Tenofovir Selectively Regulates Production of Inflammatory CytokinesandShifts the IL-12/IL-10 Balance in Human Primary Cells
Tenofovir Selectively Regulates Production of Inflammatory CytokinesandShifts the IL-12/IL-10 Balance in Human Primary Cells
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DOI：
10.1097/qai.0b013e3182185276
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发表时间：
2011-08-01
影响因子：
3.6
通讯作者：
Tolstrup, Martin
中科院分区：
文献类型：
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作者：
Melchjorsen, Jesper;Risor, Michael W.;Tolstrup, Martin
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过程中可能的免疫调节作用，重点是炎症细胞因子反应和IL-12/IL-10平衡。方法：体外观察替诺福韦和齐多夫定(AZT)对单核细胞和人外周血单核细胞(PBMC)产生促炎细胞因子的影响。刺激组包括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。采用双抗体夹心法和Luminex技术检测细胞因子水平。RNA水平通过实时聚合酶链式反应进行评估。结果：TLR配体、肿瘤坏死因子-α或活病原体刺激单核细胞后，替诺福韦减少，AZT增加IL-8和CCL3的产生。同样，替诺福韦可降低人外周血单核细胞中的CCL3水平。此外，替诺福韦显著降低IL-10的诱导，但增加IL-12的水平。AZT对IL-12、IL-10水平无明显影响。所观察到的药物诱导的细胞因子产生的变化不依赖于通过丝裂原活化蛋白激酶和核因子kappaB途径的转录调控。结论：泰诺福韦和AZT对单核细胞(CCL3和IL-8)和PBMCs(CCL3)的促炎反应有不同的影响。此外，替诺福韦在TLR配体刺激细胞或感染活细菌后改变了IL-10/IL-12的平衡，因此提示核苷逆转录酶抑制剂的选择影响整体炎症和针对继发性病原体的早期免疫反应。
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-alpha; 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-kappa B 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-alpha, 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.