Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 (Ape1/Ref-1) Modulates Antigen Presenting Cell-mediated T Helper Cell Type 1 Responses
Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 (Ape1/Ref-1) Modulates Antigen Presenting Cell-mediated T Helper Cell Type 1 Responses
复制标题
DOI：
10.1074/jbc.m116.742353
复制
发表时间：
2016-11-04
影响因子：
4.8
通讯作者：
Asao, Hironobu
中科院分区：
文献类型：
--
作者：
Akhter, Nasrin;Takeda, Yuji;Asao, Hironobu
脱嘌呤/脱嘧啶核酸内切酶1/氧化还原因子-1（Ape 1/Ref-1）是一种具有DNA修复、氧化还原调控和转录调节活性的多功能蛋白。尽管Ape 1/Ref-1在免疫系统中发挥多种作用，但其在辅助性T（Th）细胞活化和分化中的功能在很大程度上是未知的。在这项研究中，Ape 1/Ref-1在Th细胞活化的功能进行了分析，使用Ape 1/Ref-1氧化还原特异性抑制剂，E3330。当在E3330的存在下用卵清蛋白（OVA）特异性T细胞受体转基因小鼠的OT-II小鼠的脾细胞被激活时，产生IFN-γ的OT-II T细胞的诱导显著增加。相反，在缺乏抗原呈递细胞（APC）的情况下，E3330不能增强板结合抗CD 3抗体刺激的CD 4（+）T细胞产生IFN-γ。此外，E3330预处理和OVA脉冲的APC也增强了OT-II T细胞的IFN-γ产生。这些结果表明，E3330通过修饰APC功能增强Th 1应答。E3330不改变APC表面MHC-II或共刺激分子CD 80和CD 86的表达。另一方面，E3330上调IL-12 p35和p40基因表达，上调IL-12表面滞留，但降低Toll样受体（TLR）配体刺激的APC分泌IL-12。这些结果用Ape 1/Ref-1敲低实验证实。总之，我们的研究结果表明，抑制Ape 1/Ref-1氧化还原功能导致IL-12的细胞表面滞留增加，并增强Th 1应答。这是首次证实Ape 1/Ref-1调节APC产生和分泌IL-12并控制Th 1免疫应答的研究。
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1) is a multifunctional protein possessing DNA repair, redox control, and transcriptional regulatory activities. Although Ape1/Ref-1 plays multiple roles in the immune system, its functions in helper T (Th) cell activation and differentiation are largely unknown. In this study, the function of Ape1/Ref-1 in Th cell activation was analyzed using an Ape1/Ref-1 redox-specific inhibitor, E3330. When splenocytes from OT-II mice, which are ovalbumin (OVA)-specific T-cell receptor transgenic mice, were activated with OVA in the presence of E3330, the induction of IFN--producing OT-II T cells was significantly increased. In contrast, E3330 did not enhance IFN- production from plate-bound anti-CD3 antibody-stimulated CD4(+) T cells in the absence of antigen presenting cells (APCs). Furthermore, E3330-pretreated and OVA-pulsed APCs also enhanced the IFN- production from OT-II T cells. These results suggested that E3330 enhances Th1 responses by modifying APC function. E3330 did not alter the surface expression of MHC-II or the co-stimulatory molecules CD80 and CD86 on APCs. On the other hand, E3330 up-regulated the IL-12 p35 and p40 gene expression, and IL-12 surface retention, but decreased the IL-12 secretion from Toll-like receptor (TLR) ligand-stimulated APCs. These results were confirmed with Ape1/Ref-1 knockdown experiments. Taken together, our findings indicated that the suppression of Ape1/Ref-1 redox function leads to an increased cell surface retention of IL-12 and enhances Th1 responses. This is the first study to demonstrate that Ape1/Ref-1 modulates the IL-12 production and secretion from APCs and controls Th1 immune responses.