Nuclear Factor-Kappa B Family Member RelB Inhibits Human Immunodeficiency Virus-1 Tat-Induced Tumor Necrosis Factor-Alpha Production
Nuclear Factor-Kappa B Family Member RelB Inhibits Human Immunodeficiency Virus-1 Tat-Induced Tumor Necrosis Factor-Alpha Production
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DOI：
10.1371/journal.pone.0013102
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发表时间：
2010-07-29
期刊：
影响因子：
3.7
通讯作者：
Maggirwar, Sanjay B.
中科院分区：
文献类型：
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作者：
Kiebala, Michelle;Polesskaya, Oksana;Maggirwar, Sanjay B.
人类免疫缺陷病毒-1（HIV-1）相关的神经认知障碍（HAND）可能是神经炎症性的起源，据信是由对细胞因子和HIV蛋白基因产物（如HIV转录反式激活因子（达特））的炎症和氧化应激反应引发的。在此，我们证实了多西环素诱导的达特转基因小鼠脑中核因子-κ B（NF-κ B）家族成员转录因子RelB的信使RNA增加，以及Tat暴露的小胶质细胞中RelB合成增加。由于小鼠中RelB的基因消融导致多器官炎症，我们假设Tat诱导的新合成的RelB抑制小胶质细胞的细胞因子产生，可能是通过形成转录失活的RelB/RelA复合物。事实上，从RelB缺陷小鼠分离的单核细胞中的肿瘤坏死因子-α（TNF α）产生显著高于从RelB表达对照分离的单核细胞。此外，RelB在小胶质细胞中的过表达以涉及TNF α启动子的转录抑制的方式抑制Tat诱导的TNF α合成，并增加RelA在丝氨酸276处的磷酸化，这是增加RelB/RelA蛋白相互作用的先决条件。RelB中的Rel-homology-domain是这种相互作用所必需的。RelA本身的过表达反过来显著增加了TNF α启动子活性，这种作用被RelB过表达完全阻断。我们的结论是，RelB调节TNF α细胞因子的合成与RelA的竞争性干扰结合，这导致下调TNF α的生产。此外，因为达特激活小胶质细胞中的RelB和TNF α，并且因为达特通过NF-κ B诱导炎性TNF α合成，我们证实RelB作为致病性NF-κ B激活的冷冻保护、抗炎、反调节机制。这些发现确定了一种新的调节途径，用于控制HIV诱导的小胶质细胞活化和细胞因子产生，这可能对HAND的管理具有重要的治疗意义。
Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is likely neuroinflammatory in origin, believed to be triggered by inflammatory and oxidative stress responses to cytokines and HIV protein gene products such as the HIV transactivator of transcription (Tat). Here we demonstrate increased messenger RNA for nuclear factor- kappa B (NF-kappa B) family member, transcription factor RelB, in the brain of doxycycline-induced Tat transgenic mice, and increased RelB synthesis in Tat-exposed microglial cells. Since genetic ablation of RelB in mice leads to multi-organ inflammation, we hypothesized that Tat-induced, newly synthesized RelB inhibits cytokine production by microglial cells, possibly through the formation of transcriptionally inactive RelB/RelA complexes. Indeed, tumor necrosis factor-alpha (TNF alpha) production in monocytes isolated from RelB deficient mice was significantly higher than in monocytes isolated from RelB expressing controls. Moreover, RelB overexpression in microglial cells inhibited Tat-induced TNF alpha synthesis in a manner that involved transcriptional repression of the TNF alpha promoter, and increased phosphorylation of RelA at serine 276, a prerequisite for increased RelB/RelA protein interactions. The Rel-homology-domain within RelB was necessary for this interaction. Overexpression of RelA itself, in turn, significantly increased TNF alpha promoter activity, an effect that was completely blocked by RelB overexpression. We conclude that RelB regulates TNF alpha cytokine synthesis by competitive interference binding with RelA, which leads to downregulation of TNF alpha production. Moreover, because Tat activates both RelB and TNF alpha in microglia, and because Tat induces inflammatory TNF alpha synthesis via NF-kappa B, we posit that RelB serves as a cryoprotective, anti-inflammatory, counter-regulatory mechanism for pathogenic NF-kappa B activation. These findings identify a novel regulatory pathway for controlling HIV-induced microglial activation and cytokine production that may have important therapeutic implications for the management of HAND.