kikkawa, M. Kohase, et al. Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling. Biochem. Biophys. Res. Commun.2002,293:1364.
[61]Oshiumi, H., M. Matsumoto, K. Funami, et al. TICAM-1, an adapter molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat. Immun.2003,4:161
[62]Matsumoto M, Funami K, Tanabe M, et al. Subcellular Localization of Toll-Like Receptor 3 in Human Dendritic Cells. J Immunol. 2003;171(6):3154-62.
[63]Yan MH, Zhu SY, Duan CL, et al. Expression of TLR3 and IL-8, Eotaxin in the airway smooth muscle cells induced by PolyI:C[J].Chinese Journal of Cellular And Molecular Immunology,2010,26(10):966-968.
[64]Guillot L, Le Goffic R, Bloch S, et al. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus[J].The Journal of Biological Chemistry,2005,280(7):5571-5580.
[65]Scarim, A. L., M. Arnush, et al.Mechanisms of β-cell death in response to double-stranded (ds) RNA and interferon-y. dsRNA-dependent protein kinase apoptosis and nitric oxide-dependent necrosis. Am. J. Pathol.2001,159: 273-283.
[66]Robbins, M. A., L. Maksumova, et al. Nuclear factor-kB translocation mediates double-stranded ribonucleic acid-induced NIT-1β-cell apoptosis and up-regulates caspase-12 and tumor necrosis factor receptorassociated ligand (TRAIL). Endocrinology.2003,144:4616-4625.
[67]Sun R, Zhang Y, Lv Q,et al. Toll-like receptor 3 (TLR3) induces apoptosis via death receptors and mitochondria by up-regulating the transactivating p63 isoform alpha (TAP63alpha). J Biol Chem.2011;286(18):15918-28.
[68]Bruno Salaun, Isabelle Coste, Marie-Clotilde Rissoan, et al. TLR3 can directly trigger apoptosis in human cancer cells[J].The Journal of Immunology,2006, 176(8):4894-4901.
[69]Nystrom T, Nygren A, Sjoholm A. Increased levels of tumour necrosis factor-alpha (TNF-alpha) in patients with type Ⅱ diabetes mellitus after myocardial infarction are related to endothelial dysfunction. Clin Sci (Lond). 2006;110:673-681.
[70]Csiszar A, Ungvari Z. Endothelial dysfunction and vascular inflammation in type 2 diabetes:interaction of AGE/RAGE and TNF-alpha signaling. Am J Physiol Heart Circ Physiol.2008; 295:H475-H476.
[71]Zhang Y, Herbert BS, Rajashekhar G, et al. Premature senescence of highly proliferative endothelial progenitor cells is induced by tumor necrosis factoralpha via the p38 mitogen-activated protein kinase pathway[J].FASEB. 2009;23:1358-1365.
[72]Henrich D, Seebach C, Wilhelm K, et al. High dosage of simvastatin reduces TNF-alpha-induced apoptosis of endothelial progenitor cells but fails to prevent apoptosis induced by IL-lbeta in vitro[J]. Surg Res.2007;142:13-19.
[73]Shengjie Xu, Yanbo Zhao, Lu Yu,et al. Rosiglitazone Attenuates Endothelial Progenitor Cell Apoptosis Induced by TNF-α via ERK/MAPK and NF-κB Signal Pathways [J]. Pharmacol Sci,2011,117,265-274.
[74]Siedlar, M., M. Frankenberger, E. Benkhart,et al. Tolerance induced by the lipopeptide Pam3Cys is due to ablation of IL-1R-associated kinase-1[J].Immunol.2004.173:2736-2745.
[75]Sato, S., F. Nomura, T. Kawai, at al. Synergy and cross-tolerance between toll-like receptor (TLR) 2-and TLR4-mediated signaling pathways[J]. Immunol. 2000.165:7096-7101.
[76]崔新华,王竫华,王大博TNF-a诱导大鼠视网膜神经节细胞凋亡的研究[J].眼科2008,2,108-112.
