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首页> 外文期刊>Archives of Toxicology >Activation of the Nrf2 response by intrinsic hepatotoxic drugs correlates with suppression of NF-kappa B activation and sensitizes toward TNF alpha-induced cytotoxicity
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Activation of the Nrf2 response by intrinsic hepatotoxic drugs correlates with suppression of NF-kappa B activation and sensitizes toward TNF alpha-induced cytotoxicity

机译：内在肝毒性药物对Nrf2反应的激活与NF-κB激活的抑制有关，并对TNFα诱导的细胞毒性敏感

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摘要

Drug-induced liver injury (DILI) is an important problem both in the clinic and in the development of new safer medicines. Two pivotal adaptation and survival responses to adverse drug reactions are oxidative stress and cytokine signaling based on the activation of the transcription factors Nrf2 and NF-kappa B, respectively. Here, we systematically investigated Nrf2 and NF-kappa B signaling upon DILI-related drug exposure. Transcriptomics analyses of 90 DILI compounds in primary human hepatocytes revealed that a strong Nrf2 activation is associated with a suppression of endogenous NF-kappa B activity. These responses were translated into quantitative high-content live-cell imaging of induction of a selective Nrf2 target, GFP-tagged Srxn1, and the altered nuclear translocation dynamics of a subunit of NF-kappa B, GFP-tagged p65, upon TNFR signaling induced by TNF alpha using HepG2 cells. Strong activation of GFP-Srxn1 expression by DILI compounds typically correlated with suppression of NF-kappa B nuclear translocation, yet reversely, activation of NF-kappa B by TNF alpha did not affect the Nrf2 response. DILI compounds that provided strong Nrf2 activation, including diclofenac, carbamazepine and ketoconazole, sensitized toward TNF alpha-mediated cytotoxicity. This was related to an adaptive primary protective response of Nrf2, since loss of Nrf2 enhanced this cytotoxic synergy with TNF alpha, while KEAP1 downregulation was cytoprotective. These data indicate that both Nrf2 and NF-kappa B signaling may be pivotal in the regulation of DILI. We propose that the NF-kappa B-inhibiting effects that coincide with a strong Nrf2 stress response likely sensitize liver cells to pro-apoptotic signaling cascades induced by intrinsic cytotoxic pro-inflammatory cytokines.
机译：药物诱发的肝损伤（DILI）在临床和新型安全药物的开发中都是一个重要问题。分别基于转录因子Nrf2和NF-κB的激活，氧化应激和细胞因子信号转导是对药物不良反应的两个关键适应和生存反应。在这里，我们系统地调查了DILI相关药物暴露后的Nrf2和NF-κB信号传导。对人类原代肝细胞中90种DILI化合物的转录组学分析显示，Nrf2的强激活与内源性NF-κB活性的抑制有关。这些反应被转化为定量高含量活细胞成像，诱导选择性的Nrf2靶标，GFP标记的Srxn1，以及在TNFR信号诱导后，NF-κB亚基（GFP标记的p65）的核转运动力学改变。使用HepG2细胞通过TNF alpha检测。 DILI化合物对GFP-Srxn1表达的强烈激活通常与抑制NF-κB核转运有关，但相反，TNFα激活NF-κB不会影响Nrf2反应。提供强Nrf2活化作用的DILI化合物（包括双氯芬酸，卡马西平和酮康唑）对TNFα介导的细胞毒性敏感。这与Nrf2的适应性一级保护反应有关，因为Nrf2的丧失增强了与TNFα的这种细胞毒性协同作用，而KEAP1的下调具有细胞保护作用。这些数据表明，Nrf2和NF-κB信号传导可能在DILI的调节中起关键作用。我们提出，与强Nrf2应激反应相吻合的NF-κB抑制作用可能使肝细胞对由内在细胞毒性促炎细胞因子诱导的促凋亡信号级联反应敏感。

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