Deregulated MicroRNA-21 Expression in Monocytes from HIV-Infected Patients Contributes to Elevated IP-10 Secretion in HIV Infection.
Deregulated MicroRNA-21 Expression in Monocytes from HIV-Infected Patients Contributes to Elevated IP-10 Secretion in HIV Infection.
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HIV 感染患者单核细胞中 MicroRNA-21 表达失调导致 HIV 感染时 IP-10 分泌升高
DOI：
10.3389/fimmu.2017.01122
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发表时间：
2017
影响因子：
7.3
通讯作者：
Zhang ZN
中科院分区：
文献类型：
--
作者：
Wu X;Zhang LL;Yin LB;Fu YJ;Jiang YJ;Ding HB;Chu ZX;Shang H;Zhang ZN
持续的激活和炎症会损害免疫反应并引发艾滋病毒感染的疾病进展。新出现的证据支持这样的假设，即干扰素诱导蛋白10（IP-10），一种关键的炎症细胞因子，过度生产，导致免疫功能障碍和疾病进展的艾滋病毒感染。在这项研究中，我们试图阐明IP-10在HIV感染中上调产生的原因，并探讨其潜在的机制。使用模拟物支持miR-21水平导致单核细胞白血病细胞THP-1中脂多糖（LPS）诱导的IP-10的明显抑制，反之亦然。HIV患者的原代单核细胞分析显示miR-21显著低于健康对照;这与血浆中IP-10水平的趋势相反。在分化的THP-1巨噬细胞（THP-1-MA）中，由于LPS刺激导致的IP-10分泌不受miR-21调节的影响。我们发现了一个新的开关，IFN刺激基因15（ISG 15），它触发IP-10的表达，并在THP-1分化为THP-1-MA过程中显著上调。抑制ISG 15可以恢复miR-21对IP-10的调节。总之，IP-10在单核细胞中的表达受miR-21调节，而在巨噬细胞中，这种微调被ISG 15的增强表达减弱。这项研究为全面了解IP-10的分子调控机制铺平了道路，这是免疫干预策略的关键点。
Persistent activation and inflammation impair immune response and trigger disease progression in HIV infection. Emerging evidence supports the supposition that excessive production of interferon-inducible protein 10 (IP-10), a critical inflammatory cytokine, leads to immune dysfunction and disease progression in HIV infection. In this study, we sought to elucidate the cause of the upregulated production of IP-10 in HIV infection and explore the underlying mechanisms. Bolstering miR-21 levels using mimics resulted in the obvious suppression of lipopolysaccharide (LPS)-induced IP-10 in monocyte leukemia cells THP-1 and vice versa. The analysis of the primary monocytes of HIV patients revealed significantly less miR-21 than in healthy controls; this was opposite to the tendency of IP-10 levels in plasma. The secretion of IP-10 due to LPS stimulation was not affected by miR-21 modulation in the differentiated THP-1 macrophages (THP-1-MA). We found a novel switch, IFN-stimulated gene 15 (ISG15), which triggers the expression of IP-10 and is significantly upregulated during the differentiation of THP-1 into THP-1-MA. The inhibition of ISG15 can restore the regulation of IP-10 by miR-21. In summary, IP-10 expression in monocytes is regulated by miR-21, whereas in macrophages, this fine-tuning is attenuated by the enhanced expression of ISG15. This study paves the way to a comprehensive understanding of the molecular regulatory mechanism of IP-10, a key point in immune intervention strategy.