OX40配体在小鼠组织和内皮细胞表达的研究
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摘要
背景
动脉粥样硬化斑块的发生、发展,斑块由稳定状态演变成不稳定及破裂,涉及到脂质代谢异常、炎症反应、内皮功能受损、遗传等众多因素,其具体机制尚待阐明。共刺激分子OX40配体(OX40L/CD134L/gp34),是参与T细胞活化的辅助性分子,是肿瘤坏死因子(TNF)家族成员之一。OX40L主要表达在活化的抗原递呈细胞表面,如树突状细胞、B淋巴细胞、巨噬细胞,以及血管内皮细胞中。逆向信号通路是共刺激分子的重要特征,即除了配体/受体的正向信号,受体也可通过配体传递逆向信号。在斑块部位OX40L表达增高,OX40与OX40L的结合可诱导人脐静脉内皮细胞c-jun基因表达上调、趋化因子RANTES/CCL5表达增高,直接介导T细胞或OX40+T细胞向内皮细胞黏附。研究发现C57BL/6小鼠对动脉粥样硬化具有易感性,而C3H/ He和BALB / c的小鼠对动脉粥样硬化不易感,经过数量性状座位筛查出第一个动脉粥样硬化的易感基因区域, OX40L基因就位于该区域。这些研究显示OX40L在动脉粥样硬化的形成和发展中可能起到重要作用。内皮功能受损不仅是斑块发生的始动环节,而且加速斑块生长、解除内皮对高危斑块的保护,内皮功能的严重受损是斑块急性炎症反应的诱发因素之一。C反应蛋白(CRP)是动脉粥样硬化的炎症标志物之一,参与动脉粥样硬化的致炎过程。本实验室前期研究显示CRP可引起心肌细胞损伤,循环中受炎症因子刺激升高的CRP是否影响到内皮细胞OX40L的表达和信号通路,尚待研究。
目的
本论文通过观察动脉粥样硬化易感小鼠C57BL/6和不易感小鼠BALB/c心脏、肾脏、脑、骨骼肌以及脾脏等组织中OX40L基因和蛋白表达差异,CRP对小鼠主动脉内皮细胞OX40L表达的作用,探讨OX40L在动脉粥样硬化斑块形成和发展中的可能作用机制。
内容与方法
1. 8周龄正常雄性C57BL/6小鼠和BALB/c小鼠各8只,平均体重22克。提取小鼠心脏、脑、肾脏、骨骼肌和脾脏总mRNA和总蛋白,采用RT-PCR和Western Blot的方法分别检测OX40L的mRNA和蛋白表达水平。
2.应用亲和层析柱从感染、炎症期及肿瘤患者胸水中分离、纯化CRP,电泳和Western Blot鉴定。
3.采用酶消化培养法原代培养小鼠主动脉内皮细胞,用内皮细胞特异性抗体VWF抗体鉴别小鼠主动脉内皮细胞。待小鼠主动脉内皮细胞密度长至60～70%时,用100ug/ml CRP干预内皮细胞,48小时后提取内皮细胞总mRNA和总蛋白,用RT-PCR和Western Blot方法检测内皮细胞OX40L和蛋白表达水平,重复3次。
结果
1. C57BL/6小鼠的心脏OX40L的mRNA表达水平显著高于BALB/c小鼠(0.79±0.10 vs 0.60±0.05, P <0.05,n=8);脑、肾脏和骨骼肌mRNA表达水平在两个品系小鼠间无明显差异;BALB/c小鼠脾脏OX40L的mRNA表达显著高于C57BL/6小鼠(0.39±0.17 vs 0.25±0.04, P <0.05,n=8);C57BL/6小鼠的心脏、脑和肾脏OX40L蛋白表达水平表达较BALB/c小鼠显著增高(0.56±0.01 vs 0.19±0.07,0.18±0.07 vs 0.01±0.01,0.31±0.13 vs 0.03±0.01,P<0.05,n=8),骨骼肌和脾脏OX40L蛋白的表达水平两种品系小鼠之间无显著差异。
2.纯化的CRP电泳分析纯度达95%以上,Western Blot显示纯化的CRP与CRP抗体特异性结合。
3.用纯化的100ug/ml的CRP与小鼠主动脉内皮细胞共孵育48小时后,干预的内皮细胞OX40L的mRNA和蛋白质表达较未干预细胞显著增高(0.09±0.04 vs 0.76±0.12,P<0.05;0.07±0.02 vs 0.21±0.06,P<0.05,n=3)。
结论
OX40L在正常动脉粥样硬化易感C57BL/6小鼠和不易感BALB/c小鼠的心脏、脑、肾脏、骨骼肌和脾脏组织中基因和蛋白表达水平存在差异。CRP可诱导小鼠主动脉内皮细胞OX40L表达增高,提示OX40L可能在动脉粥样硬化中发挥作用。
Introduction
The occurrence, development and the process from stability to rapture of atherosclerotic plaques are associated with number of factors such as the disorder of lipid metabolism, involvement of immune system, endothelial dysfunction and genetic background. The exact mechanism is still under investigation. OX40 Ligand (OX40L/CD134L/gp34), a kind of co-stimulator molecules, belongs to the TNF super family. It acts as the auxiliary factor involving the process of inflammation. OX40L is mainly expressed on surface of the antigen presented cells, vascular endothelial cells and smooth muscle cells. The reverse signal pathway is an important factor of co-stimulatory molecules. It means that OX40L can also transducer the signal from its receptor, OX40L, to intracellular pathway. OX40L is highly expressed in the atherosclerotic plaque. The ligation of OX40 and OX40L can induce increased expression of c-jun gene and RANTES/CCL5 in human umbilicus veins endothelial cells , directly induces the adhesion of T-cells or OX40L+T cells to endothelial cells. Previous study find that the C57BL/6 mice are atherosclerosis susceptible, while the C3H/ He mice are atherosclerosis resistant. They foud the first atherosclerosis susceptible gene including OX40L gene by the mothed of quantitative trait locus. The dysfunction of endothelial cells not only is the initial step of development of atherosclerosis but also accelerate the formation of the atherosclerosis lesions. While the atherosclerosis lesions are relieve from the protection of endothelial cells The administration of OX40L monoclonal antibody reverses the plaque in atherosclerotic mice. These data suggests a pivotal role of OX40L in atherosclerosis. C-reactive protein (CRP) is an acute-phase reactant and serves as a pattern-recognition molecule in the innate immune system. It is regarded as an inflammatory marker atherosclerosis. Our previous data showed that CRP can induce the injury of cardiac myocytes. In fact, the high expression of CRP level is seen in the blood of patients with coronary artery disease. Whether the increase of CRP in the peripheral circulation influences the expression of OX40L in endothelial cells is unknown.
