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替诺福韦在人原代细胞中选择性调节炎症细胞因子的产生,并改变 IL-12/IL-10 的平衡。

Tenofovir selectively regulates production of inflammatory cytokines and shifts the IL-12/IL-10 balance in human primary cells.

机构信息

Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.

出版信息

J Acquir Immune Defic Syndr. 2011 Aug 1;57(4):265-75. doi: 10.1097/QAI.0b013e3182185276.

Abstract

OBJECTIVES

In this study, we aimed to investigate the possible immune modulatory effects of HIV nucleoside reverse transcriptase inhibitors during secondary infections and inflammation, focusing on inflammatory cytokine responses and the interleukin (IL)-12/IL-10 balance.

METHODS

We investigated the in vitro effect of tenofovir and zidovudine (AZT) on production of proinflammatory cytokines in monocytes and human peripheral blood mononuclear cells (PBMCs). Stimulation panels included Toll-Like receptor (TLR) ligands; the inflammation mediator tumor necrosis factor-α; and the pathogens cytomegalovirus, Neisseria meningitides, Escherichia coli, and Streptococcus pneumoniae. Cytokine levels were measured using enzyme-linked immunosorbent assay and luminex technology. RNA levels were assessed using real-time polymerase chain reaction. Activity of mitogen-activated protein kinase and NF-κB signaling was evaluated using flow cytometry and multispectral imaging cytometry, respectively.

RESULTS

Tenofovir decreased and AZT increased both IL-8 and CCL3 production from monocytes after stimulation with TLR ligands, tumor necrosis factor-α, or live pathogens. Similarly, tenofovir decreased CCL3 levels in human PBMCs. Furthermore, tenofovir strongly decreased induction of IL-10 but increased levels of IL-12. AZT did not affect IL-12 or IL-10 levels. The observed drug-induced changes in cytokine production were independent from transcriptional regulation through the mitogen-activated protein kinase and nuclear factor kappa B pathways.

CONCLUSIONS

Our data suggest divergent effects of tenofovir and AZT on proinflammatory responses in monocytes (CCL3 and IL-8) and PBMCs (CCL3). Moreover, tenofovir shifts the IL-10/IL-12 balance after cell stimulation with TLR ligands or infection with live bacteria, thus suggesting that the choice of nucleoside reverse transcriptase inhibitor affects overall inflammation and early immune responses against secondary pathogens.

摘要

目的

本研究旨在探讨 HIV 核苷逆转录酶抑制剂在继发感染和炎症时可能产生的免疫调节作用,重点关注炎症细胞因子反应和白细胞介素(IL)-12/IL-10 平衡。

方法

我们研究了替诺福韦和齐多夫定(AZT)对单核细胞和人外周血单个核细胞(PBMC)产生促炎细胞因子的体外作用。刺激方案包括 Toll 样受体(TLR)配体;炎症介质肿瘤坏死因子-α;以及病原体巨细胞病毒、脑膜炎奈瑟菌、大肠杆菌和肺炎链球菌。使用酶联免疫吸附试验和 Luminex 技术测量细胞因子水平。使用实时聚合酶链反应评估 RNA 水平。通过流式细胞术和多光谱成像细胞术分别评估丝裂原活化蛋白激酶和 NF-κB 信号转导的活性。

结果

替诺福韦降低了 TLR 配体、肿瘤坏死因子-α或活病原体刺激后单核细胞产生的 IL-8 和 CCL3 的水平,AZT 则增加了这些细胞因子的产生。同样,替诺福韦降低了人 PBMC 中 CCL3 的水平。此外,替诺福韦强烈降低了 IL-10 的诱导,但增加了 IL-12 的水平。AZT 不影响 IL-12 或 IL-10 水平。观察到的药物诱导的细胞因子产生变化与丝裂原活化蛋白激酶和核因子 kappa B 途径的转录调节无关。

结论

我们的数据表明,替诺福韦和 AZT 对单核细胞(CCL3 和 IL-8)和 PBMC(CCL3)中促炎反应有不同的影响。此外,替诺福韦在 TLR 配体刺激或活细菌感染后改变了 IL-10/IL-12 平衡,因此表明核苷逆转录酶抑制剂的选择会影响继发病原体的整体炎症和早期免疫反应。

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