Comparing the Effects of Rocaglates on Energy Metabolism and Immune Modulation on Cells of the Human Immune System.
Comparing the Effects of Rocaglates on Energy Metabolism and Immune Modulation on Cells of the Human Immune System.
复制标题
DOI：
10.3390/ijms24065872
复制
发表时间：
2023-03-20
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
一种有前景的广谱抗病毒药物新方法是抑制真核翻译起始因子 4A (elF4A)，这是一种 DEAD-box RNA 解旋酶，可有效减少几种致病病毒类型的复制。除了抗病原体作用之外，宿主酶活性的调节也可能对免疫系统产生影响。因此，我们对天然和合成的罗卡格拉特抑制elF4A对各种免疫细胞的影响进行了全面的研究。评估了罗卡格拉特佐他替芬、西维甾醇和 CR-31-B (−) 以及非活性对映体 CR-31-B (+) 对原代人单核细胞源性巨噬细胞 (MdMs)、单核细胞源性树突状细胞 (MdDCs)、T 细胞和 B 细胞中表面标志物表达、细胞因子释放、增殖、炎症介质和代谢活性的影响。 eF4A 的抑制降低了 M1 MdMs 的炎症潜力和能量代谢，而在 M2 MdMs 中，观察到药物特异性和较少的靶标特异性作用。 Rocaglate 治疗还通过改变细胞因子的释放来降低激活的 MdDC 的炎症潜力。在 T 细胞中，elF4A 的抑制通过降低增殖率、CD25 表达和细胞因子释放来损害其激活。 eF4A 的抑制进一步减少了 B 细胞增殖、浆细胞形成和免疫球蛋白的释放。总之，用rocaglates抑制elF4A RNA解旋酶抑制了M1 MdMs、MdDCs、T细胞和B细胞的功能。这表明罗卡格拉特在抑制病毒复制的同时，也可能抑制宿主免疫系统对旁观者组织的损伤。因此，需要调整罗卡格拉特的剂量，以防止过度的免疫抑制而不降低其抗病毒活性。
A promising new approach to broad spectrum antiviral drugs is the inhibition of the eukaryotic translation initiation factor 4A (elF4A), a DEAD-box RNA helicase that effectively reduces the replication of several pathogenic virus types. Beside the antipathogenic effect, modulation of a host enzyme activity could also have an impact on the immune system. Therefore, we performed a comprehensive study on the influence of elF4A inhibition with natural and synthetic rocaglates on various immune cells. The effect of the rocaglates zotatifin, silvestrol and CR-31-B (−), as well as the nonactive enantiomer CR-31-B (+), on the expression of surface markers, release of cytokines, proliferation, inflammatory mediators and metabolic activity in primary human monocyte-derived macrophages (MdMs), monocyte-derived dendritic cells (MdDCs), T cells and B cells was assessed. The inhibition of elF4A reduced the inflammatory potential and energy metabolism of M1 MdMs, whereas in M2 MdMs, drug-specific and less target-specific effects were observed. Rocaglate treatment also reduced the inflammatory potential of activated MdDCs by altering cytokine release. In T cells, the inhibition of elF4A impaired their activation by reducing the proliferation rate, expression of CD25 and cytokine release. The inhibition of elF4A further reduced B-cell proliferation, plasma cell formation and the release of immune globulins. In conclusion, the inhibition of the elF4A RNA helicase with rocaglates suppressed the function of M1 MdMs, MdDCs, T cells and B cells. This suggests that rocaglates, while inhibiting viral replication, may also suppress bystander tissue injury by the host immune system. Thus, dosing of rocaglates would need to be adjusted to prevent excessive immune suppression without reducing their antiviral activity.