Objective
The present study was designed to compare the expression of OX40L in tissues from normal atherosclerosis susceptible C57BL/6 mice with normal atherosclerosis resistant BALB/c mice. Investigate the effect of CRP on OX40L expression in cultured C57BL/6 mice aorta endothelial cells.
Methods
1.Eight C57BL/6 mice and eight BALB/c mice at the age of eight weeks were sacrificed, and the total mRNA as well as tissue homogenates were isolated from the heart, brain, kidney, skeletal muscle and spleen. The OX40L mRNA expression level detected by RT-PCR and the protein expression level was detected by Western Blot.
2.CRP was purified by Immobilized p-Aminophenyl Phosphoryl Choline Gel. The purified CRP was analysis by SDS-PAGE and identified by Western Blot.
3. BALB/c mice were sacrificed and the aorta was dissected. The generation of cultured endothelial cells was utilized by collagenaseⅡdigestion of the aorta. The identification of the endothelial cells carried out by immunostaining with special antibody factorⅧantibody. When the endothelial cells grow to about 60~70% of the dish, 100ug/ml CRP was applied to medium. 48 hours later, the endothelial cells were collected and the total RNA and protein homogenates were isolated. The gene expression and protein expression of OX40L were measured by RT-PCR and Western Blot respectively.
Results
1. The OX40L mRNA expression level in the heart of C57BL/6 mice was significantly higher than that of BALB/c mice (0.79±0.10 vs 0.60±0.05, P <0.05, n=8). There was no significant difference between BALB/c mice and C57BL/6 mice in brain, kidney and skeletal muscle. The OX40L mRNA level was augmented significantly in the spleen from BALB/c mice than that from C57BL/6 mice (0.39±0.17 vs 0.25±0.04, P <0.05, n=8). The protein levels of OX40L expressed significantly higher in the heart, brain and kidney from and was C57BL/6 mice than those from BALB/c mice, respectively (0.56±0.01 vs 0.19±0.07, 0.18±0.07 vs 0.01±0.01, 0.31±0.13 vs 0.03±0.01, P<0.05, n=8). No significant difference was obtained in skeletal muscle and spleen between these two kinds of mouse.
2. The purified CRP showed more than 95% purity by SDS-PAGE. The purified CRP binded specifically to CRP monoclonal antibody.
3. After 48 hours treatment of 100 ug/ml CRP, the expressions of OX40L mRNA or protein level, in the treated cultured endothelial cells were significantly augmented than those in the untreated cultured endothelial cells (0.09±0.04 vs 0.76±0.12 and 0.07±0.02 vs 0.21±0.06,P<0.05, n=3).
Conclusions
The present study showed the different expression level of OX40L tissues from BALB/c mice and C57BL/6 mice. CRP can induce the expression of OX40L in mouse aortic endothelial cells. These data suggested a role underlying the mechanism of OX40L in atherosclerosis.
