TLR4乙酰化/甲基化修饰激活对炎症免疫的调节
摘要
Toll样受体4(Toll Like Receptor4,TLR4)在巨噬细胞的抗感染(特别是抗病毒)过程中发挥重要作用。TLR4可与配体革兰阴性菌的脂多糖(Lipopolysaccharide,LPS)结合,并与MD2、CD14两个分子形成MD2/TLR4/CD14复合体而活化。活化的TLR4激活两条经典的信号转导通路：一条是MyD88依赖性信号转导路径,主要接头蛋白为MAL(TIRAP)和MyD88, TLR4通过招募Mal(TIRAP)/Myd88,激活一系列蛋白酸磷酸化激酶(如TAK1、IKKγ, IKKαA, IKKβ)、导致转录因子NF-κB激活并入核而启动炎症因子基因表达。这些炎症因子如白介素6(Inter leukin 6, IL6)、IL12. IL17.肿瘤坏死因子α(Tumor necrosis factorα, TNFα)的表达释放参与巨噬细胞的炎症免疫反应。另一条是MyD88非依赖性信号转导途径,其主要接头蛋白为TRAM和TRIF。TLR4通过招募TRAM/TRIF,激活另一些蛋白酸磷化激酶(如TBK1、IKKs/IKKi)、导致转录因子干扰素调节因子3(IFN-regulated factor3, IRF3)激活并入核,来诱导包括干扰素β(Interferon beta,IFNβ)的转录,最终引起免疫反应。
丝氨酸磷酸化被认为在TLR4的信号通路(尤其在两条通路的中下游)的激活,起到了至关重要的作用。然而至今为止,TLR4和TLR4的接头蛋白是如何被激活的,却毫无所知。最近,本实验室率先报道的蛋白乙酰化参与I型干扰素受体信号转导(Ref)为TLR4上游信号转导通路得激活提供了极为重要的线索。本论文研究证实了乙酰化和甲基化修饰对LPS引起的TLR4信号通路的激活,细胞因子合成释放以及巨噬细胞的炎症免疫调控功能具有重大的生物学意义。(一)TLR4乙酰化修饰在LPS活化的炎症信号转导中的作用
1、LPS刺激巨噬细胞系Raw264.7细胞后,利用泛乙酰化抗体进行免疫印迹检测发现TLR4可发生乙酰化修饰。免疫荧光法和免疫共沉淀法证实LPS刺激可促进CBP出核并与TLR4相互作用；抑制内源CBP表达后,TLR4乙酰化显著降低,表明CBP介导TLR4的乙酰化修饰。为探索TLR4乙酰化修饰位点,我们构建了两个突变体即第732位和第813赖氨酸(K)分别突变为精氨酸(R)(K732R,K813R),并与CBP共表达后检测乙酰化程度。结果表明,与野生型TLR4相比,两个突变体的乙酰化程度显著降低。质谱法检测到TLR4第813位K发生乙酰化修饰。此外,我们分别制备了K732和K813乙酰化修饰的特异性抗体,发现LPS刺激后TLR4的K732和K813乙酰化显著升高。以上结果表明,LPS刺激可促进CBP介导的TLR4第732位和第813位赖氨酸的乙酰化修饰。
2、应用免疫共沉淀法分析TLR4及其两个突变体K732R和K813R与TRAM、TRIF和MyD88三个接头蛋白的相互作用,结果表明,K732R突变阻断了TLR4与TRIF和MyD88的相互作用,而Κ813R突变阻断了TLR4与TRAM的相互作用。报告基因技术分析显示CBP过表达后,TLR4乙酰化程度增强,导致NF-κB和IRF3反应元件活性增加。相反,Κ732R和K813R突变均可降低IRF3反应元件的活性,而Κ732R突变则还可以使NF-κB反应元件活性降低。在TLR4-/-小鼠骨髓来源的巨噬细胞(Bone Marrow-Derived Macrophage, BMDM)中,应用半定量RT-PCR的方法分析了乙酰化对TLR4两条不同通路终产物的影响,结果显示,Κ732R和K813R突变可分别抑制IFNβ的合成释放,而Κ732R突变还可抑制IL6合成释放。以上结果表明TLR4第732位和第813位赖氨酸的乙酰化分别调控下游不同的信号通路。
3、LPS刺激巨噬细胞系Raw264.7细胞,利用泛乙酰化抗体进行免疫印迹检测发现IRF3可发生乙酰化修饰。抑制内源CBP表达后,IRF3乙酰化显著降低,表明CBP介导IRF3的乙酰化修饰。为探索IRF3乙酰化修饰位点,我们用质谱法检测到IRF3第77位的Κ发生乙酰化修饰。在此基础上,我们构建了突变体Κ77R,并与CBP共表达后检测乙酰化程度。结果表明,与野生型IRF3相比,突变体的乙酰化程度显著降低。免疫印记法分析表明,加入去乙酰化酶6(Histone Deacetylase 6, HDAC 6)后,CBP/P300介导的IRF3的乙酰化程度显著下降,表明HDAC6介导IRF3的去乙酰化。免疫共沉淀法结果显示K77R突变阻断了IRF3二聚体的形成,而去乙酰化酶的抑制剂曲古抑菌素(Trichostatin A, TSA)和烟酰胺(Nicotinamide,NAM)则增强IRF3二聚体间的相互作用。免疫荧光法证实抑制内源CBP和K77R突变均能阻止IRF3入核。以上结果表明LPS诱导的乙酰化促进IRF3形成二聚体然后进入细胞核。
主要结论：(1)LPS通过CBP介导TLR4第732位和第813位赖氨酸发生乙酰化修饰；(2)TLR4第732位赖氨酸的乙酰化参与了MyD88和TRAM/TRIF介导的信号通路的活化,而第813位赖氨酸的乙酰化则仅仅参与了TRAM/TRIF介导的信号通路的活化；(3)LPS诱导第77位赖氨酸的乙酰化促进IRF3形成二聚体进入细胞核。(二)TLR4甲基化修饰在LPS活化的炎症信号转导中的作用
1、免疫共沉淀法分析表明TLR4可以与IRF3直接相互作用。LPS刺激巨噬细胞系Raw264.7细胞,利用泛甲基抗体进行免疫印迹检测发现TLR4可发生甲基化修饰。为探索TLR4甲基化修饰位点,我们构建两个突变体R731K,R812K,并与甲基化转移酶PRMT2共表达后检测甲基化程度。结果表明,与野生型TLR4相比,两个突变体的甲基化显著降低。以上结果表明,LPS刺激可促进PRMT2介导的TLR4第731位和第812位精氨酸的甲基化修饰
2、应用免疫共沉淀法分析TLR4及其两个突变体R731K和R812K与IRF3的相互作用,结果表明,R812K突变阻断了TLR4与IRF3的相互作用。IRF3 R285K的突变也阻断TLR4与IRF3的相互作用。报告基因技术分析表明PRMT2过表达后,TLR4甲基化程度增强,导致IRF3反应元件活性增加。相反,R812K突变则降低IRF3反应元件的活性。在BMDM细胞中,用定量RT-PCR的方法检测了甲基化对TLR4-IRF3信号通路终产物的影响,结果显示,TLR4 R812K突变抑制IFNβ的合成释放。同样的结论在在293T细胞中也获得。以上结果表明,TLR4第812位精氨酸甲基化参与了IRF3的活化及其与TLR4的相互作用。
3、LPS刺激巨噬细胞系Raw264.7细胞,利用泛甲基抗体进行免疫印迹检测发现IRF3可发生甲基化修饰。为探索IRF3甲基化修饰位点,我们构建了突变体R285K,并与PRMT2共表达后检测甲基化程度。结果表明,与野生型IRF3相比,突变体的甲基化程度显著降低。免疫共沉淀法和免疫荧光法证实R285K突变阻断了IRF3二聚体的形成并且阻止其进入细胞核。以上结果表明,LPS诱导的甲基化促进IRF3形成二聚体进入细胞核。
主要结论：(1)LPS通过PRMT2介导TLR4第731位和第812位精氨酸发生甲基化修饰；(2)TLR4第812位精氨酸的甲基化参与了其与IRF3的直接相互作用以及IRF3的活化；(3)LPS诱导第285位精氨酸的甲基化促进IRF3形成二聚体进入细胞核。
Toll like receptor 4 (TLR4) plays a crucial role in anti-infection, especially antiviral responses. Upon LPS binding, TLR4 is activated, forms a complex with CD 14, MD2, and then triggers downstream signal pathways. One of them is dependent on myeloid differentiation factor 88(MyD88). Through binding to TIR domain containing adaptor protein(TIRAP) and MyD88, TLR4 activates the nuclear factor kappa B(NF-κB), which translocates to the nucleus and induces the expressions of a number of anti-inflammatory genes such as interleukin 6 (IL6), IL12, IL17, and tumor necrosis factor a(TNF-a). The other pathway is MyD88-independent. Through binding to TIR domain containing adaptor protein inducing IFNβ(TRIF) and TRIF related adaptor molecule(TRAM), TLR4 activates IFN-regulated factor-3(IRF3) and IRF7, which induce the expressions of a series of antiviral genes including interferon beta (IFN(3).
Posttranslational modifications, including acetylation and methylation, are crucial for gene transcription and signal transduction. However, the posttranslational modifications of TLR4 are largely unknown. Here we explored TLR4 acetylation and methylation in TLR4 activation.
I. The role of TLR4 acetylation in inflammatory signal transduction activated by LPS
1. Western blot analysis using a pan-acetylation antibody showed that TLR4 was acetylated after LPS stimulation in Raw264.7 cells. Immunofluorescence (IF) analysis showed that creb-binding protein (CBP) translocated to the cytoplasm upon LPS stimulation. Co-immunoprecipitation (Co-IP) experiments showed that LPS stimulation induced the binding of CBP to TLR4. TLR4 acetylation was reduced when CBP expression was down-regulated, indicating that CBP mediated TLR4 acetylation. The acetylation of TLR4 significantly decreased when lysine 732 (K732) or lysine 813 (K813) was mutated to arginine (R). Mass spectrometry analysis recovered K813 as the acetylation site. In addition, LPS-stimulated TLR4 acetylation was detected by specific antibodies targeting acetyl-K732 and acetyl-K813. Altogether, our data strongly indicated that LPS induced TLR4 K813 and K732 acetylation which was mediated by CBP.
2. K732R mutation interrupted the interaction between TLR4 with TRIF and MyD88, while K813R mutation interrupted the interaction between TLR4 and TRAM. Luciferase analysis demonstrated that enhancement of TLR4 acetylation by overexpression of CBP increased the activities of NF-κB-and IRF3-responsive elements. Both K732R and K813R mutations decreased the IRF3-responsive element activity, besides K732R mutation decreased the NF-KB-responsive element activity. Reverse transcription PCR analysis revealed that both K732R and K813R mutations inhibited the production of IFN(3 in bone marrow-derived macrophage (BMDM) from TLR4-/-mouse, while only K732R mutation inhibited the production of IL6. The above results indicated that the acetylation of lysine 732 and 813 differentially regulated downstream signaling pathways.
3. Western blot analysis using a pan-acetylation antibody showed that IRF3 was acetylated after LPS stimulation in Raw264.7 cells. IRF3 acetylation was reduced when CBP expression was down-regulated, indicating that CBP mediated IRF3 acetylation. Mass spectrometry analysis recovered K77 as the acetylation site. The acetylation of IRF3 significantly decreased when lysine 77 was mutated to arginine. IRF3 acetylation was significantly reduced when histone deacetylase 6 (HDAC6) was overexpressed, indicating that HDAC6 mediated IRF3 deacetylation. Co-IP analysis showed that K77R mutation interrupted IRF3 dimerization. The inhibitors of deacetylase trichostatin A (TSA) and nicotinamide (NAM) increased IRF3 dimerization. Both down-regulating CBP expression and K77R mutation prevented IRF3 from translocating to the nucleus. The above results indicated that acetylation at K77 induced by LPS promoted IRF3 dimerization and transloction to the nucleus.
Main conclusions:(1)LPS induced TLR4 K732 and K813 acetylation mediated by CBP.(2) Acetylation at K732 is essential for both MyD88-and TRAM/TRIF-mediated signaling pathways activation, while acetylation at K813 is essential for TRAM/TRIF-mediated signaling activation. (3)Acetylation at K77 induced by LPS promoted IRF3 dimerization and transloction to the nucleus.
