A functional role for inducible costimulator (ICOS) in atherosclerosis
A functional role for inducible costimulator (ICOS) in atherosclerosis
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DOI：
10.1016/j.atherosclerosis.2005.03.040
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发表时间：
2005-11-01
期刊：
影响因子：
5.3
通讯作者：
George, J
中科院分区：
文献类型：
--
作者：
Afek, A;Harats, D;George, J
背景：淋巴细胞似乎通过改变细胞因子的产生来影响动脉粥样硬化。而原发性淋巴细胞激活需要T细胞受体连接，共刺激信号似乎也是产生功能性T细胞反应所必需的。诱导共刺激因子（ICOS）是一种新发现的在免疫介导疾病中具有双重作用的T细胞分子。在此，我们测试了ICOS在动脉粥样硬化中的重要性。方法和结果：应用免疫组织化学方法研究ApoE-KO小鼠动脉粥样硬化斑块中ICOS及其受体的存在、定位及其在脾细胞中的表达。用人ICOS/Fc嵌合体或未融合Fc免疫ApoE-KO小鼠，给予6周的鼠粮或8周的高脂饮食。ICOS及其配体在冰中的ApoE- KO斑块中大量表达：动脉粥样硬化小鼠的脾细胞显示ICOS的组成表达降低，而oxLDL则增强了ICOS的表达，并呈剂量依赖性。在诱导形成脂肪条纹和产生ICOS阻断抗体的小鼠中，早期动脉粥样硬化增加了77%，而在诱导更晚期病变时，ICOS阻断组斑块面积增加了36%。与对照动物相比，icos免疫小鼠的脾细胞分泌ifn - γ增加，而IL-10分泌减少。免疫组织化学显示，病变中细胞因子的产生也有类似的趋势。结论：ICOS在动脉粥样硬化中是一种重要的共刺激途径，可能发挥保护作用而非促粥样硬化作用。(c) 2005年爱思唯尔爱尔兰有限公司出版
Background: Lymphocytes appear to influence atherosclerosis by altering cytokine production. Whereas primary lymphocyte activation requires T cell receptor ligation, costimulatory signals also appear requisite for generation of a functional T cell response. Inducible costimulator (ICOS) is a newly discovered T cell molecule with a dual role in immune mediated disorders. Herein, we tested the importance of ICOS in atherosclerosis.Methods and results: Atherosclerotic plaques from ApoE-KO mice were studied immunohistochemically for the presence and localization of ICOS and its receptors and its expression in splenocytes. ApoE-KO mice were immunized with human ICOS/Fc-chimera or non-fused Fc and either provided a chow diet for 6 weeks, or a high fat diet for 8 weeks.ICOS and its ligand were abundantly expressed with in plaques from ApoE- KO in ice: Spleen cells from atherosclerotic mice exhibited lowered constitutive expression of ICOS yet priming with oxLDL enhanced ICOS expression dose-dependently. In mice induced to develop fatty streaks and to generate ICOS blocking antibodies, early atherosclerosis was increased by similar to 77% whereas upon inducing more advanced lesions, the increase in plaque area upon ICOS blockade group was similar to 36%. IFN-gamma secretion by oxLDL-primed splenocytes in ICOS-immunized mice increased whereas IL-10 secretion diminished as compared to control animals. A similar trend in cytokine production was evident in the lesion by immunohistochemistry.Conclusion: ICOS appears as an influential costimulatory, pathway in atherosclerosis that may play a protective rather that a proatherogenic role. (c) 2005 Published by Elsevier Ireland Ltd.