IRF4公司
髓源性抑制细胞
癌症研究
IRF8
骨髓
生物
基因敲除
干扰素调节因子
髓样
细胞分化
免疫学
免疫系统
抑制器
转录因子
细胞培养
先天免疫系统
癌症
生物化学
遗传学
基因
作者
Sorim Nam,Kyeongah Kang,Jae Seon,Jung Ho Kim,Hee Gu Lee,Yonghwan Kim,Young Yang,Myeong-Sok Lee,Jong‐Seok Lim
标识
DOI:10.1189/jlb.1a0215-068rr
摘要
Abstract Myeloid-derived suppressor cells (MDSCs) are immature cells that do not differentiate into mature myeloid cells. Two major populations of PMN-MDSCs (Ly6GhighLy6ClowGr1highCD11b+) and MO-MDSCs (Ly6G−Ly6ChighGr-1intCD11b+) have an immune suppressive function. Interferon regulatory factor 4 (IRF4) has a role in the negative regulation of TLR signaling and is associated with lymphoid cell development. However, the roles of IRF4 in myeloid cell differentiation are unclear. In this study, we found that IRF4 expression was remarkably suppressed during the development of MDSCs in the tumor microenvironment. Both the mRNA and protein levels of IRF4 in MDSCs were gradually reduced, depending on the development of tumors in the 4T1 model. siRNA-mediated knockdown of IRF4 in bone marrow cells promoted the differentiation of PMN-MDSCs. Similarly, IRF4 inhibition in bone marrow cells using simvastatin, which has been known to inhibit IRF4 expression, increased PMN-MDSC numbers. In contrast, IRF4 overexpression in bone marrow cells inhibited the total numbers of MDSCs, especially PMN-MDSCs. Notably, treatment with IL-4, an upstream regulator of IRF4, induced IRF4 expression in the bone marrow cells, and consequently, IL-4–induced IRF4 expression resulted in a decrease in PMN-MDSC numbers. Finally, we confirmed that IRF4 expression in MDSCs can modulate their activity to inhibit T cell proliferation through IL-10 production and ROS generation, and myeloid-specific deletion of IRF4 leads to the increase of MDSC differentiation. Our present findings indicate that IRF4 reduction induced by tumor formation can increase the number of MDSCs, and increases in the IRF4 expression in MDSCs may infringe on the immune-suppressive function of MDSCs.
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