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首页> 外文期刊>Biochemical Pharmacology >Differential effects of the Nrf2 activators tBHQ and CDDO-Im on the early events of T cell activation
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Differential effects of the Nrf2 activators tBHQ and CDDO-Im on the early events of T cell activation

机译：NRF2活化剂TBHQ和CDDO-IM对T细胞激活早期事件的差异影响

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摘要

We previously demonstrated that activation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) promotes CD4+ Th2 differentiation. In the current study, we assessed the role of Nrf2 in early events following T cell activation. The Nrf2 activators, tBHQ (tert-butylhydroquinone) and CDDO-Im (the imidazolide derivative of the triterpenoid CDDO), were used in conjunction with splenocytes derived from wild-type and Nrf2-null mice to distinguish between Nrf2-specific and off-target effects. CDDO-Im inhibited early IFN gamma production in a largely Nrf2-dependent manner. In contrast, tBHQ and CDDO-Im had little effect on expression of CD25 or CD69. Furthermore, tBHQ inhibited GM-CSF and IL-2 production in both wild-type and Nrf2-null T cells, suggesting this effect is Nrf2-independent. Conversely, CDDO-Im caused a concentration-dependent increase in IL-2 secretion in wild-type, but not Nrf2-null, splenocytes, suggesting that Nrf2 promotes IL-2 production. Interestingly, both compounds inhibit NF kappa B DNA binding, where the suppression by tBHQ is Nrf2-independent and CDDO-Im is Nrf2-dependent. Surprisingly, as compared to wild-type splenocytes, Nrf2-null splenocytes showed lower nuclear accumulation of c-Jun, a member of the AP-1 family of transcription factors, which have been shown to drive multiple immune genes, including IL-2. Both Nrf2 activators caused a Nrf2-dependent trend toward increased nuclear accumulation of c-Jun. These data suggest that modulation of cytokine secretion by tBHQ likely involves multiple pathways, including AP-1, NF kappa B, and Nrf2. Overall, the data suggest that Nrf2 activation inhibits secretion of the Thl cytokine IFN gamma, and increases early production of IL-2, which has been shown to promote Th2 differentiation, and may support the later occurrence of Th2 polarization. (C) 2017 Elsevier Inc. All rights reserved.
机译：我们之前证明了转录因子的激活，核因子红细胞2相关因子2（NRF2）促进CD4 + Th2分化。在目前的研究中，我们评估了NRF2在T细胞激活后早期发生的作用。 NRF2活化剂，TBHQ（叔丁基羟基醌）和CDDO-IM（咪唑奈替肽CDOD的衍生物）与衍生自野生型和NRF2-禁石小鼠的脾细胞结合使用，以区分NRF2特异性和脱靶效果。 CDDO-IM以主要的NRF2依赖性方式抑制早期的IFNγ产生。相比之下，TBHQ和CDDO-IM对CD25或CD69表达几乎没有影响。此外，TBHQ在野生型和NRF2-NULL T细胞中抑制GM-CSF和IL-2产生，表明这种效果是NRF2无关的。相反，CDDO-IM在野生型中引起IL-2分泌的浓度依赖性增加，但不是NRF2-NULL，脾细胞，表明NRF2促进IL-2产生。有趣的是，两种化合物抑制NFκBDNA结合，其中TBHQ的抑制是NRF2无关的，CDDO-IM依赖于NRF2。令人惊讶的是，与野生型脾细胞相比，NRF2-禁度脾细胞表现出较低的C-Jun核积累，AP-1系列转录因子的成员，已被证明可以驱动多种免疫基因，包括IL-2。 NRF2激活因素均导致NRF2依赖性趋势增加了C-Jun的核积累。这些数据表明，TBHQ的细胞因子分泌的调节可能涉及多种途径，包括AP-1，NF Kappa B和NRF2。总体而言，数据表明，NRF2激活抑制THL细胞因子IFNγ的分泌，并增加了IL-2的早期产量，这已被证明促进TH2分化，并且可以支持后来发生TH2偏振的发生。 （c）2017年Elsevier Inc.保留所有权利。

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  • 来源
    《Biochemical Pharmacology》 |2018年第2018期|共10页
  • 作者

    Zagorski Joseph W.; Turley Alexandra E.; Freeborn Robert A.; VanDenBerg Kelly R.; Dover Heather E.; Kardell Brian R.; Liby Karen T.; Rockwell Cheryl E.;

  • 作者单位

    Michigan State Univ Dept Pharmacol &

    Toxicol Life Sci Bldg 1355 Bogue St E Lansing MI 48824 USA;

    Michigan State Univ Dept Pharmacol &

    Toxicol Life Sci Bldg 1355 Bogue St E Lansing MI 48824 USA;

    Michigan State Univ Dept Pharmacol &

    Toxicol Life Sci Bldg 1355 Bogue St E Lansing MI 48824 USA;

    Michigan State Univ Dept Pharmacol &

    Toxicol Life Sci Bldg 1355 Bogue St E Lansing MI 48824 USA;

    Michigan State Univ Dept Pharmacol &

    Toxicol Life Sci Bldg 1355 Bogue St E Lansing MI 48824 USA;

    Michigan State Univ Dept Pharmacol &

    Toxicol Life Sci Bldg 1355 Bogue St E Lansing MI 48824 USA;

    Michigan State Univ Dept Pharmacol &

    Toxicol Life Sci Bldg 1355 Bogue St E Lansing MI 48824 USA;

    Michigan State Univ Dept Pharmacol &

    Toxicol Life Sci Bldg 1355 Bogue St E Lansing MI 48824 USA;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    Nrf2; IL-2; IFN gamma; T cell; CDDO-Im; tBHQ; NF kappa B;

    机译：NRF2;IL-2;IFNγ;T细胞;CDDO-IM;TBHQ;NF Kappa B;

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