[77]Siedlar, M., M. Frankenberger, E. Benkhart,et al. Tolerance induced by the lipopeptide Pam3Cys is due to ablation of IL-1R-associated kinase-1[J].Immunol.2004.173:2736-2745.
[78]Jacinto, R., T. Hartung, C. McCall, et al. Lipopolysaccharide- and lipoteichoic acid-induced tolerance and cross-tolerance:distinct alterations in IL-1 receptor-associated kinase[J]. Immunol.2002.168:6136-6141.
[79]Scarim, A. L., M. Arnush, et al.Mechanisms of β-cell death in response to double-stranded (ds) RNA and interferon-y. dsRNA-dependent protein kinase apoptosis and nitric oxide-dependent necrosis. Am. J. Pathol.2001,159: 273-283.
[80]Luscher TF, Barton M. Biology of the endothelium[J]. Clin Cardiol. 1997;20(suppl Ⅱ):Ⅱ-3-Ⅱ-10.
[81]Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis[J]. Circulation.2004; 109:Ⅲ27-32.
[82]H ansson GK. Inflammation, atherosclerosis, and coronary artery disease[J]. N Eng 1 JMed,2005,352(16):1685-1695.
[83]Reiss A B, Glass A D. Atherosclerosis:immune and inflammatory aspects[J]. J Investig Med.2006,54(3):123-131.
[84]Hansson GK, Libby P.The immune response in atherosclerosis:a double-edged sword[J]. Nat Rev Immunol.2006,6(7):508-19.
[85]Edfeldt K, Swedenborg J, Hansson G K, et al. Expression of toll-like receptors in human atherosclerotic lesions:a possible pathway for plaque activation [J]. Circulation.2002,105(10):1158-1161.
[86]Netea MG, van der Graaf C, Van der Meer JW,et al.Toll-like receptors and the host defense against microbial pathogens:bringing specificity to the innate-immune system[J]. Leukoc Biol.2004,75(5):749-55.
[87]Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol.2000,20,197-216.
[88]Kurt-Jones, E. A. Cutting edge:heat shock protein (HSP) 60 activates the innate immune response:CD 14 is an essential receptor for HSP60 activation of mononuclear cells[J]. Immunol.2000,164,13-17.
[89]Shishido, T., N. Nozaki, S. Yamaguchi,et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation. 2003,108:2905-2910.
[90]Favre, J., and J-P. Henry. Role of toll-like receptor 2 and toll like receptor 4 in postischemic coronary endothelial dysfunction in mice (Abstract).Circulation. 2004.110:111-34.
[91]Schoneveld, A. H., D. P. de Kleijn, B. J. Van Middelaar,et al.In vivo evidence for involvement of toll-like receptor 2 in arterial occlusive disease (Abstract).Circulation.2004,110:111-219.
[92]Laman, J. D., A. H. Schoneveld, F. L. Moll, et al. Significance of peptidoglycan, a proinflammatoary bacterial antigen in atherosclerotic arteries and its association with vulnerable plaques.Am. J. Cardiol.2002,90:119-123.
[93]Nijhuis, M. M., Y. van der Graaf, et al. IgM antibody level against pro inflammatory bacterial peptidoglycan is inversely correlated with extent of atherosclerotic disease. Atherosclerosis.2004,173:245-251.
[94]Schoneveld AH et al. Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development. Cardiovasc Res.2005.66: 162-169.
[95]Shishido T et al. Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury. Biochem Biophys Res Commun.2006.345:1446-1453.
[96]Hamann L, Gomma A, Schroder NW, et al. A frequent Toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. J Mol Med.2005;83:478-485.
[97]Ashida K, Miyazaki K, Takayama E,et al. Characterization of the expression of TLR2 (Toll-like receptor 2) and TLR4 on circulating monocytes in coronary artery disease. JAtheroscler Thromb.2005;12:53-60.
[98]T. Ito, R. Amakawa, T. Kaisho, et al., "Interferon-α and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets," Journal of ExperimentalMedicine, vol.195, no.11, pp. 1507-1512,2002.
[99]G. Wick, M. Romen, A. Amberger, et al., "Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue," FASEB Journal, vol.11, no.13, pp. 1199-1207,1997.
