A constitutively active arylhydrocarbon receptor induces growth inhibition of Jurkat T cells through changes in the expression of genes related to apoptosis and cell cycle arrest
A constitutively active arylhydrocarbon receptor induces growth inhibition of Jurkat T cells through changes in the expression of genes related to apoptosis and cell cycle arrest
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DOI：
10.1074/jbc.m402143200
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发表时间：
2004-06-11
影响因子：
4.8
通讯作者：
Nohara, K
中科院分区：
文献类型：
--
作者：
Ito, T;Tsukumo, S;Nohara, K
已知的2，3，7，8-四氯二苯并对二恶英(TCDD)通过激活芳烃受体(AhR)抑制T细胞依赖的免疫反应。我们以前的发现表明，TCDD抑制了抗原刺激后小鼠T细胞的激活和随后的扩张，导致参与抗体产生的T细胞衍生细胞因子水平下降。在本研究中，我们通过在AhR缺失的Jurkat T细胞中瞬时表达一个结构性活性AhR(CA-AhR)突变体来研究激活的AhR对T细胞的影响。CA-AhR对Jurkat T细胞的生长有明显的抑制作用，这与我们以前的发现一致。细胞生长抑制伴随着Annexin V阳性凋亡细胞的增加和细胞在G(1)期的聚集。由于CA-AhR的A78D突变体缺乏XRE依赖的转录能力，部分抑制Jurkat T细胞的生长，因此这种生长抑制也被证明是通过依赖于异种反应元件(XRE)和非依赖的机制来实现的。此外，我们还证明了CA-AhR诱导了与细胞凋亡和细胞周期停滞相关的基因的表达变化。由于CA-AhR的A78D突变体不诱导这些表达变化，因此这些表达变化仅以XRE依赖的方式介导。综上所述，这些结果提示AhR的激活导致细胞凋亡和细胞周期停滞，特别是通过XRE依赖的机制改变与凋亡相关的基因和细胞周期停滞，导致T细胞生长抑制。
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to suppress T cell-dependent immune reactions through the activation of the arylhydrocarbon receptor (AhR). Our previous findings suggest that TCDD inhibits the activation and subsequent expansion of T cells following antigen stimulation in mice, leading to a decreased level of T cell-derived cytokines involved in antibody production. In the present study, we investigated the effects of activated AhR on T cells by transiently expressing a constitutively active AhR (CA-AhR) mutant in AhR-null Jurkat T cells. In agreement with our previous findings, CA-AhR markedly inhibited the growth of Jurkat T cells. The inhibited cell growth was found to be concomitant with both an increase in the annexin V-positive apoptotic cells and the accumulation of cells in the G(1) phase. The growth inhibition was also shown to be mediated by both xenobiotic response element (XRE)-dependent and -independent mechanisms, because an A78D mutant of the CA-AhR, which lacks the ability of XRE-dependent transcription, partially inhibited the growth of Jurkat T cells. Furthermore, we demonstrated that CA-AhR induces expression changes in genes related to apoptosis and cell cycle arrest. These expression changes were shown to be solely mediated in an XRE-dependent manner, because the A78D mutant of the CA-AhR did not induce them. To summarize, these results suggest that AhR activation causes apoptosis and cell cycle arrest, especially through expression changes in genes related to apoptosis and cell cycle arrest by the XRE-dependent mechanism, leading to the inhibition of T cell growth.