Multiple Protein Kinases via Activation of Transcription Factors NF-κB, AP-1 and C/EBP-δ Regulate the IL-6/IL-8 Production by HIV-1 Vpr in Astrocytes.
Multiple Protein Kinases via Activation of Transcription Factors NF-κB, AP-1 and C/EBP-δ Regulate the IL-6/IL-8 Production by HIV-1 Vpr in Astrocytes.
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DOI：
10.1371/journal.pone.0135633
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kumar A
中科院分区：
文献类型：
--
作者：
Gangwani MR;Kumar A
尽管抗逆转录病毒治疗在控制病毒复制方面取得了成功，但神经认知障碍仍影响着大量HIV-1感染者。星形胶质细胞正在成为一种重要的细胞类型，可能在患有HIV-1相关神经认知障碍的患者中观察到的神经炎症的持续性中发挥非常重要的作用。包括Vpr在内的HIV-1病毒蛋白通过直接和间接机制发挥神经毒性。小胶质细胞中IL-8的诱导已被证明是Vpr降低神经元存活的间接机制之一。我们发现，HIV-1 Vpr诱导星形胶质细胞中的IL-6和IL-8在一个时间依赖性的方式。利用化学抑制剂和siRNA的其他实验显示，HIV-1 Vpr通过上游蛋白激酶PI 3 K/Akt、p38-MAPK和JNK-MAPK激活转录因子NF-κB、AP-1和C/EBP-δ，导致星形胶质细胞中IL-6和IL-8的诱导。我们证明了在HIV-1感染者中观察到的神经炎症的机制之一涉及星形胶质细胞中Vpr诱导IL-6和IL-8。了解参与HIV-1神经炎症的分子通路将有助于设计辅助治疗来改善与HIV-1神经发病机制相关的一些症状。
Neurocognitive impairments affect a substantial population of HIV-1 infected individuals despite the success of anti-retroviral therapy in controlling viral replication. Astrocytes are emerging as a crucial cell type that might be playing a very important role in the persistence of neuroinflammation seen in patients suffering from HIV-1 associated neurocognitive disorders. HIV-1 viral proteins including Vpr exert neurotoxicity through direct and indirect mechanisms. Induction of IL-8 in microglial cells has been shown as one of the indirect mechanism through which Vpr reduces neuronal survival. We show that HIV-1 Vpr induces IL-6 and IL-8 in astrocytes in a time-dependent manner. Additional experiments utilizing chemical inhibitors and siRNA revealed that HIV-1 Vpr activates transcription factors NF-κB, AP-1 and C/EBP-δ via upstream protein kinases PI3K/Akt, p38-MAPK and Jnk-MAPK leading to the induction of IL-6 and IL-8 in astrocytes. We demonstrate that one of the mechanism for neuroinflammation seen in HIV-1 infected individuals involves induction of IL-6 and IL-8 by Vpr in astrocytes. Understanding the molecular pathways involved in the HIV-1 neuroinflammation would be helpful in the design of adjunct therapy to ameliorate some of the symptoms associated with HIV-1 neuropathogenesis.