[100]M. P. W. Moos, N. John, R. Grabner, et al., "The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.25, no.11,pp.2386-2391,2005.
[101]M. Komai-Koma, L. Jones, G. S. Ogg, et al., "TLR2 is expressed on activated T cells as a costimulatory receptor," Proceedings of the National Academy of Sciences of the United States of America, vol.101, no.9, pp.3029-3034,2004.
[102]M. Wagner, H. Poeck, B. Jahrsdoerfer, et al., "IL-12p70-dependent Thl induction by human B cells requires combined activation with CD40 ligand and CpG DNA," Journal of Immunology, vol.172, no.2, pp.954-963,2004.
[103]Lehner MD, Morath S, Michelsen KS, et al. Induction of cross-tolerance by lipopolysaccharide and highly purified lipoteichoic acid via different Toll-like receptors independent of paracrine mediators[J]. Immunol.2001; 166(8):5161-7.
[104]F. Cao, A. Castrillo, P. Tontonoz, F. Re, and G. I. Byrne, "Chlamydia pneumoniae-induced macrophage foam cell formation is mediated by Toll-like receptor 2," Infection and Immunity, vol.75, no.2, pp.753-759,2007.
[105]] A. Castrillo, S. B. Joseph, S. A. Vaidya, et al., "Crosstalk between LXR and Toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism," Molecular Cell, vol.12, no.4, pp.805-816,2003.
[106]C. Buono, C. J. Binder, G. Stavrakis, J. L. Witztum, L. H. Glimcher, and A. H. Lichtman, "T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses," Proceedings of the National Academy of Sciences of the United States of America, vol.102, no.5, pp.1596-1601,2005.
[107]Nomura F, Akashi S, Sakao Y.Cutting edge:endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression[J]. Immunol.2000;164(7):3476-9.
[108]Kawai T, Adachi O, Ogawa T,Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity.1999; 11(1):115-22.
[109]Medvedev AE, Kopydlowski KM, Vogel SN.Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages:dysregulation of cytokine, chemokine, and toll-like receptor 2 and 4 gene expression[J]. Immunol.2000; 164(11):5564-74.
[110]Medvedev AE, Henneke P, Schromm A,et al.Induction of tolerance to lipopolysaccharide and mycobacterial components in Chinese hamster ovary/CD14 cells is not affected by overexpression of Toll-like receptors 2 or 4[J]. Immunol.2001;167(4):2257-67.
[111]Wang, J. H., M. Doyle, B. J. Manning, et al. Induction of bacterial lipoprotein tolerance is associated with suppression of Toll-like receptor 2 expression[J]. Biol. Chem. 2002.277:36068-36075.
[112]Nakayama, K., S. Okugawa, S. Yanagimoto,et al. Involvement of IRAK-M in peptidoglycan-induced tolerance in macrophages. J. Biol. Chem. 2004.279:6629-6634.
[113]Siedlar, M., M. Frankenberger, E. Benkhart,et al. Tolerance induced by the lipopeptide Pam3Cys is due to ablation of IL-1R-associated kinase-1[J].Immunol.2004.173:2736-2745.
[114]Mizel, S. B., and J. A. Snipes. Gram-negative flagellin-induced self-tolerance is associated with a block in interleukin-1 receptor-associated kinase release from toll-like receptor 5[J]. Biol. Chem.2002.277:22414-22420.
[115]Yeo, S. J., J. G. Yoon, S. C. Hong, and A. K. Yi. CpG DNA induces self and cross-hyporesponsiveness of RAW264.7 cells in response to CpG DNA and lipopolysaccharide:alterations in IL-1 receptor-associated kinase expression[J]. Immunol.2003.170:1052-1061.
[116]Sato, S., F. Nomura, T. Kawai, at al. Synergy and cross-tolerance between toll-like receptor (TLR) 2-and TLR4-mediated signaling pathways[J]. Immunol. 2000.165:7096-7101.
[117]Li, C. H., J. H. Wang, and H. P. Redmond. Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation[J]. Leukocyte Biol.2006.79: 867-875.