动脉粥样硬化斑块的发生、发展,斑块由稳定状态演变成不稳定及破裂,涉及到脂质代谢异常、炎症反应、内皮功能受损、遗传等众多因素,其具体机制尚待阐明。共刺激分子OX40配体(OX40L/CD134L/gp34),是参与T细胞活化的辅助性分子,是肿瘤坏死因子(TNF)家族成员之一。OX40L主要表达在活化的抗原递呈细胞表面,如树突状细胞、B淋巴细胞、巨噬细胞,以及血管内皮细胞中。逆向信号通路是共刺激分子的重要特征,即除了配体/受体的正向信号,受体也可通过配体传递逆向信号。在斑块部位OX40L表达增高,OX40与OX40L的结合可诱导人脐静脉内皮细胞c-jun基因表达上调、趋化因子RANTES/CCL5表达增高,直接介导T细胞或OX40+T细胞向内皮细胞黏附。研究发现C57BL/6小鼠对动脉粥样硬化具有易感性,而C3H/ He和BALB / c的小鼠对动脉粥样硬化不易感,经过数量性状座位筛查出第一个动脉粥样硬化的易感基因区域, OX40L基因就位于该区域。这些研究显示OX40L在动脉粥样硬化的形成和发展中可能起到重要作用。内皮功能受损不仅是斑块发生的始动环节,而且加速斑块生长、解除内皮对高危斑块的保护,内皮功能的严重受损是斑块急性炎症反应的诱发因素之一。C反应蛋白(CRP)是动脉粥样硬化的炎症标志物之一,参与动脉粥样硬化的致炎过程。本实验室前期研究显示CRP可引起心肌细胞损伤,循环中受炎症因子刺激升高的CRP是否影响到内皮细胞OX40L的表达和信号通路,尚待研究。
目的
本论文通过观察动脉粥样硬化易感小鼠C57BL/6和不易感小鼠BALB/c心脏、肾脏、脑、骨骼肌以及脾脏等组织中OX40L基因和蛋白表达差异,CRP对小鼠主动脉内皮细胞OX40L表达的作用,探讨OX40L在动脉粥样硬化斑块形成和发展中的可能作用机制。
内容与方法
1. 8周龄正常雄性C57BL/6小鼠和BALB/c小鼠各8只,平均体重22克。提取小鼠心脏、脑、肾脏、骨骼肌和脾脏总mRNA和总蛋白,采用RT-PCR和Western Blot的方法分别检测OX40L的mRNA和蛋白表达水平。
2.应用亲和层析柱从感染、炎症期及肿瘤患者胸水中分离、纯化CRP,电泳和Western Blot鉴定。
3.采用酶消化培养法原代培养小鼠主动脉内皮细胞,用内皮细胞特异性抗体VWF抗体鉴别小鼠主动脉内皮细胞。待小鼠主动脉内皮细胞密度长至60～70%时,用100ug/ml CRP干预内皮细胞,48小时后提取内皮细胞总mRNA和总蛋白,用RT-PCR和Western Blot方法检测内皮细胞OX40L和蛋白表达水平,重复3次。
结果
1. C57BL/6小鼠的心脏OX40L的mRNA表达水平显著高于BALB/c小鼠(0.79±0.10 vs 0.60±0.05, P <0.05,n=8);脑、肾脏和骨骼肌mRNA表达水平在两个品系小鼠间无明显差异;BALB/c小鼠脾脏OX40L的mRNA表达显著高于C57BL/6小鼠(0.39±0.17 vs 0.25±0.04, P <0.05,n=8);C57BL/6小鼠的心脏、脑和肾脏OX40L蛋白表达水平表达较BALB/c小鼠显著增高(0.56±0.01 vs 0.19±0.07,0.18±0.07 vs 0.01±0.01,0.31±0.13 vs 0.03±0.01,P<0.05,n=8),骨骼肌和脾脏OX40L蛋白的表达水平两种品系小鼠之间无显著差异。
2.纯化的CRP电泳分析纯度达95%以上,Western Blot显示纯化的CRP与CRP抗体特异性结合。
3.用纯化的100ug/ml的CRP与小鼠主动脉内皮细胞共孵育48小时后,干预的内皮细胞OX40L的mRNA和蛋白质表达较未干预细胞显著增高(0.09±0.04 vs 0.76±0.12,P<0.05;0.07±0.02 vs 0.21±0.06,P<0.05,n=3)。
结论
OX40L在正常动脉粥样硬化易感C57BL/6小鼠和不易感BALB/c小鼠的心脏、脑、肾脏、骨骼肌和脾脏组织中基因和蛋白表达水平存在差异。CRP可诱导小鼠主动脉内皮细胞OX40L表达增高,提示OX40L可能在动脉粥样硬化中发挥作用。
Introduction
The occurrence, development and the process from stability to rapture of atherosclerotic plaques are associated with number of factors such as the disorder of lipid metabolism, involvement of immune system, endothelial dysfunction and genetic background. The exact mechanism is still under investigation. OX40 Ligand (OX40L/CD134L/gp34), a kind of co-stimulator molecules, belongs to the TNF super family. It acts as the auxiliary factor involving the process of inflammation. OX40L is mainly expressed on surface of the antigen presented cells, vascular endothelial cells and smooth muscle cells. The reverse signal pathway is an important factor of co-stimulatory molecules. It means that OX40L can also transducer the signal from its receptor, OX40L, to intracellular pathway. OX40L is highly expressed in the atherosclerotic plaque. The ligation of OX40 and OX40L can induce increased expression of c-jun gene and RANTES/CCL5 in human umbilicus veins endothelial cells , directly induces the adhesion of T-cells or OX40L+T cells to endothelial cells. Previous study find that the C57BL/6 mice are atherosclerosis susceptible, while the C3H/ He mice are atherosclerosis resistant. They foud the first atherosclerosis susceptible gene including OX40L gene by the mothed of quantitative trait locus. The dysfunction of endothelial cells not only is the initial step of development of atherosclerosis but also accelerate the formation of the atherosclerosis lesions. While the atherosclerosis lesions are relieve from the protection of endothelial cells The administration of OX40L monoclonal antibody reverses the plaque in atherosclerotic mice. These data suggests a pivotal role of OX40L in atherosclerosis. C-reactive protein (CRP) is an acute-phase reactant and serves as a pattern-recognition molecule in the innate immune system. It is regarded as an inflammatory marker atherosclerosis. Our previous data showed that CRP can induce the injury of cardiac myocytes. In fact, the high expression of CRP level is seen in the blood of patients with coronary artery disease. Whether the increase of CRP in the peripheral circulation influences the expression of OX40L in endothelial cells is unknown.