Ⅱ. The role of TLR4 methylation in inflammatory signal transduction activated by LPS
1. Co-IP analysis showed that TLR4 bound to IRF3 directly. Western blot analysis showed that TLR4 was methylated after LPS stimulation. Overexpression of PRMT2 increased TLR4 methylation. The methylation significantly decreased when R731 or R812 was mutated to K, indicating that LPS induced TLR4 methylation at R731 and R812.
2. Co-IP analysis showed that R812K mutation interrupted the interaction between TLR4 and IRF3. Luciferase analysis showed that enhancement of TLR4 methylation by overexpression of PRMT2 increased the activities of IRF3-responsive elements, while R812K mutation decreased it. RT-PCR analysis revealed that TLR4 R812K mutation inhibited the production of IFNβin BMDM from TLR4-/-mouse. These data indicated that R812 methylation is essential for TLR4 binding to IRF3 and IRF3 activation.
3. Western blot analysis also showed that IRF3 was methylated under LPS stimulation. The methylation of IRF3 significantly decreased when R285 was mutated to K. Co-IP analysis showed R285K mutation in IRF3 interrupted its dimerization and prevented IRF3 from translocating to the nucleus. The above results indicated that methylation induced by LPS promoted IRF3 dimerization and transloction to nucleus.
Main conclusions:(1)LPS induced TLR4 R731 and R812 methylation mediated by PRMT2. (2)TLR4 R812 methylation mediated the direct interaction between TLR4 and IRF3 and IRF3 activation. (3)Methylation at R285 induced by LPS promoted IRF3 dimerization and transloction to the nucleus.
丝氨酸磷酸化被认为在TLR4的信号通路(尤其在两条通路的中下游)的激活,起到了至关重要的作用。然而至今为止,TLR4和TLR4的接头蛋白是如何被激活的,却毫无所知。最近,本实验室率先报道的蛋白乙酰化参与I型干扰素受体信号转导(Ref)为TLR4上游信号转导通路得激活提供了极为重要的线索。本论文研究证实了乙酰化和甲基化修饰对LPS引起的TLR4信号通路的激活,细胞因子合成释放以及巨噬细胞的炎症免疫调控功能具有重大的生物学意义。(一)TLR4乙酰化修饰在LPS活化的炎症信号转导中的作用
1、LPS刺激巨噬细胞系Raw264.7细胞后,利用泛乙酰化抗体进行免疫印迹检测发现TLR4可发生乙酰化修饰。免疫荧光法和免疫共沉淀法证实LPS刺激可促进CBP出核并与TLR4相互作用；抑制内源CBP表达后,TLR4乙酰化显著降低,表明CBP介导TLR4的乙酰化修饰。为探索TLR4乙酰化修饰位点,我们构建了两个突变体即第732位和第813赖氨酸(K)分别突变为精氨酸(R)(K732R,K813R),并与CBP共表达后检测乙酰化程度。结果表明,与野生型TLR4相比,两个突变体的乙酰化程度显著降低。质谱法检测到TLR4第813位K发生乙酰化修饰。此外,我们分别制备了K732和K813乙酰化修饰的特异性抗体,发现LPS刺激后TLR4的K732和K813乙酰化显著升高。以上结果表明,LPS刺激可促进CBP介导的TLR4第732位和第813位赖氨酸的乙酰化修饰。
2、应用免疫共沉淀法分析TLR4及其两个突变体K732R和K813R与TRAM、TRIF和MyD88三个接头蛋白的相互作用,结果表明,K732R突变阻断了TLR4与TRIF和MyD88的相互作用,而Κ813R突变阻断了TLR4与TRAM的相互作用。报告基因技术分析显示CBP过表达后,TLR4乙酰化程度增强,导致NF-κB和IRF3反应元件活性增加。相反,Κ732R和K813R突变均可降低IRF3反应元件的活性,而Κ732R突变则还可以使NF-κB反应元件活性降低。在TLR4-/-小鼠骨髓来源的巨噬细胞(Bone Marrow-Derived Macrophage, BMDM)中,应用半定量RT-PCR的方法分析了乙酰化对TLR4两条不同通路终产物的影响,结果显示,Κ732R和K813R突变可分别抑制IFNβ的合成释放,而Κ732R突变还可抑制IL6合成释放。以上结果表明TLR4第732位和第813位赖氨酸的乙酰化分别调控下游不同的信号通路。
3、LPS刺激巨噬细胞系Raw264.7细胞,利用泛乙酰化抗体进行免疫印迹检测发现IRF3可发生乙酰化修饰。抑制内源CBP表达后,IRF3乙酰化显著降低,表明CBP介导IRF3的乙酰化修饰。为探索IRF3乙酰化修饰位点,我们用质谱法检测到IRF3第77位的Κ发生乙酰化修饰。在此基础上,我们构建了突变体Κ77R,并与CBP共表达后检测乙酰化程度。结果表明,与野生型IRF3相比,突变体的乙酰化程度显著降低。免疫印记法分析表明,加入去乙酰化酶6(Histone Deacetylase 6, HDAC 6)后,CBP/P300介导的IRF3的乙酰化程度显著下降,表明HDAC6介导IRF3的去乙酰化。免疫共沉淀法结果显示K77R突变阻断了IRF3二聚体的形成,而去乙酰化酶的抑制剂曲古抑菌素(Trichostatin A, TSA)和烟酰胺(Nicotinamide,NAM)则增强IRF3二聚体间的相互作用。免疫荧光法证实抑制内源CBP和K77R突变均能阻止IRF3入核。以上结果表明LPS诱导的乙酰化促进IRF3形成二聚体然后进入细胞核。
主要结论：(1)LPS通过CBP介导TLR4第732位和第813位赖氨酸发生乙酰化修饰；(2)TLR4第732位赖氨酸的乙酰化参与了MyD88和TRAM/TRIF介导的信号通路的活化,而第813位赖氨酸的乙酰化则仅仅参与了TRAM/TRIF介导的信号通路的活化；(3)LPS诱导第77位赖氨酸的乙酰化促进IRF3形成二聚体进入细胞核。(二)TLR4甲基化修饰在LPS活化的炎症信号转导中的作用
1、免疫共沉淀法分析表明TLR4可以与IRF3直接相互作用。LPS刺激巨噬细胞系Raw264.7细胞,利用泛甲基抗体进行免疫印迹检测发现TLR4可发生甲基化修饰。为探索TLR4甲基化修饰位点,我们构建两个突变体R731K,R812K,并与甲基化转移酶PRMT2共表达后检测甲基化程度。结果表明,与野生型TLR4相比,两个突变体的甲基化显著降低。以上结果表明,LPS刺激可促进PRMT2介导的TLR4第731位和第812位精氨酸的甲基化修饰
2、应用免疫共沉淀法分析TLR4及其两个突变体R731K和R812K与IRF3的相互作用,结果表明,R812K突变阻断了TLR4与IRF3的相互作用。IRF3 R285K的突变也阻断TLR4与IRF3的相互作用。报告基因技术分析表明PRMT2过表达后,TLR4甲基化程度增强,导致IRF3反应元件活性增加。相反,R812K突变则降低IRF3反应元件的活性。在BMDM细胞中,用定量RT-PCR的方法检测了甲基化对TLR4-IRF3信号通路终产物的影响,结果显示,TLR4 R812K突变抑制IFNβ的合成释放。同样的结论在在293T细胞中也获得。以上结果表明,TLR4第812位精氨酸甲基化参与了IRF3的活化及其与TLR4的相互作用。
3、LPS刺激巨噬细胞系Raw264.7细胞,利用泛甲基抗体进行免疫印迹检测发现IRF3可发生甲基化修饰。为探索IRF3甲基化修饰位点,我们构建了突变体R285K,并与PRMT2共表达后检测甲基化程度。结果表明,与野生型IRF3相比,突变体的甲基化程度显著降低。免疫共沉淀法和免疫荧光法证实R285K突变阻断了IRF3二聚体的形成并且阻止其进入细胞核。以上结果表明,LPS诱导的甲基化促进IRF3形成二聚体进入细胞核。
主要结论：(1)LPS通过PRMT2介导TLR4第731位和第812位精氨酸发生甲基化修饰；(2)TLR4第812位精氨酸的甲基化参与了其与IRF3的直接相互作用以及IRF3的活化；(3)LPS诱导第285位精氨酸的甲基化促进IRF3形成二聚体进入细胞核。
Toll like receptor 4 (TLR4) plays a crucial role in anti-infection, especially antiviral responses. Upon LPS binding, TLR4 is activated, forms a complex with CD 14, MD2, and then triggers downstream signal pathways. One of them is dependent on myeloid differentiation factor 88(MyD88). Through binding to TIR domain containing adaptor protein(TIRAP) and MyD88, TLR4 activates the nuclear factor kappa B(NF-κB), which translocates to the nucleus and induces the expressions of a number of anti-inflammatory genes such as interleukin 6 (IL6), IL12, IL17, and tumor necrosis factor a(TNF-a). The other pathway is MyD88-independent. Through binding to TIR domain containing adaptor protein inducing IFNβ(TRIF) and TRIF related adaptor molecule(TRAM), TLR4 activates IFN-regulated factor-3(IRF3) and IRF7, which induce the expressions of a series of antiviral genes including interferon beta (IFN(3).
Posttranslational modifications, including acetylation and methylation, are crucial for gene transcription and signal transduction. However, the posttranslational modifications of TLR4 are largely unknown. Here we explored TLR4 acetylation and methylation in TLR4 activation.
I. The role of TLR4 acetylation in inflammatory signal transduction activated by LPS
1. Western blot analysis using a pan-acetylation antibody showed that TLR4 was acetylated after LPS stimulation in Raw264.7 cells. Immunofluorescence (IF) analysis showed that creb-binding protein (CBP) translocated to the cytoplasm upon LPS stimulation. Co-immunoprecipitation (Co-IP) experiments showed that LPS stimulation induced the binding of CBP to TLR4. TLR4 acetylation was reduced when CBP expression was down-regulated, indicating that CBP mediated TLR4 acetylation. The acetylation of TLR4 significantly decreased when lysine 732 (K732) or lysine 813 (K813) was mutated to arginine (R). Mass spectrometry analysis recovered K813 as the acetylation site. In addition, LPS-stimulated TLR4 acetylation was detected by specific antibodies targeting acetyl-K732 and acetyl-K813. Altogether, our data strongly indicated that LPS induced TLR4 K813 and K732 acetylation which was mediated by CBP.
2. K732R mutation interrupted the interaction between TLR4 with TRIF and MyD88, while K813R mutation interrupted the interaction between TLR4 and TRAM. Luciferase analysis demonstrated that enhancement of TLR4 acetylation by overexpression of CBP increased the activities of NF-κB-and IRF3-responsive elements. Both K732R and K813R mutations decreased the IRF3-responsive element activity, besides K732R mutation decreased the NF-KB-responsive element activity. Reverse transcription PCR analysis revealed that both K732R and K813R mutations inhibited the production of IFN(3 in bone marrow-derived macrophage (BMDM) from TLR4-/-mouse, while only K732R mutation inhibited the production of IL6. The above results indicated that the acetylation of lysine 732 and 813 differentially regulated downstream signaling pathways.
3. Western blot analysis using a pan-acetylation antibody showed that IRF3 was acetylated after LPS stimulation in Raw264.7 cells. IRF3 acetylation was reduced when CBP expression was down-regulated, indicating that CBP mediated IRF3 acetylation. Mass spectrometry analysis recovered K77 as the acetylation site. The acetylation of IRF3 significantly decreased when lysine 77 was mutated to arginine. IRF3 acetylation was significantly reduced when histone deacetylase 6 (HDAC6) was overexpressed, indicating that HDAC6 mediated IRF3 deacetylation. Co-IP analysis showed that K77R mutation interrupted IRF3 dimerization. The inhibitors of deacetylase trichostatin A (TSA) and nicotinamide (NAM) increased IRF3 dimerization. Both down-regulating CBP expression and K77R mutation prevented IRF3 from translocating to the nucleus. The above results indicated that acetylation at K77 induced by LPS promoted IRF3 dimerization and transloction to the nucleus.
Main conclusions:(1)LPS induced TLR4 K732 and K813 acetylation mediated by CBP.(2) Acetylation at K732 is essential for both MyD88-and TRAM/TRIF-mediated signaling pathways activation, while acetylation at K813 is essential for TRAM/TRIF-mediated signaling activation. (3)Acetylation at K77 induced by LPS promoted IRF3 dimerization and transloction to the nucleus.
Ⅱ. The role of TLR4 methylation in inflammatory signal transduction activated by LPS
1. Co-IP analysis showed that TLR4 bound to IRF3 directly. Western blot analysis showed that TLR4 was methylated after LPS stimulation. Overexpression of PRMT2 increased TLR4 methylation. The methylation significantly decreased when R731 or R812 was mutated to K, indicating that LPS induced TLR4 methylation at R731 and R812.
