Attenuation of cytomegalovirus-induced endothelial intercellular adhesion molecule-1 mRNA/protein expression and T lymphocyte adhesion by a 2'-O-methoxyethyl antisense oligonucleotide.
Attenuation of cytomegalovirus-induced endothelial intercellular adhesion molecule-1 mRNA/protein expression and T lymphocyte adhesion by a 2'-O-methoxyethyl antisense oligonucleotide.
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2-O-甲氧基乙基反义寡核苷酸可减弱巨细胞病毒诱导的内皮细胞间粘附分子-1 mRNA/蛋白表达和 T 淋巴细胞粘附。
DOI：
10.1097/00007890-200002150-00019
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发表时间：
2000
期刊：
影响因子：
6.2
通讯作者：
Sedmak,DD
中科院分区：
文献类型：
--
作者：
Knight,DA;Briggs,BR;Bennett,CF;Harindranath,N;Waldman,WJ;Sedmak,DD
背景：细胞间粘附分子-1（ICAM-1）在与同种异体移植排斥相关的炎症条件下被强烈诱导，从而促进炎症部位白细胞的募集和活化。ICAM-1表达的增强也可能是病毒感染的结果，特别是人巨细胞病毒（CMV），这是移植受体中并发症的常见来源。体外研究表明，CMV感染内皮细胞（EC）导致ICAM-1表达的直接增强和随后的白细胞粘附/活化，提示CMV加重移植物血管疾病的机制。尽管用ICAM-1特异性反义寡核苷酸治疗EC已显示在模拟炎症条件下减弱ICAM-1诱导（即，TNF-α），没有研究指出它们对病毒诱导的ICAM-1表达的有效性。我们发现，接种CMV后内皮细胞ICAM-1蛋白表达的进行性增加与ICAM-1的进行性积累相关。1个mRNA。此外，我们证明，在病毒接种前用部分2′-O-甲氧基乙基修饰的ICAM-1特异性反义寡核苷酸处理EC可显著降低CMV相关的ICAM-1蛋白和mRNA表达诱导。最后，我们表明，反义介导的ICAM-1表达的衰减导致T淋巴细胞粘附到CMV感染的EC单层的显著减少，这种相互作用与同种异体T淋巴细胞活化有关，结论：这些发现首次证明反义寡核苷酸能有效逆转病毒在血行播散中的作用，诱导宿主细胞蛋白质表达，特别是ICAM-1，以及随后的T淋巴细胞粘附，从而拓宽了反义寡核苷酸的潜在临床应用。
Background.Intercellular adhesion molecule-1 (ICAM-1) is strongly induced under inflammatory conditions associated with allograft rejection, thereby promoting leukocyte recruitment and activation at the site of inflammation. Enhancement of ICAM-1 expression can also be the result of viral infection, in particular human cytomegalovirus (CMV), a frequent source of complications in the transplant recipient. In vitro studies have shown that CMV infection of endothelial cells (EC) results in the direct enhancement of ICAM-1 expression and consequent leukocyte adhesion/activation suggesting mechanisms by which CMV exacerbates graft vascular disease. Although treatment of EC with ICAM-1-specific antisense oligonucleotides has been shown to attenuate ICAM-1 induction under simulated inflammatory conditions (ie, TNF-α), no studies have addressed their effectiveness on virally-induced ICAM-1 expression.Results.In the current investigation, we show that the progressive increase in endothelial ICAM-1 protein expression that follows inoculation with CMV correlates with a progressive accumulation of ICAM-1 mRNA. Furthermore, we demonstrate that treatment of EC with a partially 2′-O-methoxyethyl modified ICAM-1-specific antisense oligonucleotide before viral inoculation significantly reduces CMV-associated induction of ICAM-1 protein and mRNA expression. Finally, we show that antisense-mediated attenuation in ICAM-1 expression results in a significant reduction of T lymphocyte adhesion to CMV-infected EC monolayers, an interaction that has been implicated in allogeneic T lymphocyte activation, in viral transmission to transiently adherent leukocytes and subsequent hematogenous dissemination.Conclusions.These findings demonstrate for the first time that antisense oligonucleotides can effectively reverse virally-induced host cellular protein expression, specifically ICAM-1, as well as consequent T lymphocytes adhesion, thus broadening the potential clinical utility of antisense oligonucleotides.