Objective
The present study was designed to compare the expression of OX40L in tissues from normal atherosclerosis susceptible C57BL/6 mice with normal atherosclerosis resistant BALB/c mice. Investigate the effect of CRP on OX40L expression in cultured C57BL/6 mice aorta endothelial cells.
Methods
1.Eight C57BL/6 mice and eight BALB/c mice at the age of eight weeks were sacrificed, and the total mRNA as well as tissue homogenates were isolated from the heart, brain, kidney, skeletal muscle and spleen. The OX40L mRNA expression level detected by RT-PCR and the protein expression level was detected by Western Blot.
2.CRP was purified by Immobilized p-Aminophenyl Phosphoryl Choline Gel. The purified CRP was analysis by SDS-PAGE and identified by Western Blot.
3. BALB/c mice were sacrificed and the aorta was dissected. The generation of cultured endothelial cells was utilized by collagenaseⅡdigestion of the aorta. The identification of the endothelial cells carried out by immunostaining with special antibody factorⅧantibody. When the endothelial cells grow to about 60~70% of the dish, 100ug/ml CRP was applied to medium. 48 hours later, the endothelial cells were collected and the total RNA and protein homogenates were isolated. The gene expression and protein expression of OX40L were measured by RT-PCR and Western Blot respectively.
Results
1. The OX40L mRNA expression level in the heart of C57BL/6 mice was significantly higher than that of BALB/c mice (0.79±0.10 vs 0.60±0.05, P <0.05, n=8). There was no significant difference between BALB/c mice and C57BL/6 mice in brain, kidney and skeletal muscle. The OX40L mRNA level was augmented significantly in the spleen from BALB/c mice than that from C57BL/6 mice (0.39±0.17 vs 0.25±0.04, P <0.05, n=8). The protein levels of OX40L expressed significantly higher in the heart, brain and kidney from and was C57BL/6 mice than those from BALB/c mice, respectively (0.56±0.01 vs 0.19±0.07, 0.18±0.07 vs 0.01±0.01, 0.31±0.13 vs 0.03±0.01, P<0.05, n=8). No significant difference was obtained in skeletal muscle and spleen between these two kinds of mouse.
2. The purified CRP showed more than 95% purity by SDS-PAGE. The purified CRP binded specifically to CRP monoclonal antibody.
3. After 48 hours treatment of 100 ug/ml CRP, the expressions of OX40L mRNA or protein level, in the treated cultured endothelial cells were significantly augmented than those in the untreated cultured endothelial cells (0.09±0.04 vs 0.76±0.12 and 0.07±0.02 vs 0.21±0.06,P<0.05, n=3).
Conclusions
The present study showed the different expression level of OX40L tissues from BALB/c mice and C57BL/6 mice. CRP can induce the expression of OX40L in mouse aortic endothelial cells. These data suggested a role underlying the mechanism of OX40L in atherosclerosis.
引文
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[14] Pepys MB, Hirschfield GM, Tennent GA, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006;440:1217-1221.
[15] Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74: 609-619.
[16] Li JJ, Fang CH. C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases. Medical hypotheses 2004;62:499-506.
[17] Jousilahti P, Vartiainen E, Tuomilehto J, et al. Symptoms of chronic bronchitis and the risk of coronary disease. Lancet 1996;348:567-572.
[18] Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet 1997;350:430-436.
[19] Hatanaka K, Li XA, Masuda K, et al. Immunohistochemical localization of C-reactive protein-binding sites in human atherosclerotic aortic lesions by a modified streptavidin-biotin-staining method. Pathology international 1995;45: 635-641.
[20] Chen Z, Chua CC, Ho YS, et al. Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. American journal of physiology 2001;280:H2313-2320.
[1] Goran K. Hansson. Inflammation, Atherosclerosis,and Coronary Artery Disease. N Engl J Med 2005; 353:429-430.
[2] GAllen P. Burke, Russell P. Tracy, Frank Kolodgie, et al. Elevated C-Reactive Protein Values and Atherosclerosis in Sudden Coronary Death. Circulation. 2002;105:2019-2023.
[3] K. Hansson, Peter Libby, Uwe Sch?nbeck,et al. Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis. Circ. Res. 2002;91;281-291.
[4] Imura A, Hori T, Imada K, et al. The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells. J Exp Med.1996;183:2185-2195.
[5] Xiaosong Wang, Massimiliano Ria, Peter M Kelmenson, et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influencesatherosclerosis susceptibility. Nature Genetics. 2005; 37: 365-372.
[6] Xiaosong Wang, Massimiliano Ria, Peter M Kelmenson, et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nature Genetics. 2005; 37: 365-372.
[7] David W Lincoln II, Ann M Larsen, Patricia G Phillips, et al. Isolation of murine aortic endothelial cells in culture and the effects of sex steroids on their growth. In Vitro Cellular & Developmental Biology.2003; 39:140-145.
[8] Mika Kobayashi, Kenji Inoue, Eiji Warabi, et al. A simple method of isolating mouse aortic endothelial cells. Journal of atherosclerosis and thrombosis. 2004; 12:138-142.
[9] Jonasson L, Holm J, Skalli O, et al. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986; 6:131–138.
