Statins inhibit iNOS‐mediated microbicidal potential of activated monocyte‐derived dendritic cells by an IFN‐β‐dependent mechanism
Statins inhibit iNOS‐mediated microbicidal potential of activated monocyte‐derived dendritic cells by an IFN‐β‐dependent mechanism
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他汀类药物通过 IFN-β 依赖性机制抑制 iNOS 介导的活化单核细胞衍生树突状细胞的杀菌潜力
DOI：
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发表时间：
2011
影响因子：
5.4
通讯作者：
Carlos Ardavín
中科院分区：
文献类型：
--
作者：
Pilar M. Dominguez;María López;U. Kalinke;Carlos Ardavín
全球有 2500 万人服用他汀类药物来治疗高胆固醇血症和降低心血管疾病的风险。然而，他汀类药物对免疫，特别是 DC 免疫生物学的副作用尚未得到深入分析。在这里，我们研究了单核细胞分化为 DC 期间洛伐他汀治疗对所得单核细胞衍生 DC (moDC) 对 TLR 介导的激活的反应性的影响。洛伐他汀在 LPS 刺激的 moDC 中正向调节 TLR4 信号传导，导致 p38 MAP 激酶强烈激活，同时促炎细胞因子和 IFN-β 产生增加。相比之下，洛伐他汀通过 IFN-αβ 受体促进 IFN-β 介导的自分泌信号传导的负调节，同时转录因子 IRF-1 的低表达，导致 iNOS 和 HO-1 酶的抑制。 iNOS/HO-1 激活缺陷导致针对 ROS 的细胞保护能力有限，并降低了杀菌潜力。这些数据使用单核细胞增多性李斯特菌感染的体内模型进行了验证，结果表明，在洛伐他汀治疗的李斯特菌感染小鼠中，脾脏炎症 moDC（专门负责 NO 和 TNF-α 的产生）对 iNOS 的激活大大减少。他汀类药物治疗可能会对病原体的免疫产生严重影响，因为炎症性 moDC 中 iNOS/HO-1 代谢激活缺陷可能导致免疫失败。
Statins are prescribed to 25 million people worldwide for treating hypercholesterolemia and reducing the risk of cardiovascular diseases. However, the side effects of statins on immunity, and particularly on DC immunobiology, have not been analyzed in‐depth. Here, we have investigated the impact of lovastatin treatment during monocyte differentiation into DCs on the responsiveness of the resulting monocyte‐derived DCs (moDCs) to TLR‐mediated activation. Lovastatin positively regulated TLR4 signaling in LPS‐stimulated moDCs, leading to strong activation of p38 MAP‐kinase paralleled by increased proinflammatory cytokine and IFN‐β production. In contrast, lovastatin promoted negative regulation of IFN‐β‐mediated autocrine signaling through the IFN‐αβ receptor, paralleled by low expression of the transcription factor IRF‐1, leading to the inhibition of the enzymes iNOS and HO‐1. Defective activation of iNOS/HO‐1 resulted in limited cytoprotective capacity against ROS and reduced microbicidal potential. These data were validated using an in vivo model of Listeria monocytogenes infection, which revealed that iNOS activation by splenic inflammatory moDCs, specialized in NO and TNF‐α production, was strongly reduced in lovastatin‐treated, Listeria‐infected mice. Statin treatment could have severe implications in immunity against pathogens due to defective iNOS/HO‐1 metabolism activation in inflammatory moDCs that might lead to immune failure.
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影响因子：
32.4
作者：
Serbina, NV;Salazar-Mather, TP;Pamer, EG
通讯作者：
Pamer, EG
影响因子：
15.9
作者：
Pahan, K;Sheikh, FG;Singh, I
通讯作者：
Singh, I
影响因子：
4.3
作者：
Sun, DX;Fernandes, G
通讯作者：
Fernandes, G
影响因子：
37.8
作者：
Maron, DJ;Fazio, S;Linton, MF
通讯作者：
Linton, MF