[118]Jacinto, R., T. Hartung, C. McCall, et al. Lipopolysaccharide- and lipoteichoic acid-induced tolerance and cross-tolerance:distinct alterations in IL-1 receptor-associated kinase [J]. Immunol.2002.168:6136-6141.
[119]Mizel, S. B., and J. A. Snipes. Gram-negative flagellin-induced self-tolerance is associated with a block in interleukin-1 receptor-associated kinase release from toll-like receptor 5[J]. Biol. Chem.2002.277:22414-22420.
[120]Frantz S et al. (2001) Role of TLR-2 in the activation of nuclear factor-kappa B by oxidative stress in cardiac myocytes. J Biol Chem 276:5197-5203
[121]Oyama J et al. (2004) Reduced myocardial ischemiareperfusion injury in toll-like receptor 4-deficient mice.Circulation 109:784-789
[122]Kimberly Burns,Sophie Janssens,Brian Brissoni,et al.Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4. J Exp Med.2003; 197(2):263-268.
[123]DixitVM, Green S, SarmaV,et al. Tumor necrosis factor-alpha induction ofnovel gene products in human endothelial cells including amacrophage-specific chemotaxin[J]. J BiolChem,1990,265(5):2973-2978.
[124]EvansP C, OvaaH, HamonM,et al. Zinc-fingerproteinA20, a regulator of inflammation cell surviva.I has de-ubiquitinating activity[J].Biochem J,2004, 387(Pt3):727-734.
[125]ArveloM B, Cooper JT, LongoC,et al. A20 protectsmice from galactosamine/lipopolysaccharide acute toxic lethal hepatitis[J].Hepatoloy, 2002,35(3):535-543.
[126]Zhu X et al. (2006) MyD88 and NOS2 are essential for Toll-like receptor 4-mediated survival effect in cardiomyocytes. Am J Physiol Heart Circ Physiol 291:H1900-H1909
[127]吴丽娟,刘国栋,陈伟等,锌指蛋白A20对人单核细胞LPS应答的影响[J].第三军医大学学报2007,29(14).
[128]Zhao Y, Katzman RB, Delmolino LM, et al. The notch regulator MAML1 interacts with p53 and functions as a coactivator. J Biol Chem,2007, 282(16):11969-11981.
[129]Sundaram MV. The love-hate relationship between Ras and Notch.Genes Dev, 2005,19(16):1825-1839.
[130]Ayyanan A, Civenni G, Ciarloni L, et al. Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. Proc Natl Acad Sci U S A,2006,103(10):3799-3804.
[1]Covacu R, Arvidsson L, Andersson A, et al., TLR activation induces TNF-alpha production from adult neural stem/progenitor cells. J Immunol 182:6889-95,2009.
[2]Jager J, Dekker JM, Kooy A, et al., Endothelial Dysfunction and Low-Grade Inflammation Explain Much of the Excess Cardiovascular Mortality in Individuals With Type 2 Diabetes. Arterioscler Thromb Vasc Biol.26:000-009, 2006.
[3]Hornung V,Rothenfusser S,Britsch S,et al., Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodexynucleotides.J Immunol,168: 4531-4537,2002.
[4][4]Akira S,Takeda K, Kaisho T. Toll-like receptors:critical proteins linking innate and acquired immunity[J]. Nat Immunol,2 (8):6752680,2001.
[5]Akira S, Takeda K:Toll-like receptor signalling. Nat Rev Immunol,4:499-511, 2004.
[6]Palliser D, Huang Q, Hacohen N, et al. A role for Toll-like receptor 4 in dendritic cell activation and cytolytic CD8+T cell differentiation in response to a recombinant heat shock fusion protein. J Immunol,172:2885-93,2004.
[7]R. Ross, "Atherosclerosis—an inflammatory disease," New England Journal of Medicine, vol.340, no.2, pp.115-126,1999.
[8]G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan,"Innate and adaptive immunity in the pathogenesis of atherosclerosis," Circulation Research, vol.91, no.4, pp.281-291,2002.