2. Co-IP analysis showed that R812K mutation interrupted the interaction between TLR4 and IRF3. Luciferase analysis showed that enhancement of TLR4 methylation by overexpression of PRMT2 increased the activities of IRF3-responsive elements, while R812K mutation decreased it. RT-PCR analysis revealed that TLR4 R812K mutation inhibited the production of IFNβin BMDM from TLR4-/-mouse. These data indicated that R812 methylation is essential for TLR4 binding to IRF3 and IRF3 activation.
3. Western blot analysis also showed that IRF3 was methylated under LPS stimulation. The methylation of IRF3 significantly decreased when R285 was mutated to K. Co-IP analysis showed R285K mutation in IRF3 interrupted its dimerization and prevented IRF3 from translocating to the nucleus. The above results indicated that methylation induced by LPS promoted IRF3 dimerization and transloction to nucleus.
Main conclusions:(1)LPS induced TLR4 R731 and R812 methylation mediated by PRMT2. (2)TLR4 R812 methylation mediated the direct interaction between TLR4 and IRF3 and IRF3 activation. (3)Methylation at R285 induced by LPS promoted IRF3 dimerization and transloction to the nucleus.
引文
[1]Staudinger JL, Xu C, Biswas A, et al. Post-translational modification of pregnane x receptor. Pharmacol Res,2011:1-7
[2]Vissers, J.H.A., Nicassio, et al. The many faces of ubiquitinated histone H2A: insights from the DUBs. Cell Div,2008,3:8-16.
[3]Weake, V.M., Workman, J.L. Histone ubiquitination:triggering gene activity. Mol. Cell,2008,29,653-663.
[4]Laribee,R.N., Fuchs, et al. H2B ubiquitylation in transcriptional control; a fact-finding mission. Genes Dev,2007,21:737-743.
[5]Thingholm, T.E,Jensen, Larsen, et al. Analytical strategies for phosphoproteomics. Proteomics,2009,9:1451-1468.
[6]Reinders, J., Sickmann, A.State-of-the-art in phosphoproteomics. Proteomics, 2005,5:4052-4061.
[7]Paradela, A., Albar, J.P., Advances in the analysis of protein phosphorylation. J.Proteome Res,2008,7:1809-1818.
[8]Galichet, A., Gruissem, W. Developmentally controlled farnesylation modulates AtNAPl;1 function in cell proliferation and cell expansion during Arabidopsis leaf development. Plant Physiol,2006,142 (4):1412-1426.
[9]Geyer, H., Geyer, R. Strategies for analysis of glycoprotein glycosylation. Biochim. Biophys. Acta,2006,1764:1853-1869.
[10]Collins, B.E., Paulson,J.C.Cell surface biology mediated by low affinity multivalent protein-glycan interactions. Curr. Opin. Chem. Biol,2004, 8:617-625.
[11]Wang, D.A., Sebti, S.M.. Palmitoylated cysteine 192 is required for RhoB tumor-suppressive and apoptotic activities. J. Biol. Chem,2005,280 (19):19243-9249.
[12]Sette C. Post-translational regulation of star proteins and effects on their biological functions. Adv Exp Med Biol,2010,693:54-66.
[13]Woon Ki Paikl, David C. Paik2, Sangduk Kim 1.Historical review:the field of protein methylation. Trends Biochem Sci,2007,32(3):146-52.
[14]Neuberger, A. and Sanger, F. The availability of e-acetyl-dlysine and e-Methyl-dl-lysine for growth. Biochem. J,1944,38:125-129.
[15]Pahlich, S. et al Protein arginine methylation:Cellular functions and methods of analysis. Biochim. Biophys. Acta,2006,1764:1890-1903.
[16]MedzhitovR,Preston HurlburtP,JanewayCAJr. A human homologue of the Toll protein signals activation of adaptive immunity. Nature,1997,388(6640):394-397.
[17]Akira S. Immunological mechanism in man against infection Nippon Naika Gakkai Zasshi,2001,90(12):2360-5.
[18]Gururajan M, Jacob J, Pulendran B.Toll-like receptor expression and distinct murine splenic and mucosal B-cell subsets. PLoS One,2007,2:e863.
[19]Zarember KA, Godowski PJ. Tissue expression of human Toll like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol,2002,168:554-61.
[20]Babu S, Blauvelt CP, Kumaraswami V, Nutman TB. Cutting edge:diminished T cell TLR expression and function modulates the immune response in human filarial infection. J Immunol,2006,176:3885-9.
[21]Miyake K, Ogata H, Nagai Y, et al. recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1. J Endotoxin Res,2000,6:389-91.
[22]Tanimura N, Saitoh S, Matsumoto F et al. Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochem Biophys Res Commun,2008,368:94-9.
[23]Tanimura N, Saitoh S, Matsumoto F, et al. Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochem Biophys Res Commun,2008,368:94-9.
[24]O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of toll like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev,2009, 61:177-97.
[25]Zhang JS, Feng WG, Li CL, et al.NF-kappa Bregulates the LPS-induced expression of interleukin 12 p40 in murine peritoneal macrophages:roles of PKC, PKA, ERK, p38 MAPK, and proteasome. Cell Immunol,2000,204:38-45.
[26]Jiang Z, Georgel P, Li C, Choe J, Crozat K, Rutschmann S, et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proc Natl Acad Sci USA,2006,103:10961-6.
[27]Jiang Z, Georgel P, Li C, et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proc Natl Acad Sci USA,2006,103:10961-6.
[28]O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of toll like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev,2009, 61:177-97
[29]O'Neill LA, Bowie AG. The family of five:TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol,2007,7:353-64.
[30]Uematsu S, Akira S. Toll-like receptors and Type Ⅰ interferons. J Biol Chem, 2007,282:15319-23.
[31]Kumar H, Kawai T, Akira S. Toll-like receptors and innate.immunity. Biochem Biophys Res Commun,2009,388:621-5.
[32]Arbour NC,LorenzE,Schutte BC, et al.TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.NatGenet,2000,25(2):187-191.
[33]Baltimore D, Boldin MP, O'Connell RM, et al. MicroRNAs:new regulators of immune cell development and function. Nat Immunol,2008,9:839-45.
[34]John B, Crispe IN. TLR-4 regulates CD8+ T cell trapping in the liver. J Immunol, 2005,175(3):1643-50.
[35]Lysakova-Devine T, Keogh B, Harrington B, et al Viral inhibitory peptide of TLR4, a peptide derived from vaccinia protein A46, specifically inhibits TLR4 by directly targeting MyD88 adaptor-like and TRIF-related adaptor molecule. J Immunol,2010,185(7):4261-71
[36]Tabiasco J, Devevre E, Rufer N, Human effector CD8+ T lymphocytes express TLR3 as a functional coreceptor. J Immunol,2006,177(12):8708-13.
[37]Smits EL, Ponsaerts P, Berneman ZN, Van Tendeloo VF. The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist,2008, 13:859-75.
[38]Schon M, Bong AB, Drewniok C, et al. Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J Natl Cancer Inst, 2003,95:1138-49.
[39]Wang EL, Qian ZR, Nakasono M, et al. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. Br J Cancer,2010,102:908-15.
[40]An H,Yu Y,Zhang M, et al Involvement of ERK,p38 and NFκcappaB signal transduction in tegulation og TLR2,TLR4 and TLR9 gene expression induced by lipopolysaccharide in mouse dendritc cells. Immanology,2002,106(1):3845.
[41]Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer, 2009,9:57-63.
[42]Eui Young So and Toru Ouchi. The application of Toll like receptors for cancer therapy. Iternational Journal of Biological Sciences,2010,6(7):675-681.
[43]Okamoto M, Oshikawa T, Tano T, et al. Mechanism of anticancer host response induced by OK-432, a streptococcal preparation, mediated by phagocytosis andToll-like receptor 4 signaling. J Immunother,2006,29:78-86.
[44]Huang B, Zhao J, Unkeless JC, et al. TLR signaling by tumor and immune cells:a double-edged sword. Oncogene,2008,27:218-24.
[45]Androulidaki A, Iliopoulos D, Arranz A, et al. The kinase Aktl controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity,2009,31:220-31.
[46]Arbour NC,LorenzE,Schutte BC, et al.TLR4 mutations are associated with endotoxin hyporesponsiveness in human.NatGenet,2000,25(2):187-191. [47] Roh E, Lee HS, Kwak JA, et al. MD-2 as the Target of Nonlipid Chalcone in the Inhibition of Endotoxin LPS-Induced TLR4 Activity. J Infect Dis,2011, 203(7):1012-20.
[48]Bumbasirevic V, Radenkovic D, Jankovic Z, et al. Severe acute pancreatitis: overall and early versus late mortality in intensive care units. Pancreas,2009, 38(2):122-125.
[49]Zhang X, Chen L, Luo L, et al. Study of the protective effects of dexamethasone on ileum mucosa injury in rats with severe acute pancreatitis. Pancreas,2008, 37(3):e74-e82.
[50]Andrei E. Medvedev, Wenji Piao, Joanna Shoenfelt, et al. Role of TLR4 Tyrosine Phosphorylation in Signal Transduction and Endotoxin Tolerance.The Journal of biological chemistry,2008,282(22):16042-16053.
[51]Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med,2000,343(5):338-44.
[52]Liu X, Wang L, Zhao K, et al.The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature,2008,451 (7180):846-50.
[53]Wang L, Tang Y, Cole PA, et al.Structure and chemistry of the p300/CBP and Rtt1O9 histone acetyltransferases:implications for histone acetyltransferase evolution and function. Curr Opin Struct Biol,2008,18(6):741-7.
[54]Ghosh AK, Varga J. The transcriptional coactivator and acetyltransferase p300 in fibroblast biology and fibrosis. J Cell Physiol,2007,213:663-671.
[55]Di Wang, Jun Loub, Chuan Ouyanga, et al. Ras-related protein Rab10 facilitates TLR4 signaling by promoting replenishment of TLR4 onto the plasma membrane. Proc Natl Acad Sci U S A,2010,107(31):13806-11.
[56]O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of toll like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev,2009, 61:177-97.
[57]O'Neill LA, Bowie AG. The family of five:TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol,2007,7:353-64.
[58]Uematsu S, Akira S. Toll-like receptors and Type I interferons.J Biol Chem,2007, 282:15319-23.
[59]Kumar H, Kawai T, Akira S. Toll-like receptors and innate.immunity. Biochem Biophys Res Commun,2009,388:621-5.
[60]Rajput A, Kovalenko A, Bogdanov K, et al. RIG-I RNA Helicase Activation of IRF3 Transcription Factor Is Negatively Regulated by Caspase-8-Mediated Cleavage of the RIP1 Protein. Immunity,2011,34(3):340-51.
[61]Clark K, Peggie M, Plater L, et al. Novel cross-talk within the IKK family controls innate immunity. Biochem J,2011,434(1):93-104.
[62]Liu N, Liu JT, Ji YY, et al. C-reactive protein triggers inflammatory responses partly via TLR4/IRF3/NF-κB signaling pathway in rat vascular smooth muscle cells.Life Sci,2010,87(11-12):367-74.
[63]Navarro L, David M. p38-dependent activation of interferon regulatory factor 3 by lipopolysaccharide. Journal of Biological Chemistry,1999,274 (50):35535-35538,
[64]Yoneyama M, SuharaW, Fukuhara Y, et al. Direct triggering of the type I interferon systemby virus infection:activation of a transcription factor complex containing IRF-3 and CBP/p300. The EMBO Journal,1998,7 (4):1087-1095.
[65]Peri F, Piazza M, Calabrese V et al. Exploring the LPS/TLR4 signal pathway with small molecules. Biochem Soc Trans,2010,38(5):1390-5.
[66]Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol,2004,5(10):987-95.
[67]Dillon S, Agrawal A, Van Dyke T, et al.A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol,2004, 172(8):4733-43.
[68]Rhee SH, Hwang D. Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase. J Biol Chem,2000,275(44):34035-40.
[69]Andrei E. Medvedev, Wenji Piao, Joanna Shoenfelt. Role of TLR4 Tyrosine Phosphorylation in Signal Transduction and Endotoxin Tolerance. JBC,2007, 246(31):3542-57.
[70]Blander JM, Medzhitov R.Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature,2006,440(7085):808-12.
[71]Fitzgerald, K. A., Palsson-McDermott, Bowie AG, et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature,2001,413: 78-83.
