Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome
Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome
复制标题
血管紧张素 II 通过血管紧张素 II 1 型受体 PKA 介导的蛋白酶体激活调节 Th1 T 细胞分化
DOI：
10.1159/000487562
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发表时间：
2018-02
影响因子：
--
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Qin Xian-Yun;Yan Bo;Zhang Yun-Long;Li Hui-Hua;Zhang Yun-Long;Li Hui-Hua;Liu Ying;Chi Ya-Fei;Zeng Xiang-Jun;Li HH;Liu Y
背景/目的：初始CD4+ T细胞分化为辅助性T细胞（Th1和Th2），在心血管疾病中起重要作用。然而，血管紧张素II （Ang II）促进Th1分化的分子机制尚不清楚。本研究的目的是确定Ang ii诱导的Th1分化是否受泛素-蛋白酶体系统（UPS）的调节。方法：在不同抑制剂存在或不存在的情况下，用Ang II （100 nM）处理Jurkat细胞。实时荧光定量PCR检测基因mRNA水平。分别用ELISA法和Western blot法检测蛋白水平。结果：Ang II治疗显著诱导Th0向Th1细胞分化，而血管紧张素II型1受体（AT1R）抑制剂氯沙坦（LST）可明显阻断这一分化。此外，Ang II显著提高了蛋白酶体催化亚基（β1、β1i、β2i和β5i）的活性和表达，并呈剂量和时间依赖性。然而，LST和PKA抑制剂H-89显著抑制了Ang ii诱导的蛋白酶体活性。在机制上，Ang ii诱导的Th1分化至少部分是通过蛋白酶体介导的i -κB α和MKP-1的降解以及STAT1和NF-κB的激活。结论：本研究首次证实Ang II激活at1r - pka -蛋白酶体通路，促进i -κB α和MKP-1降解，激活STAT1和NF-κB，从而导致Th1分化。因此，抑制蛋白酶体激活可能是th1介导疾病的潜在治疗靶点。
Background/Aims: Naive CD4+ T cells differentiate into T helper cells (Th1 and Th2) that play an essential role in the cardiovascular diseases. However, the molecular mechanism by which angiotensin II (Ang II) promotes Th1 differentiation remains unclear. The aim of this study was to determine whether the Ang II-induced Th1 differentiation regulated by ubiquitin-proteasome system (UPS). Methods: Jurkat cells were treated with Ang II (100 nM) in the presence or absence of different inhibitors. The gene mRNA levels were detected by real-time quantitative PCR analysis. The protein levels were measured by ELISA assay or Western blot analysis, respectively. Results: Ang II treatment significantly induced a shift from Th0 to Th1 cell differentiation, which was markedly blocked by angiotensin II type 1 receptor (AT1R) inhibitor Losartan (LST). Moreover, Ang II significantly increased the activities and the expression of proteasome catalytic subunits (β1, β1i, β2i and β5i) in a dose- and time-dependent manner. However, Ang II-induced proteasome activities were remarkably abrogated by LST and PKA inhibitor H-89. Mechanistically, Ang II-induced Th1 differentiation was at least in part through proteasome-mediated degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB. Conclusions: This study for the first time demonstrates that Ang II activates AT1R-PKA-proteasome pathway, which promotes degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB thereby leading to Th1 differentiation. Thus, inhibition of proteasome activation might be a potential therapeutic target for Th1-mediated diseases.
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影响因子：
37.8
作者：
Vinh A;Chen W;Blinder Y;Weiss D;Taylor WR;Goronzy JJ;Weyand CM;Harrison DG;Guzik TJ
通讯作者：
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DOI：
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发表时间：
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影响因子：
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DOI：
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发表时间：
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期刊：
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影响因子：
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影响因子：
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作者：
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M. Groettrup;S. Khan;K. Schwarz;G. Schmidtke