[9]M. Muzio, D. Bosisio, N. Polentarutti, et al., "Differential expression and regulation of Toll-like receptors (TLR) in human leukocytes:selective expression of TLR3 in dendritic cells," Journal of Immunology, vol.164, no. 11, pp.5998-6004,2000.
[10]N. Kadowaki, S. Ho, S. Antonenko, et al., "Subsets of human dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens," Journal of Experimental Medicine, vol.194, no.6, pp. 863-869,2001.
[11]V. Hornung, S. Rothenfusser, S. Britsch, et al., "Quantitative expression of Toll-like receptor 1-10mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides," Journal of Immunology,vol.168, no.9, pp.4531-4537,2002.
[12]N. Kadowaki, S. Ho, S. Antonenko, et al., "Subsets of human dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens," Journal of Experimental Medicine, vol.194, no.6, pp. 863-869,2001.
[13]H.-L. Geng, H.-Q. Lu, L.-Z. Zhang, et al., "Increased expression of Toll like receptor 4 on peripheral-blood mononuclear cells in patients with coronary arteriosclerosis disease," Clinical and Experimental Immunology, vol.143, no.2, pp.269-273,2006.
[14]S. Kuwahata, S. Fujita, K. Orihara, et al., "High expression level of Toll-like receptor 2 onmonocytes is an important risk factor for arteriosclerotic disease,' Atherosclerosis, vol.209, no.1, pp.248-254,2010.
[15]X. H. Xu, P. K. Shah, E. Faure, et al., "Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL,"Circulation, vol.104, no.25, pp.3103-3108, 2001.
[16]P. Holvoet, P. C. Davey, D. De Keyzer, et al., "Oxidized low-density lipoprotein correlates positively with Toll-like receptor 2 and interferon regulatory factor-1 and inversely with superoxide dismutase-1 expression: studies in hypercholesterolemic swine and THP-1 cells," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.26, no.7, pp.1558-1565,2006.
[17]T. Ito, R. Amakawa, T. Kaisho, et al., "Interferon-a and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets," Journal of ExperimentalMedicine, vol.195, no.11, pp. 1507-1512,2002.
[18]M. Matsumoto, K. Funami, M. Tanabe, et al., "Subcellular localization of Toll-like receptor 3 in human dendritic cells,"Journal of Immunology, vol.171, no.6, pp.3154-3162,2003.
[19]S. Bauer, C. J. Kirschning, H. Hacker, et al., "Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition," Proceedings of the National Academyof Sciences of the United States of America, vol.98, no.16, pp.9237-9242,2001.
[20]T. Ito, R. Amakawa, T. Kaisho, et al., "Interferon-a and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets," Journal of ExperimentalMedicine, vol.195, no.11, pp. 1507-1512,2002.
[21]G. Wick, M. Romen, A. Amberger, et al., "Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue," FASEB Journal, vol.11, no.13, pp. 1199-1207,1997.
[22]G. Millonig, H. Niederegger, W. Rabl, et al., "Network of vascular-associated dendritic cells in intima of healthy young individuals," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.21, no.4, pp.503-508,2001.
[23]J. Jongstra-Bilen, M. Haidari, S.-N. Zhu, M. Chen, D. Guha, and M. I. Cybulsky, "Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis," Journal of Experimental Medicine, vol.203,no.9, pp.2073-2083,2006.
[24]M. P. W. Moos, N. John, R. Grabner, et al., "The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.25, no.11,pp.2386-2391,2005.
[25]S. Stemme, B. Faber, J. Holm, O.Wiklund, J. L.Witztum, and G. K. Hansson, "T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein," Proceedings of the National Academy of Sciences of the United States of America, vol.92, no.9, pp.3893-3897,1995.
[26]X. Zhou, A. Nicoletti, R. Elhage, and G. K. Hansson,"Transfer of CD4+ T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice," Circulation, vol.102, no.24, pp.2919-2922,2000.
[27]S. Babu, C. P. Blauvelt, V. Kumaraswami, and T. B. Nutman,"Cutting edge: diminished T cell TLR expression and function modulates the immune response in human filarial infection," Journal of Immunology, vol.176, no.7, pp.3885-3889,2006.