[72]Yamamoto, M., Sato, S, Hemmi, H, et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature,2002,420:324-329.
[73]Horng, T., Barton, G. M., Flavell, R. A, et al. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature,2002,420:329-333.
[74]Yamamoto, M., Takeda, K., and Akira, S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol. Immunol,2004,40:861-868
[75]Slivka PF, Shridhar M, Lee GI, et al. A peptide antagonist of the TLR4-MD2 interaction. Chembiochem,2009,10(4):645-9.
[76]Kobayashi M, Saitoh S, Tanimura N, et al.Regulatory roles for MD-2 and TLR4 in ligand-induced receptor clustering. J Immunol,2006,176(10):6211-8.
[77]Simpson A, Martinez FD. The role of lipopolysaccharide in the development of atopy in humans. Clin Exp Allergy,2010,40(2):209-23.
[78]Alberto Visintin, Kristen A. Halmen, Naseema Khan, et al. MD-2 expression is not required for cell surface targeting of Toll-like receptor 4 (TLR4).Journal of Leukocyte Biology,2006,80:1584-1592.
[79]Biel M, Wascholowsi V, Giannis A. Epigenetic—an epicenter of gene regulation: histones and histone-modifying enzymes. Angew Chemlnt Ed Engl,2005,44 (21): 3186-3216.
[80]Schoenheimer, R. et al. Studies in protein metabolism Ⅶ. The metabolism of tyrosine. J. Biol. Chem,1939,127:333-344.
[81]Pahlich S, Zakaryan RP, Gehring H.Protein arginine methylation:Cellular functions and methods of analysis. Biochim. Biophys. Acta, 2006,1764,1890-1903
[82]Cuthb Cuthbert GL, Daujat S, Snowden AW, ert GL, et al. Histone deimination antagonizes arginine methylation. Cell,2004,118:545-553.
[83]Wang Y, Wysocka J, Sayegh J,et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science,2004,306:279-283.
[84]McBride, A.E. and Silver, P.A. State of the arg:protein methylation at arginine comes of age. Cell,2001,106:5-8.
[85]Bedford, M.T. and Richard, S. Arginine methylation an emerging regulator of protein function. Mol. Cell,2005,18:263-272.
[86]Iwasaki H, Kovacic JC, Olive M, et al. Disruption of protein arginine N-methyltransferase 2 regulates leptin signaling and produces leanness in vivo through loss of STAT3 methylation. Circ Res,2010,107(8):992-1001.
[87]Lan F, Shi Y. Epigenetic regulation:methylation of histone and non-histone proteins. Sci China C Life Sci,2009,52(4):311-22.
[88]Du TT, Huang QH, et al. The roles of histone lysine methylation in epigenetic regulation. Yi Chuan,2007,29(4):387-92.
[89]Briggs SD, Xiao T, Sun ZW, et al. Gene silencing:trans-histone regulatory pathway in chromatin. Nature,418,498 (2002).
[90]Dover J, Schneider J, Tawiah-Boateng MA, et al. Methylation of histone H3 by COMPASS requires ubiquitination of histone H2B by Rad6. J. Biol Chem,2002, 277:28368-28371.
[91]Ng, H. H., Xu, R. M., Zhang, Y, et al. Ubiquitination of histone H2B by Rad6 is required for efficient Dotl-mediated methylation of histone H3 lysine 79. J. Biol. Chem,2002,277:34655-34657.
[92]Wen J, Fu J, Zhang W, et al. Genetic and epigenetic changes in lung carcinoma and their clinical implications. Mod Pathol,2011,18:1-9.
[93]Pan H, Luo XG, Guo S, et al. Histone methylation and its relationship with cancer. Sheng Li Ke Xue Jin Zhan,2010,41(1):22-6.
[94]Lee, D.Y. et al. Role of protein methylation in regulation of transcription. Endocr. Rev,2005,26:147-170.
[95]Fackelmayer, F.O.Protein arginine methylltransferases:guardians of the Arg? Trends Biochem. Sci,2005,30:666-671.
[96]Yanatatsaneejit P, Mutirangura A, Kitkumthorn N. Human Papillomavirus's Physical State and Cyclin Al Promoter Methylation in Cervical Cancer. Int J Gynecol Cancer,2011,15:1-11.
[97]Wysocka J, Swigut T, Xiao H, et al.A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature,2006,442(7098) 86-90.
[98]Shi X, Hong T, Walter K L, et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature,2006,442(7098):96-99.
[99]Kanamaluru D, Xiao Z, Fang S, et al. Arginine Methylation by PRMT5 at a Naturally Occurring Mutation Site Is Critical for Liver Metabolic Regulation by Small Heterodimer Partner. Mol Cell Biol,2011,31(7):1540-50
[100]Rust HL, Zurita-Lopez CI, Clarke SG, et al. Mechanistic studies on the Transciptional Coactivator Protein Arginine Methyltransferase 1. Biochemistry, 2011 Mar 21. [Epub ahead of print]
[101]Butler JS, Zurita-Lopez CI, Clarke SG, et al. Protein arginine methyltransferase 1 (PRMT1) methylates Ash2L, A shared component of mammalian histone H3K4 methyltransferase complexes. J Biol Chem.2011 Feb 1. [Epub ahead of print]
[102]Aggarwal P, Vaites LP, Kim JK, et al. Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase.Cancer Cell,2010,18(4):329-40.
[103]Biancotto C, Frige G, Minucci S. Histone modification therapy of cancer. Adv Genet,2010,70:341-86.
[104]Teresa K. Barth, Axel Imhof. Fast signals and slow marks:the dynamics of histone modifications.Trends in Biochemical Sciences,2010,35(11):618-6
[105]Scharf AN, Barth TK, Imhof A. Establishment of histone modifications afterchromatin assembly. Nucleic Acids Res,2009,37:5032-5040.
[106]Metzger E, Imhof A, Patel D, et al. Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone. Nature,2010,464(7289):792-6.
[107]Mateescu B, England P, Halgand F, et al. Tethering of HP1 proteins to chromatin isrelieved by phosphoacetylation of histone H3. EMBO Rep,2004,5:490-496.
[108]Jacobs, S.A. and Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science,2002,295:2080-2083.
[109]Fischle W, Wang Y, Jacobs SA, et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev,2003,17:1870-1881.
[110]Henikoff, S.Histone modifications:combinatorial complexity or cumulative simplicity? Proc. Natl. Acad. Sci. U. S. A,2005,102:5308-5309.
[111]Fischle W, Wang Y, Allis CD. Binary switches and modification cassettes inhistone biology and beyond. Nature,2003,425:475-479.
[112]Johnson L, Mollah S, Garcia B A, et al. Mass spectrometry analysis of histone H3 reveals distinct combinations of post-translational modifications. Nucleic Acids Res,2004,32 (22):6511-6518
[113]Rhee SH, Hwang D. Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase. J Biol Chem,2000,275(44):34035-40.
[114]Balkwill F, Coussens LM. Cancer:an inflammatory link. Nature,2004,431:405-6.
[1]Chervonsky AV, Medzhitov RM, Denzin LK, et al. Subtle conformational changes induced in major histocompatibility complex class Ⅱ mocecules by binding peptides[J].Proc Natl Acad Sci USA,1998,95(17):10094-10099.
[2]Medzhitov R, Janeway CA Jr. An ancient system of host defense[J].Curr Opin Immunol,1998,10(1):12-15.
[3]Medzhitov R, Preston Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity[J].Nature,1997, 388(6640):394-397.
[4]Roach JC, Glusman G, Rowen L, et al. The evolution of vertebrate Toll-like receptors. [J]. Proc Natl Acad Sci USA,2005,102(27):9577-9582.
[5]Akira S, Takeda K. Functions of toll-like receptors:lessons from KO mice [J]. C R Biol,2004,327(6):581-589.
[6]Wakabayashi Y, Kobayashi M, Akashi-Takamura S, et al. A protein associated with toll-like receptor 4 (PRAT4A) regulates cell surface expression of TLR4[J]. J Immunol,2006,177(3):1772-1779.
[7]Visintin A, Halmen KA, Khan N, et al. MD-2 expression is not required for cell surface targeting of Toll-like receptor 4 (TLR4)[J]. J Leukoc Biol,2006, 80(6):1584-1592.
[8]Johnsen IB, Nguyen TT, Ringdal M, et al. Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling[J]. EMBO J,2006, 25(14):3335-3346.
[9]Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B,Giese T, et al.Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides[J]. JImmunol,2002,168:4531-4537.
[10]Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens[J]. J Exp Med,2001,194:863-869.
[11]Gururajan M, Jacob J, Pulendran B. Toll-like receptor expression and responsiveness of distinct murine splenic and mucosal B-cell subsets[J]. PLoS One,2007,2:e863.
[12]Zarember KA, Godowski PJ. Tissue expression of human Tolllike receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines[J]. J Immunol,2002,168:554-561.
[13]Babu S, Blauvelt CP, Kumaraswami V, Nutman TB. Cutting edge:diminished T cell TLR expression and function modulates the immune response in human filarial infection[J]. J Immunol,2006,176:3885-3889.
[14]Carpenter S, O'Neill LA. How important are Toll-like receptors for antimicrobial responses[J]. Cell Microbiol,2007,9:1891-1901.
[15]Zhu J, Mohan C. Toll-like receptor signaling pathways-therapeutic opportunities[J]. Mediators Inflamm,2010,78:123-125.
[16]Akira S. Immunological mechanism in man against infection[J]. Nippon Naika Gakkai Zasshi,2001,90(12):2360-2365.
[17]Kawasaki K, Nogawa H, Nishijima M. Identification of mouse MD-2 residues important for forming the cell surface TLR4-MD-2 complex recognized by anti-TLR4-MD-2 antibodies, and for conferring LPS and taxol responsiveness on mouse TLR4 by alanine-scanning mutagenesis[J]. J Immunol.2003, 170(1):413-420.
[18]Kurt-Jones EA, Popova L, Kwinn L, et al. Pattern recognition receptors TLR4 and CD 14 mediate response to respiratory syncytial virus[J]. Nat Immunol.2000, 1(5):398-401.
[19]Taylor KR, Yamasaki K, Radek KA, et al. Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2[J]. J Biol Chem,2007,282(25):18265-18275.
[20]Lin FY, Chen YH, Tasi JS, et al. Endotoxin induces toll-like receptor 4 expression in vascular smooth muscle cells via NADPH oxidase activation and mitogen-activated protein kinase signaling pathways[J]. Arterioscler Thromb Vasc Biol,2006,26(12):2630-2637.
[21]Ozinsky A, Underhill DM, Fontenot JD, et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors[J].Proc Natl Acad Sci USA,2000,97(25):13766-13771.
[22]Hayashi F, Smith KD, Ozinsky A, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5[J]. Nature,2001, 410(6832):1099-1103.
[23]Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single stranded RNA via toll-like receptor 7 and 8[J]. Science,2004,303(5663):1526-1529.
[24]Hornung V, Guenthner-Biller M, Bourquin C, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7[J]. Nat Med,2005,2:63-70.
[25]Jurk M, Heil F, Vollmer J, et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848[J]. Nat Immunol,2002,3(6):499.
[26]Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA[J]. Nature,2000,408(6813):740-745.
[27]Alexopoulou L, Holt AC, Medzhitov R, et al. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3[J]. Nature,2001, 413(6857):732-738.
[28]Wang Z, Xiang L, Shao J, et al. The 3'CCACCA sequence of tRNAAla(UGC) is the motif that is important in inducing Thl-like immune response, and this motif can be recognized by Toll-like receptor 3[J]. Clin Vaccine Immunol, 2006,13(7):733-739.
[29]Zhang D, Zhang G, Hayden MS, et al. A toll-like receptor that prevents infection by uropathogenic bacteria[J]. Science,2004,5;303(5663):1522-1526.
[30]Sioud M.RNAi therapy: antibodies guide the way[J]. Gene Ther,2006, 13(3):194-195.
[31]O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of toll like receptors for infectious and inflammatory diseases and cancer[J]. Pharmacol Rev,2009, 61:177-197.
[32]O'Neill LA, Bowie AG. The family of five:TIR-domain-containing adaptors in Toll-like receptor signalling[J]. Nat Rev Immunol,2007,7:353-364.
[33]Uematsu S, Akira S. Toll-like receptors and Type I interferons[J]. J Biol Chem, 2007,282:15319-15323.
[34]Kumar H, Kawai T, Akira S. Toll-like receptors and innate.immunity[J]. Biochem Biophys Res Commun,2009,388:621-625.
