Xia Yun-Hong, Lu Zhen, Zhao Min, Dai Wen-Ting, Ding Lu, Hu Li-Xia, Jiang Guo-Lin
Department of Oncology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
Department of General Surgery, The Fourth Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
Oncotarget. 2017 Jul 5;8(33):55084-55093. doi: 10.18632/oncotarget.19027. eCollection 2017 Aug 15.
Tumor-specific hepatic stellate cells (tHSCs) contributes to tumorigenesis and progression of hepatocellular carcinoma (HCC). The potential function of tHSCs on dendritic cells (DCs) was studied here. We discovered that tHSCs co-culture induced upregulation of DIgR2 (dendritic cell-derived immunoglobulin receptor 2) in bone marrow-derived DCs (mDCs). Activation of MEK-ERK is required for DIgR2 expression in mDCs. MEK-ERK inhibitors or shRNA-mediated silence of MEK1/2 in mDCs inhibited tHSCs-induced DIgR2 expression. Meanwhile, tHSCs stimulation decreased production of multiple cytokines (CD80, CD86 and IL-12) in mDCs. Such an effect was almost reversed by DIgR2 shRNA in mDCs. Further, tHSCs-stimulated mDCs induced T-cell hypo-responsiveness, leading to decreased cytotoxic T lymphocyte (CTL) activity and reduced IFN-γ production in splenic T cells. T cell proliferation inhibition and apoptosis were also noticed. These actions on T cells were again largely inhibited by DIgR2 shRNA in mDCs. Together, our results indicate that tHSCs directly induces DIgR2 expression in DCs to inhibit T cells.
肿瘤特异性肝星状细胞（tHSCs）促进肝细胞癌（HCC）的发生和发展。本文研究了tHSCs对树突状细胞（DCs）的潜在作用。我们发现tHSCs共培养可诱导骨髓来源的DCs（mDCs）中DIgR2（树突状细胞衍生的免疫球蛋白受体2）表达上调。mDCs中DIgR2的表达需要MEK-ERK的激活。MEK-ERK抑制剂或mDCs中shRNA介导的MEK1/2沉默可抑制tHSCs诱导的DIgR2表达。同时，tHSCs刺激可降低mDCs中多种细胞因子（CD80、CD86和IL-12）的产生。mDCs中的DIgR2 shRNA几乎可逆转这种效应。此外，tHSCs刺激的mDCs可诱导T细胞低反应性，导致脾T细胞中细胞毒性T淋巴细胞（CTL）活性降低和IFN-γ产生减少。还观察到T细胞增殖抑制和凋亡。mDCs中的DIgR2 shRNA再次在很大程度上抑制了对T细胞的这些作用。总之，我们的结果表明tHSCs直接诱导DCs中DIgR2的表达以抑制T细胞。