[28]M. Komai-Koma, L. Jones, G. S. Ogg, et al., "TLR2 is expressed on activated T cells as a costimulatory receptor," Proceedings of the National Academy of Sciences of the United States of America, vol.101, no.9, pp.3029-3034,2004.
[29]V. Hornung, S. Rothenfusser, S. Britsch, et al., "Quantitative expression of Toll-like receptor 1-10mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides," Journal of Immunology, vol.168, no.9, pp.4531-4537,2002.
[30]M. Wagner, H. Poeck, B. Jahrsdoerfer, et al., "IL-12p70-dependent Thl induction by human B cells requires combined activation with CD40 ligand and CpG DNA," Journal of Immunology, vol.172, no.2, pp.954-963,2004.
[31]N. L. Bernasconi, N. Onai, and A. Lanzavecchia, "A role for Toll-like receptors in acquired immunity:up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells," Blood, vol.101, no.11, pp.4500-4504,2003.
[32]M. Kulka, L. Alexopoulou, R. A. Flavell, and D. D. Metcalfe,"Activation of mast cells by double-stranded RNA:evidence for activation through Toll-like receptor 3," Journal of Allergy and Clinical Immunology, vol.114, no.1, pp. 174-182,2004.
[33]M. Kaartinen, A. Penttila, and P. T. Kovanen, "Mast cells of two types differing in neutral protease composition in the human aortic intima: demonstration of tryptase-and tryptase/chymase-containing mast cells in normal intimas, fatty streaks, and the shoulder region of atheromas," Arteriosclerosis and Thrombosis, vol.14, no.6, pp.966-972,1994.
[34]C. Erridge, A. Burdess, A. J. Jackson, et al., "Vascular cell responsiveness to Toll-like receptor ligands in carotid atheroma," European Journal of Clinical Investigation, vol.38, no.10, pp.713-720,2008.
[35]O. Pryshchep,W.Ma-Krupa, B. R. Younge, J. J. Goronzy, and C. M. Weyand, "Vessel-specific Toll-like receptor profiles in human medium and large arteries," Circulation, vol.118, no.12, pp.1276-1284,2008.
[36]K. Edfeldt, J. Swedenborg, G. K. Hansson, and Z.-Q. Yan,"Expression of Toll-like receptors in human atherosclerotic lesions:a possible pathway for plaque activation," Circulation, vol.105, no.10, pp.1158-1161,2002.
[37]X. Yang, D. Coriolan, K. Schultz, D. T. Golenbock, and D.Beasley, "Toll-like receptor 2 mediates persistent chemokine release by Chlamydia pneumoniae-infected vascular smooth muscle cells," Arteriosclerosis, Thrombosis, and Vascular Biology,vol.25, no.11, pp.2308-2314,2005.
[38]T.-J. Hong, J.-E. Ban, K.-H. Choi, et al., "TLR-4 agonistic lipopolysaccharide upregulates interleukin-8 at the transcriptional and post-translational level in vascular smooth muscle cells," Vascular Pharmacology, vol.50, no.1-2, pp. 34-39,2009.
[39]X. Yang, D. Coriolan, K. Schultz, D. T. Golenbock, and D. Beasley, "Toll-like receptor 2 mediates persistent chemokine release by Chlamydia pneumoniae-infected vascular smooth muscle cells," Arteriosclerosis, Thrombosis, and Vascular Biology,vol.25, no.11, pp.2308-2314,2005.
[40]A. E. Mullick, K. Soldau, W. B. Kiosses, T. A. Bell Ⅲ, P. S. Tobias, and L. K. Curtiss, "Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events," Journal of Experimental Medicine, vol.205, no.2, pp.373-383,2008.
[41]C. Erridge, A. Burdess, A. J. Jackson, et al., "Vascular cell responsiveness to Toll-like receptor ligands in carotid atheroma," European Journal of Clinical Investigation, vol.38, no.10, pp.713-720,2008.