[35]Jiang Z, Georgel P, Li C, Choe J, Crozat K, Rutschmann S, et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis[J]. Proc Natl Acad Sci USA,2006; 103:10961-10966.
[36]Zhu J, Mohan C. Toll-Like Receptor Signaling Pathways-Therapeutic Opportunities [J]. Mediators of Inflammation,2010,1:1-7
[37]Kawai T, Akira S. TLR signaling[J]. Cell Death Differ,2006,13(5):816-825.
[38]Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans[J]. NatGenet,2000,25(2):187-191.
[39]John B, Crispe IN. TLR-4 regulates CD8+ T cell trapping in the liver[J]. J Immunol,2005,175(3):1643-1650.
[40]Lysakova-Devine T, Keogh B, Harrington B, et al. Viral inhibitory peptide of TLR4, a peptide derived from vaccinia protein A46, specifically inhibits TLR4 by directly targeting MyD88 adaptor-like and TRIF-related adaptor molecule[J]. J Immunol,2010,185(7):4261-4271.
[41]Tabiasco J, Devevre E, Rufer N. Human effector CD8+ T lymphocytes express TLR3 as a functional coreceptor[J]. J Immunol,2006,177(12):8708-8713.
[42]Smits EL, Ponsaerts P, Berneman ZN, Van Tendeloo VF. The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy[J]. Oncologist,2008, 13:859-875.
[43]Schon M, Bong AB, Drewniok C, et al. Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod[J]. J Natl Cancer Inst, 2003,95:1138-1149.
[44]An H,Yu Y,Zhang M,et al. Involvement of ERK,p38 and NFκappaB signal transduction in tegulation og TLR2,TLR4 and TLR9 gene expression induced by lipopolysaccharide in mouse dendritc cells[J]. Immanology,2002,106(1):3845.
[45]Papadimitraki ED, Choulaki C, Koutala E, et al. Expansion of toll-like receptor 9-expressing B cells in active systemic lupus erythematosus:implications for the induction and maintenance of the autoimmune process[J]. Arthritis Rheum,2006, 54(11):3601-3611.
[46]Sacre SM, Andreakos E, Kiriakidis S, et al. The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis[J]. Am J Pathol,2007,170(2):518-525.
[47]Maratheftis CI, Andreakos E, Moutsopoulos HM, et al. Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes[J]. Clin Cancer Res,2007, 13(4):1154-1160.
[48]Xu N, Yao HP, Sun Z, et al. Toll-like receptor 7 and 9 expression in peripheral blood mononuclear cells from patients with chronic hepatitis B and related hepatocellular carcinoma[J]. Acta Pharmacol Sin,2008,29(2):239-244.
[49]. Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer[J]. Nat Rev Cancer,2009,9:57-63.
[50]Eui Young So and Toru Ouchi.The application of Toll like receptors for cancer therapy[J]. Iternational Journal of Biological Sciences,2010,6(7):675-681
[51]Okamoto M, Oshikawa T, Tano T, Ahmed SU, Kan S, Sasai A,et al. Mechanism of anticancer host response induced by OK-432, a streptococcal preparation, mediated by phagocytosis andToll-like receptor 4 signaling[J]. J Immunother, 2006,29:78-86.
[52]Huang B, Zhao J, Unkeless JC, Feng ZH, Xiong H. TLR signaling by tumor and immune cells:a double-edged sword[J].Oncogene,2008,27:218-224.
[1]Haggarty SJ, Koeler KM, Wong JC, et al. Domain selective small moleculer inhibitor of histone deacetylass 6(HDAC)-mediated tubulin deacetylation[J]. Proc Natl Acad Sci USA,2003,100(8):4389-439.
[2]Gregoretti IV, Lee YM, Goodson HV. Molecular evolution of the histone deacetylase family:functional implications of phylogenetic analysis[J]. J Mol Biol, 2004,338(1):17-31.
[3]Yang XJ, Seto E. HATs and HDACs:from structure, function and regulation to novel strategies for therapy and prevention[J]. Oncogene,26:5310-5318.
[4]Haigis MC, Guarente LP. Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction[J]. Genes Dev,20:2913-2921.
[5]Gao L, Cueto MA, Asselbergs F, et al. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family[J]. J Biol Chem 2002,277(28):25748-55.
[6]Yang XJ, Seto E. The Rpd3/Hdal family of lysine deacetylases:frombacteria and yeast to mice and men[J]. Nat Rev Mol Cell Biol,2008,9(3):206-218.
[7]Chandrima Das, M. Scott Lucia, Kirk C, et al. CBP/p300-mediated acetylation of histone H3 on lysine 56[J]. Nature Letters,2009,459:113-117.
[8]Michishita E, Park JY, Burneskis JM, et al. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins[J]. Mol Biol Cell,2005,16:4623-4635.
[9]Jin Q, Yan T, Ge X, Sun C, Shi X, Zhai Q. Cytoplasm-localized SIRT1 enhances apoptosis[J]. J Cell Physiol,2007,213(1):88-97.
[10]Stephanie Spangeab, TobiasWagnerb, Thorsten Heinzelb, et al. Acetylation of non-histone proteins modulates cellular signalling at multiple levels[J]. The International Journal of Biochemistry & Cell Biology.2009,41:185-198.
[11]Shahper N. Khan, Asad U. Khan. Role of histone acetylation in cell physiology and diseases:An update[J].Clinica Chimica Acta,2010,411 (19-20):1401-1411.
[12]Boda Zhou, Andriana Margariti, Lingfang Zeng, et al. Role of histone deacetylases in vascular cell homeostasis and arteriosclerosis [J]. Cardiovascular Research, 2011,10:1-8.
[13]. Chang S, Young BD, Li S, et al. Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase[J]. Cell,2006,126:321-334.
[14]Mottet D, Bellahcene A, Pirotte S, et al. Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis[J]. Circ Res,2007, 101:1237-1246.
[15]Okamoto H, Fujioka Y, Takahashi A, et al. Trichostatin A, an inhibitor of histone deacetylase, inhibits smooth muscle cell proliferation via induction of p21(WAF1) [J]. J Atheroscler Thromb,2006;13:183-191.
[16]Song S, Kang SW, Choi C. Trichostatin A enhances proliferation and migration of vascular smooth muscle cells by downregulating thioredoxin 1[J]. Cardiovasc Res, 2010,85:241-249.
[17]Xiao Q, Zeng L, Zhang Z, et al. Sca-1+ progenitors derived from embryonic stem cells differentiate into endothelial cells capable of vascular repair after arterial injury[J]. Arterioscler Thromb Vasc Biol,2006,26:2244-2251.
[18]Zeng L, Xiao Q, Margariti A, et al. HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells[J]. J Cell Biol,2006, 174:1059-1069.
[19]Margariti A, Xiao Q, Zampetaki A, et al. Splicing of HDAC7 modulates the SRF-myocardin complex during stem-cell differentiation towards smooth muscle cells[J]. J Cell Sci,2009,122:460-470.
[20]Lan Phaml, Bria Kaiserl, Amanda Romsa,et. HDAC3 and HDAC7 have opposite effects on osteoclast differentiation[J]. JBC,2011,1-17.
[21]Gao YS, Hubbert CC, Lu J, et al. Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis[J]. Mol Cell Biol,2007, 27:8637-8647.
[22]Zhang X, Yuan Z, Zhang Y, et al.HDAC6 modulates cell motility by altering the acetylation level of cortactin[J]. Mol Cell,2007,27:197-213.
[23]Zhang Y, Zhang M, Dong H, et al. Deacetylation of cortactin by SIRT1 promotes cell migration[J]. Oncogene,2009,28:445-460.
[24]Yan ZQ, Yao QP, Zhang ML, et al. Histone deacetylases modulate vascular smooth muscle cell migration induced by cyclic mechanical strain[J]. J Biomech,2009, 42:945-948.
[25]Song S, Kang SW, Choi C. Trichostatin A enhances proliferation and migration of vascular smooth muscle cells by downregulating thioredoxin 1[J]. Cardiovasc Res, 2010,85:241-249.
[26]Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1[J]. Proc Natl Acad Sci USA, 2007,104:12861-12866.
[27]Lagouge M, Argmann C, Gerhart-Hines Z, et al.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha[J]. Cell,2006,127:1109-1122.
[28]Schwer B, Bunkenborg J, Verdin RO, et al.Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2[J]. Proc Natl Acad Sci USA,2006,103:10224-10229.
[29]Hallows WC, Lee S, Denu JM. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases[J]. Proc Natl Acad Sci USA,2006,103:10230-10235.
[30]Haigis MC, Mostoslavsky R, Haigis KM, et al.SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells[J].Cell,2006,126:941-954.
[31]Westphal CH, Dipp MA, Guarente L.A therapeutic role for sirtuins in diseases of aging[J]. Trends Biochem Sci,2007,32:555-560.
[32]Kaeberlein M, McVey M, Guarente L.The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms[J]. Genes Dev,1999,13:2570-2580.
[33]Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans[J]. Nature,2001,10:227-230.
[34]Wood JG, Rogina B, Lavu S. Sirtuin activators mimic caloric restriction and delay ageing in metazoans[J]. Nature,2004,430:686-689.
[35]Imai S, Armstrong CM, Kaeberlein M, et al.Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histon deacetylase[J].Nature,2000,403:795-800.
[36]Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae[J].Science,2000, 289:2126-2128.
[37]Shi T, Wang F, Stieren E,et al. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes[J]. J Biol Chem,2005,280:13560-13567.
[38]Li X, Zhang S, Blander G et al.SIRT1 deacetylates and positively regulates the nuclear receptor LXR[J]. Mol Cell,2007,28:91-106.
[39]Potente M, Ghaeni L, Baldessari D, et al.SIRT1 controls endothelial angiogenic functions during vascular growth[J]. Genes Dev,2007,21:2644-2658.
[40]Mattagajasingh I, Kim CS, Naqvi A, et al. SIRT1 promotesendothelium dependent vascular relaxation by activating endothelial nitric oxide synthase[J]. Proc Natl Acad Sci USA,2007,104:14855-14860.
[41]Kim D, Nguyen MD, Dobbin MM, et al.SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis[J]. EMBO,2007,26:3169-3179.
[42]van der Veer E, Nong Z, O'Neil C, et al. Pre-B-cell colony-enhancing factor regulates NAD+-dependent protein deacetylase activity and promotes vascular smooth muscle cell maturation[J]. Circ Res,2005,97:25-34.
[43]Patel VA, Zhang QJ, Siddle K, et al. Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling[J]. Circ Res,2001, 88:895-902.
[44]Lei WW, Zhang KH, Pan XC, et al. Histone deacetylase 1 and 2 differentially regulate apoptosis by opposing effects on extracellular signal-regulated kinase 1/2[J]. Cell Death Dis,2010,1(5):e44.
[45]Firestein R, Blander G, Michan S, et al.The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth[J]. PLoS One,2008,3:e2020.
[46]Kabra N, Li Z, Chen L, et al.SirTl is an inhibitor of proliferation and tumor formation in colon cancer[J]. J Biol Chem,2009,284:18210-18217.
[47]Gottlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells[J]. EMBO J,2001, 20(24):69-78.
[48]Miller TA, Witter DJ, Belvedere S. Histone deacetylase inhibitors [J].. J Med Chem, 2003,46(24):5097-116.
[49]Stimson L, Wood V, Khan O, Fotheringham S, et al. HDAC inhibitor-based therapies and haematological malignancy[J]. Ann Oncol,2009,20:1293-1302.
[50]Drummond DC, Noble CO, Kirpotin DB, et al. Clinical development of histone deacetylase inhibitors as anticancer agents[J]. Annu Rev Pharmacol Toxicol,2005, 45:495-528.
[51]Mitsiades N, Mitsiades CS, Richardson PG, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells[J]. Blood,2003, 101:4055-4062.
[52]Neuzil J, Swettenham E, Gellert N. Sensitization of mesothelioma to TRAIL apoptosis by inhibition of histone deacetylase:role of Bcl-xL down-regulation[J]. Biochem Biophys Res Commun,2004,314:186-191.
[53]Shankar S, Singh TR, Fandy TE, et al. Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells:involvement of both death receptor and mitochondrial pathways[J]. Int J Mol Med,2005, 16:1125-1138.
[54]Singh TR, Shankar S, Srivastava RK. HDAC inhibitors enhance the apoptosis inducing potential of TRAIL in breast carcinoma[J]. Oncogene,2005, 24:4609-4623.
[55]Zhang XD, Gillespie SK, Borrow JM, et al. The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells[J]. Mol Cancer Ther,2004,3:425-435.