[10] Ai Kotani, Toshiyuki Hori, Yumi Matsumura,et al.Signaling of gp34 (OX40 ligand) induces vascular endothelial cells to produce a CC chemokine RANTES/CCL5. Immunology Letters. 2002; 84: 1-7.
[11] Eva J.A van Wanrooij, Gijs H.M van Puijvelde, Paula de Vos, et al. Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice. Arterioscler Thromb Vasc Biol. 2007; 27:204-210.
[12] Vincenzo Pasceri, James T. Willerson and Edward T. H. Yeh, et al. Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial cells. Circulation 2000; 102: 2165-2168.
[13] Bruno Baudin, Arnaud Bruneel, Nelly Bosselut ,et al. A protocol for isolation and culture of human umbilical vein endothelial cells.Nature Protocols. 2007; 2: 481-485.
[14] Allen P. Burke, Russell P. Tracy, Frank Kolodgie, et al. Elevated C-Reactive Protein values and atherosclerosis in sudden coronary death: association with different pathologies. Circulation. 2002; 105: 2019-2023.
[1] WHO. The world health report 2004: changing history, World Health Organization. Geneva; May 2004.
[2] Binder CJ,Chang MK, Shaw PX, et al. Innate and acquire immunity inatherogenesis. Nat Med. 2002; 8: 1218-1226.
[3] Skalen K, Gustafsson M, Rydberg EK, et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002; 417: 750-4.
[4] Leitinger N. Oxidized phospholipids as modulators of inflammation in atherosclerosis. Curr Opin Lipidol. 2003; 14: 421-30.
[5] Dai G, Kaazempur-Mofrad MR, Natarajan S, et al. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis- susceptible and-resistant regions of human vasculature. Proc Natl Acad Sci U S A. 2004; 101: 14871-6.
[6] Norbert Leitinger. Cholesterol ester oxidation products in atherosclerosis. Mol Asp Med. 2003; 24: 239-250.
[7] Eriksson EE, Xie X, Werr J, et al. Importance of primary capture and L-selectin-dependent secondary capture in leukocyte accumulation in inflammation and atherosclerosis in vivo. J Exp Med. 2001; 194: 205-18.
[8] Aldons J. Lusis. Atherosclerosis. Nature. 2000; 407: 233-241.
[9] Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 2003; 3: 609–620.
[10] Watts, T. H. TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 2005; 23: 23–68.
[11] Sugamura, K., N. Ishii, A. D. Weinberg. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat. Rev. Immunol. 2004; 4: 420–431.
[12] Lieping Chen. Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity. Nat. Rev. Immunol. 2004; 4: 336–347.
[13] Godfrey W. R., F. F. Fagnoni, M. A. Harara, et al. Identification of a human OX-40 ligand, a costimulator of CD4+T cells with homology to tumor necrosis factor. J. Exp. Med. 1994; 180: 757-762.
[14] Latza U, Durkop H, Sehnitiger S, et al. The human OX40 homolog: cDNA structure ,expression and chromosomal assignment of the ACT35 antigen[J]. Eur Imunol. 1994; 24: 677-683.
[15] Calderhead DM, Buhlmann JE, van den Eertwegh AJ, et al. Cloning of mouse Ox40: a T cell activation marker that may mediate T-B cell interactions. J Immunol. 1993; 151: 5261–5271.
[16] Deanne M.Compaan, Sarah G. Hymowitz, et al. The crystal structure of the costimulatory OX40-OX40L complex. Structure. 2006; 14: 1321-1330.
[17] Ohshima Y, Tanaka H, Tozawa Y, et al. Expression and function of OX40 ligand on human dendritic cells. J. Immunol. 1997; 159: 3838-3848.
[18] Brocker, T., A. Gulbranson-Judge, S. Flynn, M. Riedinger, et al. CD4 T cell traffic control: in vivo evidence that ligation of OX40 on CD4 T cells by OX40-ligand expressed on dendritic cells leads to the accumulation of CD4 T cells in B follicles. Eur. J. Immunol. 1999; 29: 1610-1616.
[19] Imura, A., T. Hori, K. Imada, et al. The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells. J. Exp. Med. 1996; 183: 2185-2195.
[20] Gramaglia I., A. D. Weinberg, M. Lemon, et al. OX40 ligand: a potent co-stimulatory molecule for sustaining primary CD4 T cell responses. J. Immunol. 1998; 161: 6510-6517.
[21] Gramaglia I., A. Jember, S. D. Pippig, et al. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J. Immunol. 2000; 165: 3043-3050
[22] Pejman Soroosh, Shouji Ine, Kazuo Sugamura, et al. OX40-OX40L Ligand Interaction through T cell-T cell Contact Contributes to CD4 T Cell Longevity. J. Immunol. 2006; 6: 5975-5987.
[23] Linton PJ, Bautista B, Biederman E, et al. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo.J Exp Med. 2003; 197: 875-883.
[24] Linton PJ, Bautista B, Biederman E, et al. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo.J Exp Med. 2003; 197: 875-883.
[25] Stuber, E., and W. Strober. The T cell-B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response. J. Exp. Med. 1996; 183: 979.
[26] Lane P. Role of OX40 signal in co-ordinating CD4 T cell selection, migration, and cytokine differentiation in T helper (Th) 1 and Th2 cells [J]. J Exp Med. 2000; 191: 201-206.