[42]M. Zakkar, H. Chaudhury, G. Sandvik, et al., "Increased endothelial mitogen-activated protein kinase phosphatase-1 expression suppresses proinflammatory activation at sites that are resistant to atherosclerosis,' Circulation Research, vol.103, no.7, pp.726-732,2008.
[43]K. S.Michelsen, M. H.Wong, P. K. Shah, et al., "Lack of Toll like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E," Proceedings of the National Academy of Sciences of the United States of America, vol.101, no.29, pp. 10679-10684,2004.
[44]B. Y. Ishida, P. J. Blanche, A. V. Nichols, M. Yashar, and B. Paigen, "Effects of atherogenic diet consumption on lipoproteins in mouse strains C57BL/6 and C3H," Journal of Lipid Research, vol.32, no.4, pp.559-568,1991.
[45]W. Shi, N. J. Wang, D. M. Shih, V. Z. Sun, X. Wang, and A. J. Lusis, "Determinants of atherosclerosis susceptibility in the C3H and C57BL/6 mouse model:evidence for involvement of endothelial cells but not blood cells or cholesterol metabolism," Circulation Research, vol.86, no.10, pp.1078-1084, 2000.
[46]C. Monaco, S. M. Gregan, T. J. Navin, B. M. J. Foxwell, A. H. Davies, and M. Feldmann, "Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis," Circulation, vol.120, no.24, pp.2462-2469,2009.
[47]J.-G. Lee, E.-J. Lim, D.-W. Park, S.-H. Lee, J.-R. Kim, and S.-H. Baek, "A combination of Lox-1 and Noxl regulates TLR9- mediated foam cell formation," Cellular Signalling, vol.20, no.12, pp.2266-2275,2008.
[48]F. Cao, A. Castrillo, P. Tontonoz, F. Re, and G. I. Byrne, "Chlamydia pneumoniae-induced macrophage foam cell formation is mediated by Toll-like receptor 2," Infection and Immunity, vol.75, no.2, pp.753-759,2007.
[49]S. E. Doyle, R. M. O'Connell, G. A. Miranda, et al., "Toll-like receptors induce a phagocytic gene program through p38," Journal of Experimental Medicine, vol.199, no.1, pp.81-90,2004.
[50]P. E. Almeida, A. R. Silva, C. M. Maya-Monteiro, et al., "Mycobacterium bovis bacillus Calmette-Guerin infection induces TLR2-dependent peroxisome proliferator-activated receptor gamma expression and activation:functions in inflammation, lipid metabolism, and pathogenesis," Journal of Immunology, vol.183, no.2, pp.1337-1345,2009.
[51]M. R. Kazemi, C.M.McDonald, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold, "Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by Toll-like receptor agonists," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.25, no.6, pp.1220-1224,2005.
[52]K. R. Feingold, M. R. Kazemi, A. L. Magra, et al., "ADRP/ADFP and Mall expression are increased in macrophages treated with TLR agonists,' Atherosclerosis, vol.209, no.1, pp.81-88,2010.
[53]A. Castrillo, S. B. Joseph, S. A. Vaidya, et al., "Crosstalk between LXR and Toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism," Molecular Cell, vol.12, no.4, pp.805-816,2003.
[54]E. Trogan, J. E. Feig, S. Dogan, et al., "Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficientmice," Proceedings of the National Academy of Sciences of the United States of America, vol.103, no.10, pp.3781-3786,2006.
[55]P. Davenport and P. G. Tipping, "The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice,' American Journal of Pathology, vol.163, no.3, pp.1117-1125,2003.
[56]C. Buono, C. J. Binder, G. Stavrakis, J. L. Witztum, L. H. Glimcher, and A. H. Lichtman, "T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses," Proceedings of the National Academy of Sciences of the United States of America, vol.102, no.5, pp.1596-1601,2005.
[57]S. Potteaux, B. Esposito, O. van Oostrom, et al., "Leukocytederived interleukin 10 is required for protection against atherosclerosis in low-density lipoprotein receptor knockout mice," Arteriosclerosis, Thrombosis, and Vascular Biology, vol.24, no.8, pp.1474-1478,2004.