[56]Takai N, Kawamata N, Gui D, et al. Human ovarian carcinoma cells:histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis[J]. Cancer,2004,101:2760-2770.
[57]Dehm SM, Bonham K. SRC gene expression in human cancer:the role of transcriptional activation[J]. Biochem Cell Biol,2004,82:263-274.
[58]Heruth DP, Zirnstein GW, Bradley JF, et al. Sodium butyrate causes an increase in the block to transcriptional elongation in the c-myc gene in SW837 rectal carcinoma cells[J]. J Biol Chem,1993,268:20466-20472.
[59]Lallemand F, Courilleau D, Sabbah M, et al. Direct inhibition of the expression of cyclin D1 gene by sodium butyrate[J]. Biochem Biophys Res Commun,1996, 229:163-169.
[2]Vissers, J.H.A., Nicassio, et al. The many faces of ubiquitinated histone H2A: insights from the DUBs. Cell Div,2008,3:8-16.
[3]Weake, V.M., Workman, J.L. Histone ubiquitination:triggering gene activity. Mol. Cell,2008,29,653-663.
[4]Laribee,R.N., Fuchs, et al. H2B ubiquitylation in transcriptional control; a fact-finding mission. Genes Dev,2007,21:737-743.
[5]Thingholm, T.E,Jensen, Larsen, et al. Analytical strategies for phosphoproteomics. Proteomics,2009,9:1451-1468.
[6]Reinders, J., Sickmann, A.State-of-the-art in phosphoproteomics. Proteomics, 2005,5:4052-4061.
[7]Paradela, A., Albar, J.P., Advances in the analysis of protein phosphorylation. J.Proteome Res,2008,7:1809-1818.
[8]Galichet, A., Gruissem, W. Developmentally controlled farnesylation modulates AtNAPl;1 function in cell proliferation and cell expansion during Arabidopsis leaf development. Plant Physiol,2006,142 (4):1412-1426.
[9]Geyer, H., Geyer, R. Strategies for analysis of glycoprotein glycosylation. Biochim. Biophys. Acta,2006,1764:1853-1869.
[10]Collins, B.E., Paulson,J.C.Cell surface biology mediated by low affinity multivalent protein-glycan interactions. Curr. Opin. Chem. Biol,2004, 8:617-625.
[11]Wang, D.A., Sebti, S.M.. Palmitoylated cysteine 192 is required for RhoB tumor-suppressive and apoptotic activities. J. Biol. Chem,2005,280 (19):19243-9249.
[12]Sette C. Post-translational regulation of star proteins and effects on their biological functions. Adv Exp Med Biol,2010,693:54-66.
[13]Woon Ki Paikl, David C. Paik2, Sangduk Kim 1.Historical review:the field of protein methylation. Trends Biochem Sci,2007,32(3):146-52.
[14]Neuberger, A. and Sanger, F. The availability of e-acetyl-dlysine and e-Methyl-dl-lysine for growth. Biochem. J,1944,38:125-129.
[15]Pahlich, S. et al Protein arginine methylation:Cellular functions and methods of analysis. Biochim. Biophys. Acta,2006,1764:1890-1903.
[16]MedzhitovR,Preston HurlburtP,JanewayCAJr. A human homologue of the Toll protein signals activation of adaptive immunity. Nature,1997,388(6640):394-397.
[17]Akira S. Immunological mechanism in man against infection Nippon Naika Gakkai Zasshi,2001,90(12):2360-5.
[18]Gururajan M, Jacob J, Pulendran B.Toll-like receptor expression and distinct murine splenic and mucosal B-cell subsets. PLoS One,2007,2:e863.
[19]Zarember KA, Godowski PJ. Tissue expression of human Toll like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol,2002,168:554-61.
[20]Babu S, Blauvelt CP, Kumaraswami V, Nutman TB. Cutting edge:diminished T cell TLR expression and function modulates the immune response in human filarial infection. J Immunol,2006,176:3885-9.
[21]Miyake K, Ogata H, Nagai Y, et al. recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1. J Endotoxin Res,2000,6:389-91.
[22]Tanimura N, Saitoh S, Matsumoto F et al. Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochem Biophys Res Commun,2008,368:94-9.
[23]Tanimura N, Saitoh S, Matsumoto F, et al. Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochem Biophys Res Commun,2008,368:94-9.
[24]O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of toll like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev,2009, 61:177-97.
[25]Zhang JS, Feng WG, Li CL, et al.NF-kappa Bregulates the LPS-induced expression of interleukin 12 p40 in murine peritoneal macrophages:roles of PKC, PKA, ERK, p38 MAPK, and proteasome. Cell Immunol,2000,204:38-45.
[26]Jiang Z, Georgel P, Li C, Choe J, Crozat K, Rutschmann S, et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proc Natl Acad Sci USA,2006,103:10961-6.
[27]Jiang Z, Georgel P, Li C, et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proc Natl Acad Sci USA,2006,103:10961-6.
[28]O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of toll like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev,2009, 61:177-97
[29]O'Neill LA, Bowie AG. The family of five:TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol,2007,7:353-64.
[30]Uematsu S, Akira S. Toll-like receptors and Type Ⅰ interferons. J Biol Chem, 2007,282:15319-23.
[31]Kumar H, Kawai T, Akira S. Toll-like receptors and innate.immunity. Biochem Biophys Res Commun,2009,388:621-5.
[32]Arbour NC,LorenzE,Schutte BC, et al.TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.NatGenet,2000,25(2):187-191.
[33]Baltimore D, Boldin MP, O'Connell RM, et al. MicroRNAs:new regulators of immune cell development and function. Nat Immunol,2008,9:839-45.
[34]John B, Crispe IN. TLR-4 regulates CD8+ T cell trapping in the liver. J Immunol, 2005,175(3):1643-50.
[35]Lysakova-Devine T, Keogh B, Harrington B, et al Viral inhibitory peptide of TLR4, a peptide derived from vaccinia protein A46, specifically inhibits TLR4 by directly targeting MyD88 adaptor-like and TRIF-related adaptor molecule. J Immunol,2010,185(7):4261-71
[36]Tabiasco J, Devevre E, Rufer N, Human effector CD8+ T lymphocytes express TLR3 as a functional coreceptor. J Immunol,2006,177(12):8708-13.
[37]Smits EL, Ponsaerts P, Berneman ZN, Van Tendeloo VF. The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist,2008, 13:859-75.
[38]Schon M, Bong AB, Drewniok C, et al. Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J Natl Cancer Inst, 2003,95:1138-49.
[39]Wang EL, Qian ZR, Nakasono M, et al. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. Br J Cancer,2010,102:908-15.
[40]An H,Yu Y,Zhang M, et al Involvement of ERK,p38 and NFκcappaB signal transduction in tegulation og TLR2,TLR4 and TLR9 gene expression induced by lipopolysaccharide in mouse dendritc cells. Immanology,2002,106(1):3845.
[41]Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer, 2009,9:57-63.
[42]Eui Young So and Toru Ouchi. The application of Toll like receptors for cancer therapy. Iternational Journal of Biological Sciences,2010,6(7):675-681.
[43]Okamoto M, Oshikawa T, Tano T, et al. Mechanism of anticancer host response induced by OK-432, a streptococcal preparation, mediated by phagocytosis andToll-like receptor 4 signaling. J Immunother,2006,29:78-86.
[44]Huang B, Zhao J, Unkeless JC, et al. TLR signaling by tumor and immune cells:a double-edged sword. Oncogene,2008,27:218-24.
[45]Androulidaki A, Iliopoulos D, Arranz A, et al. The kinase Aktl controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity,2009,31:220-31.
[46]Arbour NC,LorenzE,Schutte BC, et al.TLR4 mutations are associated with endotoxin hyporesponsiveness in human.NatGenet,2000,25(2):187-191. [47] Roh E, Lee HS, Kwak JA, et al. MD-2 as the Target of Nonlipid Chalcone in the Inhibition of Endotoxin LPS-Induced TLR4 Activity. J Infect Dis,2011, 203(7):1012-20.
[48]Bumbasirevic V, Radenkovic D, Jankovic Z, et al. Severe acute pancreatitis: overall and early versus late mortality in intensive care units. Pancreas,2009, 38(2):122-125.
[49]Zhang X, Chen L, Luo L, et al. Study of the protective effects of dexamethasone on ileum mucosa injury in rats with severe acute pancreatitis. Pancreas,2008, 37(3):e74-e82.
[50]Andrei E. Medvedev, Wenji Piao, Joanna Shoenfelt, et al. Role of TLR4 Tyrosine Phosphorylation in Signal Transduction and Endotoxin Tolerance.The Journal of biological chemistry,2008,282(22):16042-16053.
[51]Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med,2000,343(5):338-44.
[52]Liu X, Wang L, Zhao K, et al.The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature,2008,451 (7180):846-50.
[53]Wang L, Tang Y, Cole PA, et al.Structure and chemistry of the p300/CBP and Rtt1O9 histone acetyltransferases:implications for histone acetyltransferase evolution and function. Curr Opin Struct Biol,2008,18(6):741-7.
[54]Ghosh AK, Varga J. The transcriptional coactivator and acetyltransferase p300 in fibroblast biology and fibrosis. J Cell Physiol,2007,213:663-671.
[55]Di Wang, Jun Loub, Chuan Ouyanga, et al. Ras-related protein Rab10 facilitates TLR4 signaling by promoting replenishment of TLR4 onto the plasma membrane. Proc Natl Acad Sci U S A,2010,107(31):13806-11.
[56]O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of toll like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev,2009, 61:177-97.
[57]O'Neill LA, Bowie AG. The family of five:TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol,2007,7:353-64.
[58]Uematsu S, Akira S. Toll-like receptors and Type I interferons.J Biol Chem,2007, 282:15319-23.
[59]Kumar H, Kawai T, Akira S. Toll-like receptors and innate.immunity. Biochem Biophys Res Commun,2009,388:621-5.
[60]Rajput A, Kovalenko A, Bogdanov K, et al. RIG-I RNA Helicase Activation of IRF3 Transcription Factor Is Negatively Regulated by Caspase-8-Mediated Cleavage of the RIP1 Protein. Immunity,2011,34(3):340-51.
[61]Clark K, Peggie M, Plater L, et al. Novel cross-talk within the IKK family controls innate immunity. Biochem J,2011,434(1):93-104.
[62]Liu N, Liu JT, Ji YY, et al. C-reactive protein triggers inflammatory responses partly via TLR4/IRF3/NF-κB signaling pathway in rat vascular smooth muscle cells.Life Sci,2010,87(11-12):367-74.
[63]Navarro L, David M. p38-dependent activation of interferon regulatory factor 3 by lipopolysaccharide. Journal of Biological Chemistry,1999,274 (50):35535-35538,
[64]Yoneyama M, SuharaW, Fukuhara Y, et al. Direct triggering of the type I interferon systemby virus infection:activation of a transcription factor complex containing IRF-3 and CBP/p300. The EMBO Journal,1998,7 (4):1087-1095.
[65]Peri F, Piazza M, Calabrese V et al. Exploring the LPS/TLR4 signal pathway with small molecules. Biochem Soc Trans,2010,38(5):1390-5.
[66]Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol,2004,5(10):987-95.
[67]Dillon S, Agrawal A, Van Dyke T, et al.A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol,2004, 172(8):4733-43.
[68]Rhee SH, Hwang D. Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase. J Biol Chem,2000,275(44):34035-40.
[69]Andrei E. Medvedev, Wenji Piao, Joanna Shoenfelt. Role of TLR4 Tyrosine Phosphorylation in Signal Transduction and Endotoxin Tolerance. JBC,2007, 246(31):3542-57.
[70]Blander JM, Medzhitov R.Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature,2006,440(7085):808-12.
[71]Fitzgerald, K. A., Palsson-McDermott, Bowie AG, et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature,2001,413: 78-83.
[72]Yamamoto, M., Sato, S, Hemmi, H, et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature,2002,420:324-329.
[73]Horng, T., Barton, G. M., Flavell, R. A, et al. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature,2002,420:329-333.
[74]Yamamoto, M., Takeda, K., and Akira, S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol. Immunol,2004,40:861-868
[75]Slivka PF, Shridhar M, Lee GI, et al. A peptide antagonist of the TLR4-MD2 interaction. Chembiochem,2009,10(4):645-9.
[76]Kobayashi M, Saitoh S, Tanimura N, et al.Regulatory roles for MD-2 and TLR4 in ligand-induced receptor clustering. J Immunol,2006,176(10):6211-8.
