Methamphetamine signals transcription of IL1β and TNFα in a reactive oxygen species-dependent manner and interacts with HIV-1 Tat to decrease antioxidant defense mechanisms.
Methamphetamine signals transcription of IL1β and TNFα in a reactive oxygen species-dependent manner and interacts with HIV-1 Tat to decrease antioxidant defense mechanisms.
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DOI：
10.3389/fncel.2022.911060
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发表时间：
2022
影响因子：
5.3
通讯作者：
Marcondes, Maria Cecilia Garibaldi
中科院分区：
文献类型：
--
作者：
Basova, Liana V. V.;Vien, Whitney;Bortell, Nikki;Najera, Julia A. A.;Marcondes, Maria Cecilia Garibaldi
甲基苯丙胺（冰毒）滥用是一种常见的与艾滋病病毒（HIV）共病的情况，它与中枢神经系统（CNS）炎症加重有关，这加剧了与HIV相关的神经系统疾病，这些疾病是由该药物直接或间接引发的。我们利用成熟的人类先天免疫巨噬细胞系（THP1）证明，冰毒立即诱导产生的活性氧物质（ROS）在炎症基因转录增加中起作用，且与HIV - 1 Tat肽相互作用。冰毒和Tat单独及共同作用时，会影响转录活动的早期事件，这从整个基因组中RNA聚合酶（RNAPol）募集模式的变化可以看出，其通过依赖ROS和不依赖ROS的机制起作用。白细胞介素1β（IL1β）和肿瘤坏死因子α（TNFα）这两个在炎症反应中起关键作用的基因，均以依赖ROS的方式被激活。我们发现这种效应是通过激活由cFOS和cJUN转录因子组成的激活蛋白1（AP - 1）而发生的，并且受SRC激酶调节。HIV - 1 Tat也能够诱导ROS的产生，但在冰毒的情况下，它没有进一步影响ROS的作用，而是通过其他转录因子独立于ROS促进基因活性。例如，HIV - 1 Tat增加了核因子κB（NFkB）的激活，并激活了由Tata盒结合肽、ING4和IRF2调节的基因簇。重要的是，HIV - 1 Tat降低了抗氧化基因的表达，其对解毒机制的抑制可能导致在冰毒情况下由ROS诱导的氧化应激加重。我们的研究结果提供了证据，证明冰毒通过ROS以及与HIV Tat的相互作用促进了诸如IL1β和TNFα等炎症基因的转录。
Methamphetamine (Meth) abuse is a common HIV co-morbidity that is linked to aggravated Central Nervous System (CNS) inflammation, which accentuates HIV- associated neurological disorders, triggered both directly or indirectly by the drug. We used the well-established human innate immune macrophage cell line system (THP1) to demonstrate that Reactive Oxygen Species (ROS) immediately induced by Meth play a role in the increased transcription of inflammatory genes, in interaction with HIV-1 Tat peptide. Meth and Tat, alone and together, affect early events of transcriptional activity, as indicated by changes in RNA polymerase (RNAPol) recruitment patterns throughout the genome, via ROS-dependent and -independent mechanisms. IL1β (IL1β) and TNF α (TNFα), two genes with defining roles in the inflammatory response, were both activated in a ROS-dependent manner. We found that this effect occurred via the activation of the activator protein 1 (AP-1) comprising cFOS and cJUN transcription factors and regulated by the SRC kinase. HIV-1 Tat, which was also able to induce the production of ROS, did not further impact the effects of ROS in the context of Meth, but promoted gene activity independently from ROS, via additional transcription factors. For instance, HIV-1 Tat increased NFkB activation and activated gene clusters regulated by Tata box binding peptide, ING4 and IRF2. Importantly, HIV-1 Tat decreased the expression of anti-oxidant genes, where its suppression of the detoxifying machinery may contribute to the aggravation of oxidative stress induced by ROS in the context of Meth. Our results provide evidence of effects of Meth via ROS and interactions with HIV Tat that promote the transcription of inflammatory genes such as IL1β and TNFα.
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影响因子：
3.7
作者：
Basova L;Najera JA;Bortell N;Wang D;Moya R;Lindsey A;Semenova S;Ellis RJ;Marcondes MCG
通讯作者：
Marcondes MCG
影响因子：
4.7
作者：
Ding, M;Li, JJ;Vallyathan, V
通讯作者：
Vallyathan, V
影响因子：
7.4
作者：
Hensley, K;Robinson, KA;Floyd, RA
通讯作者：
Floyd, RA
影响因子：
6.6
作者：
Hsieh, Hsi-Lung;Wang, Hui-Hsin;Yang, Chuen-Mao
通讯作者：
Yang, Chuen-Mao
影响因子：
4.7
作者：
Basova, Liana V.;Kesby, James P.;Marcondes, Maria Cecilia Garibaldi
通讯作者：
Marcondes, Maria Cecilia Garibaldi