Exosomes from Melatonin Treated Hepatocellularcarcinoma Cells Alter the Immunosupression Status through STAT3 Pathway in Macrophages.
Exosomes from Melatonin Treated Hepatocellularcarcinoma Cells Alter the Immunosupression Status through STAT3 Pathway in Macrophages.
复制标题
褪黑素处理的肝细胞癌细胞的外泌体通过巨噬细胞中的 STAT3 途径改变免疫抑制状态
DOI：
10.7150/ijbs.19642
复制
发表时间：
2017
影响因子：
9.2
通讯作者：
Sun G
中科院分区：
文献类型：
--
作者：
Cheng L;Liu J;Liu Q;Liu Y;Fan L;Wang F;Yu H;Li Y;Bu L;Li X;Wei W;Wang H;Sun G
免疫抑制是肿瘤侵袭和转移的重要因素。褪黑激素是一种众所周知的激素，具有一定的细胞毒和免疫调节作用，抑制肿瘤功能。外泌体是由多种细胞释放的小膜囊泡，其含有不同的大分子，如mRNA和microRNA（miRNAs），以及可以介导细胞之间通信的蛋白质。肿瘤来源的外泌体可引起免疫抑制，然而，不知道褪黑激素是否可通过改变肿瘤来源的外泌体的功能来减弱免疫抑制状态。在本研究中，我们评估了肝细胞癌来源的exosomes（Exo-con）和0.1 mM褪黑激素处理的肝细胞癌细胞来源的exosomes（Exo-MT）对炎症因子和程序性死亡配体1（PD-L1）表达的影响，通过将Exo-con和Exo-MT分别与THP-1细胞或RAW 264.7细胞分化的巨噬细胞共培养。流式细胞术和免疫荧光分析表明，Exo-MT可下调巨噬细胞PD-L1的表达，而Exo-con可上调巨噬细胞PD-L1的表达。此外，Exo-con上调巨噬细胞中细胞因子如IL-6、IL-10、IL-1 β和TNF-α的分泌。因此，Exo-MT可以减弱这些炎性细胞因子的高表达。此外，体内实验证实了体外发现的结果。与Exo-con组相比，Exo-MT组的PD-L1表达和细胞因子分泌较低。为了确定一种特定的机制，我们的研究表明，与Exo-con组相比，Exo-MT降低了STAT3的激活。总之，我们发现来自褪黑激素处理的肝细胞癌细胞的外泌体通过巨噬细胞中的STAT 3途径改变了免疫抑制状态。我们的研究可能为探讨褪黑激素调节免疫抑制状态的机制提供了新的途径。
Immunosuppression is a significant factor in the progression of tumor invasion and metastasis. Melatonin, a well-known hormone, has certain cytotoxic and immune regulatory effects to inhibit tumor function. Exosomes are small membrane vesicles released by many kinds of cells, which contain different macromolecules, such as mRNAs and microRNAs (miRNAs), and proteins that can mediate communications between cells. Tumor-derived exosomes may cause immunosuppression, however, it is unknown whether melatonin can attenuate an immunosuppressive status by altering the function of tumor-derived exosomes. In the present study, we evaluated the effects of hepatocellularcarcinoma-derived exosomes (Exo-con) and exosomes derived from hepatocellularcarcinoma cells treated with 0.1 mM melatonin (Exo-MT), on the expression of inflammatory factors and programmed death ligand 1(PD-L1) by co-culturing Exo-con and Exo-MT, respectively, with macrophages differentiated from THP-1 cells or RAW264.7 cells. Our in vitro results indicate that Exo-MT can downregulate the expression of PD-L1 on macrophages while Exo-con can upregulate the expression of PD-L1 through flow cytometry and immunofluorescence analysis. In addition, Exo-con upregulates the secretion of cytokines, such as IL-6, IL-10, IL-1β, and TNF-α in macrophages. Accordingly, Exo-MT could attenuate the high expression of these inflammatory cytokines. Furthermore, in vivo experiments confirmed the results found in vitro. PD-L1 expression and cytokine secretion were lower in the Exo-MT group compared with those in the Exo-con group. Working to identify a specific mechanism, our research shows that Exo-MT decreases STAT3 activation compared to the Exo-con group. In summary, we found exosomes from melatonin treated hepatocellularcarcinoma cells alters the immunosupression status through STAT3 pathway in macrophages. Our study may provide a new avenue to investigate the mechanisms of melatonin in regulating an immunosuppressive status.