[77]Simpson A, Martinez FD. The role of lipopolysaccharide in the development of atopy in humans. Clin Exp Allergy,2010,40(2):209-23.
[78]Alberto Visintin, Kristen A. Halmen, Naseema Khan, et al. MD-2 expression is not required for cell surface targeting of Toll-like receptor 4 (TLR4).Journal of Leukocyte Biology,2006,80:1584-1592.
[79]Biel M, Wascholowsi V, Giannis A. Epigenetic—an epicenter of gene regulation: histones and histone-modifying enzymes. Angew Chemlnt Ed Engl,2005,44 (21): 3186-3216.
[80]Schoenheimer, R. et al. Studies in protein metabolism Ⅶ. The metabolism of tyrosine. J. Biol. Chem,1939,127:333-344.
[81]Pahlich S, Zakaryan RP, Gehring H.Protein arginine methylation:Cellular functions and methods of analysis. Biochim. Biophys. Acta, 2006,1764,1890-1903
[82]Cuthb Cuthbert GL, Daujat S, Snowden AW, ert GL, et al. Histone deimination antagonizes arginine methylation. Cell,2004,118:545-553.
[83]Wang Y, Wysocka J, Sayegh J,et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science,2004,306:279-283.
[84]McBride, A.E. and Silver, P.A. State of the arg:protein methylation at arginine comes of age. Cell,2001,106:5-8.
[85]Bedford, M.T. and Richard, S. Arginine methylation an emerging regulator of protein function. Mol. Cell,2005,18:263-272.
[86]Iwasaki H, Kovacic JC, Olive M, et al. Disruption of protein arginine N-methyltransferase 2 regulates leptin signaling and produces leanness in vivo through loss of STAT3 methylation. Circ Res,2010,107(8):992-1001.
[87]Lan F, Shi Y. Epigenetic regulation:methylation of histone and non-histone proteins. Sci China C Life Sci,2009,52(4):311-22.
[88]Du TT, Huang QH, et al. The roles of histone lysine methylation in epigenetic regulation. Yi Chuan,2007,29(4):387-92.
[89]Briggs SD, Xiao T, Sun ZW, et al. Gene silencing:trans-histone regulatory pathway in chromatin. Nature,418,498 (2002).
[90]Dover J, Schneider J, Tawiah-Boateng MA, et al. Methylation of histone H3 by COMPASS requires ubiquitination of histone H2B by Rad6. J. Biol Chem,2002, 277:28368-28371.
[91]Ng, H. H., Xu, R. M., Zhang, Y, et al. Ubiquitination of histone H2B by Rad6 is required for efficient Dotl-mediated methylation of histone H3 lysine 79. J. Biol. Chem,2002,277:34655-34657.
[92]Wen J, Fu J, Zhang W, et al. Genetic and epigenetic changes in lung carcinoma and their clinical implications. Mod Pathol,2011,18:1-9.
[93]Pan H, Luo XG, Guo S, et al. Histone methylation and its relationship with cancer. Sheng Li Ke Xue Jin Zhan,2010,41(1):22-6.
[94]Lee, D.Y. et al. Role of protein methylation in regulation of transcription. Endocr. Rev,2005,26:147-170.
[95]Fackelmayer, F.O.Protein arginine methylltransferases:guardians of the Arg? Trends Biochem. Sci,2005,30:666-671.
[96]Yanatatsaneejit P, Mutirangura A, Kitkumthorn N. Human Papillomavirus's Physical State and Cyclin Al Promoter Methylation in Cervical Cancer. Int J Gynecol Cancer,2011,15:1-11.
[97]Wysocka J, Swigut T, Xiao H, et al.A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature,2006,442(7098) 86-90.
[98]Shi X, Hong T, Walter K L, et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature,2006,442(7098):96-99.
[99]Kanamaluru D, Xiao Z, Fang S, et al. Arginine Methylation by PRMT5 at a Naturally Occurring Mutation Site Is Critical for Liver Metabolic Regulation by Small Heterodimer Partner. Mol Cell Biol,2011,31(7):1540-50
[100]Rust HL, Zurita-Lopez CI, Clarke SG, et al. Mechanistic studies on the Transciptional Coactivator Protein Arginine Methyltransferase 1. Biochemistry, 2011 Mar 21. [Epub ahead of print]
[101]Butler JS, Zurita-Lopez CI, Clarke SG, et al. Protein arginine methyltransferase 1 (PRMT1) methylates Ash2L, A shared component of mammalian histone H3K4 methyltransferase complexes. J Biol Chem.2011 Feb 1. [Epub ahead of print]
[102]Aggarwal P, Vaites LP, Kim JK, et al. Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase.Cancer Cell,2010,18(4):329-40.
[103]Biancotto C, Frige G, Minucci S. Histone modification therapy of cancer. Adv Genet,2010,70:341-86.
[104]Teresa K. Barth, Axel Imhof. Fast signals and slow marks:the dynamics of histone modifications.Trends in Biochemical Sciences,2010,35(11):618-6
[105]Scharf AN, Barth TK, Imhof A. Establishment of histone modifications afterchromatin assembly. Nucleic Acids Res,2009,37:5032-5040.
[106]Metzger E, Imhof A, Patel D, et al. Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone. Nature,2010,464(7289):792-6.
[107]Mateescu B, England P, Halgand F, et al. Tethering of HP1 proteins to chromatin isrelieved by phosphoacetylation of histone H3. EMBO Rep,2004,5:490-496.
[108]Jacobs, S.A. and Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science,2002,295:2080-2083.
[109]Fischle W, Wang Y, Jacobs SA, et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev,2003,17:1870-1881.
[110]Henikoff, S.Histone modifications:combinatorial complexity or cumulative simplicity? Proc. Natl. Acad. Sci. U. S. A,2005,102:5308-5309.
[111]Fischle W, Wang Y, Allis CD. Binary switches and modification cassettes inhistone biology and beyond. Nature,2003,425:475-479.
[112]Johnson L, Mollah S, Garcia B A, et al. Mass spectrometry analysis of histone H3 reveals distinct combinations of post-translational modifications. Nucleic Acids Res,2004,32 (22):6511-6518
[113]Rhee SH, Hwang D. Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase. J Biol Chem,2000,275(44):34035-40.
[114]Balkwill F, Coussens LM. Cancer:an inflammatory link. Nature,2004,431:405-6.
[1]Chervonsky AV, Medzhitov RM, Denzin LK, et al. Subtle conformational changes induced in major histocompatibility complex class Ⅱ mocecules by binding peptides[J].Proc Natl Acad Sci USA,1998,95(17):10094-10099.
[2]Medzhitov R, Janeway CA Jr. An ancient system of host defense[J].Curr Opin Immunol,1998,10(1):12-15.
[3]Medzhitov R, Preston Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity[J].Nature,1997, 388(6640):394-397.
[4]Roach JC, Glusman G, Rowen L, et al. The evolution of vertebrate Toll-like receptors. [J]. Proc Natl Acad Sci USA,2005,102(27):9577-9582.
[5]Akira S, Takeda K. Functions of toll-like receptors:lessons from KO mice [J]. C R Biol,2004,327(6):581-589.
[6]Wakabayashi Y, Kobayashi M, Akashi-Takamura S, et al. A protein associated with toll-like receptor 4 (PRAT4A) regulates cell surface expression of TLR4[J]. J Immunol,2006,177(3):1772-1779.
[7]Visintin A, Halmen KA, Khan N, et al. MD-2 expression is not required for cell surface targeting of Toll-like receptor 4 (TLR4)[J]. J Leukoc Biol,2006, 80(6):1584-1592.
[8]Johnsen IB, Nguyen TT, Ringdal M, et al. Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling[J]. EMBO J,2006, 25(14):3335-3346.
[9]Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B,Giese T, et al.Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides[J]. JImmunol,2002,168:4531-4537.
[10]Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens[J]. J Exp Med,2001,194:863-869.
[11]Gururajan M, Jacob J, Pulendran B. Toll-like receptor expression and responsiveness of distinct murine splenic and mucosal B-cell subsets[J]. PLoS One,2007,2:e863.
[12]Zarember KA, Godowski PJ. Tissue expression of human Tolllike receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines[J]. J Immunol,2002,168:554-561.
[13]Babu S, Blauvelt CP, Kumaraswami V, Nutman TB. Cutting edge:diminished T cell TLR expression and function modulates the immune response in human filarial infection[J]. J Immunol,2006,176:3885-3889.
[14]Carpenter S, O'Neill LA. How important are Toll-like receptors for antimicrobial responses[J]. Cell Microbiol,2007,9:1891-1901.
[15]Zhu J, Mohan C. Toll-like receptor signaling pathways-therapeutic opportunities[J]. Mediators Inflamm,2010,78:123-125.
[16]Akira S. Immunological mechanism in man against infection[J]. Nippon Naika Gakkai Zasshi,2001,90(12):2360-2365.
[17]Kawasaki K, Nogawa H, Nishijima M. Identification of mouse MD-2 residues important for forming the cell surface TLR4-MD-2 complex recognized by anti-TLR4-MD-2 antibodies, and for conferring LPS and taxol responsiveness on mouse TLR4 by alanine-scanning mutagenesis[J]. J Immunol.2003, 170(1):413-420.
[18]Kurt-Jones EA, Popova L, Kwinn L, et al. Pattern recognition receptors TLR4 and CD 14 mediate response to respiratory syncytial virus[J]. Nat Immunol.2000, 1(5):398-401.
[19]Taylor KR, Yamasaki K, Radek KA, et al. Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2[J]. J Biol Chem,2007,282(25):18265-18275.
[20]Lin FY, Chen YH, Tasi JS, et al. Endotoxin induces toll-like receptor 4 expression in vascular smooth muscle cells via NADPH oxidase activation and mitogen-activated protein kinase signaling pathways[J]. Arterioscler Thromb Vasc Biol,2006,26(12):2630-2637.
[21]Ozinsky A, Underhill DM, Fontenot JD, et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors[J].Proc Natl Acad Sci USA,2000,97(25):13766-13771.
[22]Hayashi F, Smith KD, Ozinsky A, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5[J]. Nature,2001, 410(6832):1099-1103.
[23]Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single stranded RNA via toll-like receptor 7 and 8[J]. Science,2004,303(5663):1526-1529.
[24]Hornung V, Guenthner-Biller M, Bourquin C, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7[J]. Nat Med,2005,2:63-70.
[25]Jurk M, Heil F, Vollmer J, et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848[J]. Nat Immunol,2002,3(6):499.
[26]Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA[J]. Nature,2000,408(6813):740-745.
[27]Alexopoulou L, Holt AC, Medzhitov R, et al. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3[J]. Nature,2001, 413(6857):732-738.
[28]Wang Z, Xiang L, Shao J, et al. The 3'CCACCA sequence of tRNAAla(UGC) is the motif that is important in inducing Thl-like immune response, and this motif can be recognized by Toll-like receptor 3[J]. Clin Vaccine Immunol, 2006,13(7):733-739.
[29]Zhang D, Zhang G, Hayden MS, et al. A toll-like receptor that prevents infection by uropathogenic bacteria[J]. Science,2004,5;303(5663):1522-1526.
[30]Sioud M.RNAi therapy: antibodies guide the way[J]. Gene Ther,2006, 13(3):194-195.
[31]O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of toll like receptors for infectious and inflammatory diseases and cancer[J]. Pharmacol Rev,2009, 61:177-197.
[32]O'Neill LA, Bowie AG. The family of five:TIR-domain-containing adaptors in Toll-like receptor signalling[J]. Nat Rev Immunol,2007,7:353-364.
[33]Uematsu S, Akira S. Toll-like receptors and Type I interferons[J]. J Biol Chem, 2007,282:15319-15323.
[34]Kumar H, Kawai T, Akira S. Toll-like receptors and innate.immunity[J]. Biochem Biophys Res Commun,2009,388:621-625.
[35]Jiang Z, Georgel P, Li C, Choe J, Crozat K, Rutschmann S, et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis[J]. Proc Natl Acad Sci USA,2006; 103:10961-10966.
[36]Zhu J, Mohan C. Toll-Like Receptor Signaling Pathways-Therapeutic Opportunities [J]. Mediators of Inflammation,2010,1:1-7
[37]Kawai T, Akira S. TLR signaling[J]. Cell Death Differ,2006,13(5):816-825.
[38]Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans[J]. NatGenet,2000,25(2):187-191.
[39]John B, Crispe IN. TLR-4 regulates CD8+ T cell trapping in the liver[J]. J Immunol,2005,175(3):1643-1650.