[27] Kazuko Murata, Masato Nose, Lishomwa C. Ndhlovu, et al. Constitutive OX40/OX40 Ligand Interaction Induces Autoimmune-Like Diseases.J Immunol. 2002; 169: 4628-4636.
[28] Ian R. Humphreys, Gerhard Walzl, Lorna Edwards, et al A Critical Role for OX40 in T Cell–mediated Immunopathology during Lung Viral Infection. J Exp Med. 2003; 198: 1237-1242.
[29] Takaori-Kondo A, Horizontal T, Fukunaga K, et al. Both amino-and carboxyl-terminal domains of TRAF3 negatively regulate NF-kappa B activation induced by OX40 signaling. Biochem biophys res common. 2000; 272: 856-863.
[30] Hong Ye, Hao Wu. Thermodynamic characterization of the interaction between TRAF2 and tumor necrosis factor receptor peptides by isothermal titration calorimetry[J]. Proc Natl Acad Sci USA. 2000; 97: 8961.
[31] Yumi Matsumura, Toshiyuki Hori, Shin Kawamata, et al. Intracellular Signaling of gp34, the OX40 Ligand: Induction of c-jun and c-fos mRNAExpression Through gp34 upon Binding of Its Receptor, OX40. J. Immunol. 1999; 163: 3007-3011.
[32] L Jonasson, J Holm, O Skalli, et al. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Atherosclerosis. 1986; 6: 131-138.
[33] PAIGEN B., Mitchell D., Reue A., et al. Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc. NatI. Acad. Sci. 1987; 84: 3763-3767.
[34] Xiaosong Wang, Massimiliano Ria, Peter M Kelmenson, et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nature Genetics. 2005; 37: 365-372.
[35] Eva J.A van Wanrooij, Gijs H.M van Puijvelde, Paula de Vos, et al. Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice. Arterioscler Thromb Vasc Biol. 2007; 27: 204-210.
[36]王燃燃.彭道泉.赵水平.冠心病相关的炎症新指标OX40L.中国心血管杂志. 2006; 34: 1110-1112.
[2] Deanne M.Compaan, Sarah G. Hymowitz,et al. The crystal structure of the costimulatory OX40-OX40L complex. Structure. 2006; 14: 1321-1330.
[3] Ohshima Y, Tanaka H, Tozawa Y, et al. Expression and function of OX40 ligand on human dendritic cells. J. Immunol. 1997; 159: 3838-3848.
[4] Brocker, T., A. Gulbranson-Judge, S. Flynn, M. Riedinger, et al. CD4 T cell traffic control: in vivo evidence that ligation of OX40 on CD4 T cells by OX40-ligand expressed on dendritic cells leads to the accumulation of CD4 T cells in B follicles. Eur. J. Immunol. 1999; 29: 1610-1616.
[5] Imura, A., T. Hori, K. Imada, et al. The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells. J. Exp. Med. 1996; 183: 2185-2195.
[6] Gramaglia I., A. D. Weinberg, M. Lemon, et al. OX40 ligand: a potent co-stimulatory molecule for sustaining primary CD4 T cell responses. J. Immunol. 1998; 161: 6510-6517.
[7] Pejman Soroosh, Shouji Ine, Kazuo Sugamura, et al. OX40-OX40L Ligand Interaction through T cell-T cell Contact Contributes to CD4 T Cell Longevity. J. Immunol. 2006; 6: 5975-5987.
[8] Linton PJ, Bautista B, Biederman E, et al. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo.J Exp Med. 2003; 197: 875-883.
[9] Xiaosong Wang, Massimiliano Ria, Peter M Kelmenson, et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nature Genetics. 2005; 37: 365-372.
[10] Aldons J. Lusis. Atherosclerosis. Nature. 2000; 407: 233-241.
[11] Jin-Chuan Yan, Dong-Ming Liu, Cui-Ping Wang, et al. Increased levels of soluble and membrane-bound OX40 ligand in patients with acute coronary syndrome. Biomed. Pharmaco. 2008. Epub ahead of print.
[12] Paigen, B., Morrow, A., Brandon, C., et al. Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis. 1985; 57: 65–73.
[13] S. Bj?rkerud and B. Bj?rkerud. Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. Am J Pathol. 1996; 149: 367– 380.
[14] L Jonasson, J Holm, O Skalli, et al. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Atherosclerosis. 1986; 6: 131-138.
[15] Eva J.A van Wanrooij, Gijs H.M van Puijvelde, Paula de Vos, et al. Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice. Arterioscler Thromb Vasc Biol. 2007; 27: 204-210.
[1] Albert CM, Ma J, Rifai N, et al. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 2002;105:2595-2599.
[2] Ridker PM, Cushman M, Stampfer M, et al. Inflammation, aspirin, and the riskof cardiovascular disease in apparently healthy men. The New England journal of medicine 1997;336:973-979.
[3] Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. Jama 2001;285:2481-2485.
[4] Li L, Roumeliotis N, Sawamura T, et al.. C-reactive protein enhances LOX-1 expression in human aortic endothelial cells: relevance of LOX-1 to C-reactive protein-induced endothelial dysfunction. Circulation research 2004;95:877-883.
[5] Suh W, Kim KL, Choi JH, et al. C-reactive protein impairs angiogenic functions and decreases the secretion of arteriogenic chemo-cytokines in human endothelial progenitor cells. Biochemical and biophysical research communications 2004; 321: 65-71.