[58]S. Manicassamy, R. Ravindran, J. Deng, et al., "Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity," Nature Medicine, vol.15, no. 4,pp.401-409,2009.
[59]C. F. Yu, W. M. Peng, J. Oldenburg, et al., "Human plasmacytoid dendritic cells support Th17 cell effector function in response to TLR7 ligation," Journal of Immunology, vol.184,no.3, pp.1159-1167,2010.
[60]M.-Y. Chou, L. Fogelstrand, K.Hartvigsen, et al., "Oxidationspecific epitopes are dominant targets of innate natural antibodies in mice and humans," Journal of Clinical Investigation, vol.119, no.5, pp.1335-1349,2009.
[61]M. J. Lewis, T. H. Malik, M. R. Ehrenstein, J. J. Boyle, M. Botto, and D. O. Haskard, "Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice," Circulation, vol.120, no.5, pp.417-426,2009.
[62]Frantz S et al. (2001) Role of TLR-2 in the activation of nuclear factor-kappa B by oxidative stress in cardiac myocytes. J Biol Chem 276:5197-5203
[63]Zhu X et al. (2006) MyD88 and NOS2 are essential for Toll-like receptor 4-mediated survival effect in cardiomyocytes. Am J Physiol Heart Circ Physiol 291:H1900-H1909
[64]Nemoto S et al. (2002) Escherichia coli LPS-induced LV dysfunction:role of toll-like receptor-4 in the adult heart. Am J Physiol Heart Circ Physiol 282: H2316-H2323
[65]Tavener SA et al. (2004) Immune cell Toll-like receptor 4 is required for cardiac myocyte impairment during endotoxemia. Circ Res 95:700-707
[66]Knuefermann P et al. (2004) Toll-like receptor 2 mediates Staphylococcus aureus-induced myocardial dysfunction and cytokine production in the heart.Circulation 110:3693-3698.
[67]Triantafilou K, Orthopoulos G, Vakakis E, Ahmed MA, Golenbock DT, Lepper PM, Triantafilou M. Human cardiac inflammatory responses triggered by Coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent. Cell Microbiol.2005 Aug;7(8):1117-26.
[68]Fuse K,Chan G,Liu Y et al. Myeloid differentiation factor288 plays a crucial role in the pathogenesis of Coxsackievirus B32induced myocarditis and influences type I interferon production [J]. Circulation,2005; 112(15): 22762-2285.
[69]Hardarson H S,Baker J S,Yang Z et al. Toll21ike receptor 3 is an essential component of the innate stress response in virus2induced cardiac injury[J] AmJ Physiol Heart Circ Physiol,2007;292 (1):H2512H258.
[70]Oyama J et al. (2004) Reduced myocardial ischemiareperfusion injury in toll-like receptor 4-deficient mice.Circulation 109:784-789
[71]Hua F, Ha T, Ma J, Li Y, Kelley J, Gao X, Browder IW, Kao RL, Williams DL, Li C.Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism. J Immunol.2007 Jun 1;178(11):7317-24.
[72]Farm J, Musette P, Douin Eehinard V, et al. Toll Like receptor 2 deficient mice mprotected against postischemic coronary endothelial dysfunction [J]. Arterioscer Thromb Vasc Biol,2007,27(5):1064-71.
[73]Ha T et al. (2005) Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload. Cardiovasc Res 68:224-234
[74]Ha T et al. (2006) Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo. Am J Physiol Heart Circ Physiol 290:H985-H994
[75]Freund C et al. (2005) Requirement of nuclear factorkappaB in angiotensin Ⅱ-and isoproterenol-induced cardiac hypertrophy in vivo. Circulation 111:2319-2325.
[76]Birks EJ et al. (2004) Increased toll-like receptor 4 in the myocardium of patients requiring left ventricular assist devices. J Heart Lung Transplant 23: 228-235
[77]Shishido T et al. (2003) Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction.Circulation 108:2905-2910
[78]Nozaki N et al. (2004) Modulation of doxorubicininduced cardiac dysfunction in toll-like receptor-2-knockout mice. Circulation 110:2869-2874