[40]Lysakova-Devine T, Keogh B, Harrington B, et al. Viral inhibitory peptide of TLR4, a peptide derived from vaccinia protein A46, specifically inhibits TLR4 by directly targeting MyD88 adaptor-like and TRIF-related adaptor molecule[J]. J Immunol,2010,185(7):4261-4271.
[41]Tabiasco J, Devevre E, Rufer N. Human effector CD8+ T lymphocytes express TLR3 as a functional coreceptor[J]. J Immunol,2006,177(12):8708-8713.
[42]Smits EL, Ponsaerts P, Berneman ZN, Van Tendeloo VF. The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy[J]. Oncologist,2008, 13:859-875.
[43]Schon M, Bong AB, Drewniok C, et al. Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod[J]. J Natl Cancer Inst, 2003,95:1138-1149.
[44]An H,Yu Y,Zhang M,et al. Involvement of ERK,p38 and NFκappaB signal transduction in tegulation og TLR2,TLR4 and TLR9 gene expression induced by lipopolysaccharide in mouse dendritc cells[J]. Immanology,2002,106(1):3845.
[45]Papadimitraki ED, Choulaki C, Koutala E, et al. Expansion of toll-like receptor 9-expressing B cells in active systemic lupus erythematosus:implications for the induction and maintenance of the autoimmune process[J]. Arthritis Rheum,2006, 54(11):3601-3611.
[46]Sacre SM, Andreakos E, Kiriakidis S, et al. The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis[J]. Am J Pathol,2007,170(2):518-525.
[47]Maratheftis CI, Andreakos E, Moutsopoulos HM, et al. Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes[J]. Clin Cancer Res,2007, 13(4):1154-1160.
[48]Xu N, Yao HP, Sun Z, et al. Toll-like receptor 7 and 9 expression in peripheral blood mononuclear cells from patients with chronic hepatitis B and related hepatocellular carcinoma[J]. Acta Pharmacol Sin,2008,29(2):239-244.
[49]. Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer[J]. Nat Rev Cancer,2009,9:57-63.
[50]Eui Young So and Toru Ouchi.The application of Toll like receptors for cancer therapy[J]. Iternational Journal of Biological Sciences,2010,6(7):675-681
[51]Okamoto M, Oshikawa T, Tano T, Ahmed SU, Kan S, Sasai A,et al. Mechanism of anticancer host response induced by OK-432, a streptococcal preparation, mediated by phagocytosis andToll-like receptor 4 signaling[J]. J Immunother, 2006,29:78-86.
[52]Huang B, Zhao J, Unkeless JC, Feng ZH, Xiong H. TLR signaling by tumor and immune cells:a double-edged sword[J].Oncogene,2008,27:218-224.
[1]Haggarty SJ, Koeler KM, Wong JC, et al. Domain selective small moleculer inhibitor of histone deacetylass 6(HDAC)-mediated tubulin deacetylation[J]. Proc Natl Acad Sci USA,2003,100(8):4389-439.
[2]Gregoretti IV, Lee YM, Goodson HV. Molecular evolution of the histone deacetylase family:functional implications of phylogenetic analysis[J]. J Mol Biol, 2004,338(1):17-31.
[3]Yang XJ, Seto E. HATs and HDACs:from structure, function and regulation to novel strategies for therapy and prevention[J]. Oncogene,26:5310-5318.
[4]Haigis MC, Guarente LP. Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction[J]. Genes Dev,20:2913-2921.
[5]Gao L, Cueto MA, Asselbergs F, et al. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family[J]. J Biol Chem 2002,277(28):25748-55.
[6]Yang XJ, Seto E. The Rpd3/Hdal family of lysine deacetylases:frombacteria and yeast to mice and men[J]. Nat Rev Mol Cell Biol,2008,9(3):206-218.
[7]Chandrima Das, M. Scott Lucia, Kirk C, et al. CBP/p300-mediated acetylation of histone H3 on lysine 56[J]. Nature Letters,2009,459:113-117.
[8]Michishita E, Park JY, Burneskis JM, et al. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins[J]. Mol Biol Cell,2005,16:4623-4635.
[9]Jin Q, Yan T, Ge X, Sun C, Shi X, Zhai Q. Cytoplasm-localized SIRT1 enhances apoptosis[J]. J Cell Physiol,2007,213(1):88-97.
[10]Stephanie Spangeab, TobiasWagnerb, Thorsten Heinzelb, et al. Acetylation of non-histone proteins modulates cellular signalling at multiple levels[J]. The International Journal of Biochemistry & Cell Biology.2009,41:185-198.
[11]Shahper N. Khan, Asad U. Khan. Role of histone acetylation in cell physiology and diseases:An update[J].Clinica Chimica Acta,2010,411 (19-20):1401-1411.
[12]Boda Zhou, Andriana Margariti, Lingfang Zeng, et al. Role of histone deacetylases in vascular cell homeostasis and arteriosclerosis [J]. Cardiovascular Research, 2011,10:1-8.
[13]. Chang S, Young BD, Li S, et al. Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase[J]. Cell,2006,126:321-334.
[14]Mottet D, Bellahcene A, Pirotte S, et al. Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis[J]. Circ Res,2007, 101:1237-1246.
[15]Okamoto H, Fujioka Y, Takahashi A, et al. Trichostatin A, an inhibitor of histone deacetylase, inhibits smooth muscle cell proliferation via induction of p21(WAF1) [J]. J Atheroscler Thromb,2006;13:183-191.
[16]Song S, Kang SW, Choi C. Trichostatin A enhances proliferation and migration of vascular smooth muscle cells by downregulating thioredoxin 1[J]. Cardiovasc Res, 2010,85:241-249.
[17]Xiao Q, Zeng L, Zhang Z, et al. Sca-1+ progenitors derived from embryonic stem cells differentiate into endothelial cells capable of vascular repair after arterial injury[J]. Arterioscler Thromb Vasc Biol,2006,26:2244-2251.
[18]Zeng L, Xiao Q, Margariti A, et al. HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells[J]. J Cell Biol,2006, 174:1059-1069.
[19]Margariti A, Xiao Q, Zampetaki A, et al. Splicing of HDAC7 modulates the SRF-myocardin complex during stem-cell differentiation towards smooth muscle cells[J]. J Cell Sci,2009,122:460-470.
[20]Lan Phaml, Bria Kaiserl, Amanda Romsa,et. HDAC3 and HDAC7 have opposite effects on osteoclast differentiation[J]. JBC,2011,1-17.
[21]Gao YS, Hubbert CC, Lu J, et al. Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis[J]. Mol Cell Biol,2007, 27:8637-8647.
[22]Zhang X, Yuan Z, Zhang Y, et al.HDAC6 modulates cell motility by altering the acetylation level of cortactin[J]. Mol Cell,2007,27:197-213.
[23]Zhang Y, Zhang M, Dong H, et al. Deacetylation of cortactin by SIRT1 promotes cell migration[J]. Oncogene,2009,28:445-460.
[24]Yan ZQ, Yao QP, Zhang ML, et al. Histone deacetylases modulate vascular smooth muscle cell migration induced by cyclic mechanical strain[J]. J Biomech,2009, 42:945-948.
[25]Song S, Kang SW, Choi C. Trichostatin A enhances proliferation and migration of vascular smooth muscle cells by downregulating thioredoxin 1[J]. Cardiovasc Res, 2010,85:241-249.
[26]Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1[J]. Proc Natl Acad Sci USA, 2007,104:12861-12866.
[27]Lagouge M, Argmann C, Gerhart-Hines Z, et al.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha[J]. Cell,2006,127:1109-1122.
[28]Schwer B, Bunkenborg J, Verdin RO, et al.Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2[J]. Proc Natl Acad Sci USA,2006,103:10224-10229.
[29]Hallows WC, Lee S, Denu JM. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases[J]. Proc Natl Acad Sci USA,2006,103:10230-10235.
[30]Haigis MC, Mostoslavsky R, Haigis KM, et al.SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells[J].Cell,2006,126:941-954.
[31]Westphal CH, Dipp MA, Guarente L.A therapeutic role for sirtuins in diseases of aging[J]. Trends Biochem Sci,2007,32:555-560.
[32]Kaeberlein M, McVey M, Guarente L.The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms[J]. Genes Dev,1999,13:2570-2580.
[33]Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans[J]. Nature,2001,10:227-230.
[34]Wood JG, Rogina B, Lavu S. Sirtuin activators mimic caloric restriction and delay ageing in metazoans[J]. Nature,2004,430:686-689.
[35]Imai S, Armstrong CM, Kaeberlein M, et al.Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histon deacetylase[J].Nature,2000,403:795-800.
[36]Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae[J].Science,2000, 289:2126-2128.
[37]Shi T, Wang F, Stieren E,et al. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes[J]. J Biol Chem,2005,280:13560-13567.
[38]Li X, Zhang S, Blander G et al.SIRT1 deacetylates and positively regulates the nuclear receptor LXR[J]. Mol Cell,2007,28:91-106.
[39]Potente M, Ghaeni L, Baldessari D, et al.SIRT1 controls endothelial angiogenic functions during vascular growth[J]. Genes Dev,2007,21:2644-2658.
[40]Mattagajasingh I, Kim CS, Naqvi A, et al. SIRT1 promotesendothelium dependent vascular relaxation by activating endothelial nitric oxide synthase[J]. Proc Natl Acad Sci USA,2007,104:14855-14860.
[41]Kim D, Nguyen MD, Dobbin MM, et al.SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis[J]. EMBO,2007,26:3169-3179.
[42]van der Veer E, Nong Z, O'Neil C, et al. Pre-B-cell colony-enhancing factor regulates NAD+-dependent protein deacetylase activity and promotes vascular smooth muscle cell maturation[J]. Circ Res,2005,97:25-34.
[43]Patel VA, Zhang QJ, Siddle K, et al. Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling[J]. Circ Res,2001, 88:895-902.
[44]Lei WW, Zhang KH, Pan XC, et al. Histone deacetylase 1 and 2 differentially regulate apoptosis by opposing effects on extracellular signal-regulated kinase 1/2[J]. Cell Death Dis,2010,1(5):e44.
[45]Firestein R, Blander G, Michan S, et al.The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth[J]. PLoS One,2008,3:e2020.
[46]Kabra N, Li Z, Chen L, et al.SirTl is an inhibitor of proliferation and tumor formation in colon cancer[J]. J Biol Chem,2009,284:18210-18217.
[47]Gottlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells[J]. EMBO J,2001, 20(24):69-78.
[48]Miller TA, Witter DJ, Belvedere S. Histone deacetylase inhibitors [J].. J Med Chem, 2003,46(24):5097-116.
[49]Stimson L, Wood V, Khan O, Fotheringham S, et al. HDAC inhibitor-based therapies and haematological malignancy[J]. Ann Oncol,2009,20:1293-1302.
[50]Drummond DC, Noble CO, Kirpotin DB, et al. Clinical development of histone deacetylase inhibitors as anticancer agents[J]. Annu Rev Pharmacol Toxicol,2005, 45:495-528.
[51]Mitsiades N, Mitsiades CS, Richardson PG, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells[J]. Blood,2003, 101:4055-4062.
[52]Neuzil J, Swettenham E, Gellert N. Sensitization of mesothelioma to TRAIL apoptosis by inhibition of histone deacetylase:role of Bcl-xL down-regulation[J]. Biochem Biophys Res Commun,2004,314:186-191.
[53]Shankar S, Singh TR, Fandy TE, et al. Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells:involvement of both death receptor and mitochondrial pathways[J]. Int J Mol Med,2005, 16:1125-1138.
[54]Singh TR, Shankar S, Srivastava RK. HDAC inhibitors enhance the apoptosis inducing potential of TRAIL in breast carcinoma[J]. Oncogene,2005, 24:4609-4623.
[55]Zhang XD, Gillespie SK, Borrow JM, et al. The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells[J]. Mol Cancer Ther,2004,3:425-435.
[56]Takai N, Kawamata N, Gui D, et al. Human ovarian carcinoma cells:histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis[J]. Cancer,2004,101:2760-2770.
[57]Dehm SM, Bonham K. SRC gene expression in human cancer:the role of transcriptional activation[J]. Biochem Cell Biol,2004,82:263-274.
[58]Heruth DP, Zirnstein GW, Bradley JF, et al. Sodium butyrate causes an increase in the block to transcriptional elongation in the c-myc gene in SW837 rectal carcinoma cells[J]. J Biol Chem,1993,268:20466-20472.
[59]Lallemand F, Courilleau D, Sabbah M, et al. Direct inhibition of the expression of cyclin D1 gene by sodium butyrate[J]. Biochem Biophys Res Commun,1996, 229:163-169.