[6] Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 2002;106:913-919.
[7] Venugopal SK, Devaraj S, Yuhanna I, et al. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation 2002;106:1439-1441.
[8] Wang Q, Zhu X, Xu Q, et al. Effect of C-reactive protein on gene expression in vascular endothelial cells. American journal of physiology 2005;288: H1539- 1545.
[9] Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. The New England journal of medicine 2000; 342:836-843.
[10] Devaraj S, Kumaresan PR, Jialal I. Effect of C-reactive protein on chemokineexpression in human aortic endothelial cells. Journal of molecular and cellular cardiology 2004; 36:405-410.
[11] Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation 2003; 107:398- 404.
[12] Singh U, Dasu MR, Yancey PG, et al. Human C-reactive protein promotes oxidized low-density lipoprotein uptake and matrix metalloproteinase-9 release in wistar rats. Journal of lipid research. 2008.
[13] Hattori Y, Matsumura M, Kasai K. Vascular smooth muscle cell activation by C-reactive protein. Cardiovascular research 2003;58:186-195.
[14] Pepys MB, Hirschfield GM, Tennent GA, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006;440:1217-1221.
[15] Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74: 609-619.
[16] Li JJ, Fang CH. C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases. Medical hypotheses 2004;62:499-506.
[17] Jousilahti P, Vartiainen E, Tuomilehto J, et al. Symptoms of chronic bronchitis and the risk of coronary disease. Lancet 1996;348:567-572.
[18] Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet 1997;350:430-436.
[19] Hatanaka K, Li XA, Masuda K, et al. Immunohistochemical localization of C-reactive protein-binding sites in human atherosclerotic aortic lesions by a modified streptavidin-biotin-staining method. Pathology international 1995;45: 635-641.
[20] Chen Z, Chua CC, Ho YS, et al. Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. American journal of physiology 2001;280:H2313-2320.
[1] Goran K. Hansson. Inflammation, Atherosclerosis,and Coronary Artery Disease. N Engl J Med 2005; 353:429-430.
[2] GAllen P. Burke, Russell P. Tracy, Frank Kolodgie, et al. Elevated C-Reactive Protein Values and Atherosclerosis in Sudden Coronary Death. Circulation. 2002;105:2019-2023.
[3] K. Hansson, Peter Libby, Uwe Sch?nbeck,et al. Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis. Circ. Res. 2002;91;281-291.
[4] Imura A, Hori T, Imada K, et al. The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells. J Exp Med.1996;183:2185-2195.
[5] Xiaosong Wang, Massimiliano Ria, Peter M Kelmenson, et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influencesatherosclerosis susceptibility. Nature Genetics. 2005; 37: 365-372.
[6] Xiaosong Wang, Massimiliano Ria, Peter M Kelmenson, et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nature Genetics. 2005; 37: 365-372.
[7] David W Lincoln II, Ann M Larsen, Patricia G Phillips, et al. Isolation of murine aortic endothelial cells in culture and the effects of sex steroids on their growth. In Vitro Cellular & Developmental Biology.2003; 39:140-145.
[8] Mika Kobayashi, Kenji Inoue, Eiji Warabi, et al. A simple method of isolating mouse aortic endothelial cells. Journal of atherosclerosis and thrombosis. 2004; 12:138-142.
[9] Jonasson L, Holm J, Skalli O, et al. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986; 6:131–138.
[10] Ai Kotani, Toshiyuki Hori, Yumi Matsumura,et al.Signaling of gp34 (OX40 ligand) induces vascular endothelial cells to produce a CC chemokine RANTES/CCL5. Immunology Letters. 2002; 84: 1-7.
[11] Eva J.A van Wanrooij, Gijs H.M van Puijvelde, Paula de Vos, et al. Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice. Arterioscler Thromb Vasc Biol. 2007; 27:204-210.
[12] Vincenzo Pasceri, James T. Willerson and Edward T. H. Yeh, et al. Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial cells. Circulation 2000; 102: 2165-2168.
[13] Bruno Baudin, Arnaud Bruneel, Nelly Bosselut ,et al. A protocol for isolation and culture of human umbilical vein endothelial cells.Nature Protocols. 2007; 2: 481-485.
[14] Allen P. Burke, Russell P. Tracy, Frank Kolodgie, et al. Elevated C-Reactive Protein values and atherosclerosis in sudden coronary death: association with different pathologies. Circulation. 2002; 105: 2019-2023.
[1] WHO. The world health report 2004: changing history, World Health Organization. Geneva; May 2004.
[2] Binder CJ,Chang MK, Shaw PX, et al. Innate and acquire immunity inatherogenesis. Nat Med. 2002; 8: 1218-1226.
[3] Skalen K, Gustafsson M, Rydberg EK, et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002; 417: 750-4.
[4] Leitinger N. Oxidized phospholipids as modulators of inflammation in atherosclerosis. Curr Opin Lipidol. 2003; 14: 421-30.
[5] Dai G, Kaazempur-Mofrad MR, Natarajan S, et al. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis- susceptible and-resistant regions of human vasculature. Proc Natl Acad Sci U S A. 2004; 101: 14871-6.
[6] Norbert Leitinger. Cholesterol ester oxidation products in atherosclerosis. Mol Asp Med. 2003; 24: 239-250.
[7] Eriksson EE, Xie X, Werr J, et al. Importance of primary capture and L-selectin-dependent secondary capture in leukocyte accumulation in inflammation and atherosclerosis in vivo. J Exp Med. 2001; 194: 205-18.
[8] Aldons J. Lusis. Atherosclerosis. Nature. 2000; 407: 233-241.
[9] Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 2003; 3: 609–620.
[10] Watts, T. H. TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 2005; 23: 23–68.
[11] Sugamura, K., N. Ishii, A. D. Weinberg. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat. Rev. Immunol. 2004; 4: 420–431.
[12] Lieping Chen. Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity. Nat. Rev. Immunol. 2004; 4: 336–347.
[13] Godfrey W. R., F. F. Fagnoni, M. A. Harara, et al. Identification of a human OX-40 ligand, a costimulator of CD4+T cells with homology to tumor necrosis factor. J. Exp. Med. 1994; 180: 757-762.
[14] Latza U, Durkop H, Sehnitiger S, et al. The human OX40 homolog: cDNA structure ,expression and chromosomal assignment of the ACT35 antigen[J]. Eur Imunol. 1994; 24: 677-683.
[15] Calderhead DM, Buhlmann JE, van den Eertwegh AJ, et al. Cloning of mouse Ox40: a T cell activation marker that may mediate T-B cell interactions. J Immunol. 1993; 151: 5261–5271.
[16] Deanne M.Compaan, Sarah G. Hymowitz, et al. The crystal structure of the costimulatory OX40-OX40L complex. Structure. 2006; 14: 1321-1330.
[17] Ohshima Y, Tanaka H, Tozawa Y, et al. Expression and function of OX40 ligand on human dendritic cells. J. Immunol. 1997; 159: 3838-3848.
[18] Brocker, T., A. Gulbranson-Judge, S. Flynn, M. Riedinger, et al. CD4 T cell traffic control: in vivo evidence that ligation of OX40 on CD4 T cells by OX40-ligand expressed on dendritic cells leads to the accumulation of CD4 T cells in B follicles. Eur. J. Immunol. 1999; 29: 1610-1616.
[19] Imura, A., T. Hori, K. Imada, et al. The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells. J. Exp. Med. 1996; 183: 2185-2195.
[20] Gramaglia I., A. D. Weinberg, M. Lemon, et al. OX40 ligand: a potent co-stimulatory molecule for sustaining primary CD4 T cell responses. J. Immunol. 1998; 161: 6510-6517.
[21] Gramaglia I., A. Jember, S. D. Pippig, et al. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J. Immunol. 2000; 165: 3043-3050
[22] Pejman Soroosh, Shouji Ine, Kazuo Sugamura, et al. OX40-OX40L Ligand Interaction through T cell-T cell Contact Contributes to CD4 T Cell Longevity. J. Immunol. 2006; 6: 5975-5987.
[23] Linton PJ, Bautista B, Biederman E, et al. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo.J Exp Med. 2003; 197: 875-883.
[24] Linton PJ, Bautista B, Biederman E, et al. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo.J Exp Med. 2003; 197: 875-883.
[25] Stuber, E., and W. Strober. The T cell-B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response. J. Exp. Med. 1996; 183: 979.
[26] Lane P. Role of OX40 signal in co-ordinating CD4 T cell selection, migration, and cytokine differentiation in T helper (Th) 1 and Th2 cells [J]. J Exp Med. 2000; 191: 201-206.
[27] Kazuko Murata, Masato Nose, Lishomwa C. Ndhlovu, et al. Constitutive OX40/OX40 Ligand Interaction Induces Autoimmune-Like Diseases.J Immunol. 2002; 169: 4628-4636.
[28] Ian R. Humphreys, Gerhard Walzl, Lorna Edwards, et al A Critical Role for OX40 in T Cell–mediated Immunopathology during Lung Viral Infection. J Exp Med. 2003; 198: 1237-1242.
[29] Takaori-Kondo A, Horizontal T, Fukunaga K, et al. Both amino-and carboxyl-terminal domains of TRAF3 negatively regulate NF-kappa B activation induced by OX40 signaling. Biochem biophys res common. 2000; 272: 856-863.
[30] Hong Ye, Hao Wu. Thermodynamic characterization of the interaction between TRAF2 and tumor necrosis factor receptor peptides by isothermal titration calorimetry[J]. Proc Natl Acad Sci USA. 2000; 97: 8961.
[31] Yumi Matsumura, Toshiyuki Hori, Shin Kawamata, et al. Intracellular Signaling of gp34, the OX40 Ligand: Induction of c-jun and c-fos mRNAExpression Through gp34 upon Binding of Its Receptor, OX40. J. Immunol. 1999; 163: 3007-3011.
[32] L Jonasson, J Holm, O Skalli, et al. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Atherosclerosis. 1986; 6: 131-138.
[33] PAIGEN B., Mitchell D., Reue A., et al. Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc. NatI. Acad. Sci. 1987; 84: 3763-3767.
[34] Xiaosong Wang, Massimiliano Ria, Peter M Kelmenson, et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nature Genetics. 2005; 37: 365-372.
[35] Eva J.A van Wanrooij, Gijs H.M van Puijvelde, Paula de Vos, et al. Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice. Arterioscler Thromb Vasc Biol. 2007; 27: 204-210.
[36]王燃燃.彭道泉.赵水平.冠心病相关的炎症新指标OX40L.中国心血管杂志. 2006; 34: 1110-1112.