Tumor necrosis factor-related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype.
Tumor necrosis factor-related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype.
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肿瘤坏死因子相关凋亡诱导的配体在巨噬细胞中诱导促炎细胞因子的表达，并重新教育肿瘤相关的巨噬细胞对抗肿瘤表型。
DOI：
10.1091/mbc.e15-04-0209
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发表时间：
2015-09-15
影响因子：
3.3
通讯作者：
Zheng D
中科院分区：
文献类型：
--
作者：
Gao J;Wang D;Liu D;Liu M;Ge Y;Jiang M;Liu Y;Zheng D
本研究发现肿瘤坏死因子相关的凋亡诱导配体(TRAIL)可诱导巨噬细胞，尤其是肿瘤相关巨噬细胞(TAMs)表达IL-1β、IL-6和肿瘤坏死因子α。TRAIL使TAMs再培养为M1样表型，并诱导其对肿瘤细胞的细胞毒作用。本研究为TRAIL在巨噬细胞免疫调节中的作用提供了新的证据，并为基于TRAIL的抗肿瘤治疗提供了新的思路。肿瘤坏死因子相关的凋亡诱导配体(TRAIL)可以诱导多种肿瘤细胞的凋亡，但不能诱导大多数正常细胞的凋亡，是一种很有前途的肿瘤治疗候选药物。尽管众所周知，TRAIL及其受体在包括免疫细胞在内的多种正常细胞中都有表达，但其免疫作用和调节机制尚不清楚。在本研究中，我们证实了TRAIL对巨噬细胞的核因子-κB(核因子-κB)活性及其下游促炎细胞因子IL-1β(IL-1β)、IL-6和肿瘤坏死因子α的表达的影响。TRAIL还以NF-κB依赖的方式诱导microRNA-146a(miR-146a)的表达。因此，miR-146a作为负反馈调节因子参与了促炎细胞因子表达的下调。在TRAIL诱导的巨噬细胞中，组蛋白脱乙酰基酶活性被曲古抑素A抑制后，miR-146a的表达增强，这是由于TRAIL诱导的巨噬细胞中miR-146a启动子上的核因子-κB的DNA结合活性上调所致，提示组蛋白乙酰化参与了抑制miR-146a的表达。进一步研究发现，HDAC亚型HDAC1直接调节TRAIL刺激的巨噬细胞miR-146a的表达。最后，利用对TRAIL敏感的人非小细胞肺癌细胞系NCI-H460来阐明TRAIL与肿瘤相关巨噬细胞(TAMs)相关的生理意义。我们证明了TRAIL将TAMS重新培养成类似M1的表型，并在肿瘤细胞中诱导了细胞毒效应。这些数据为TRAIL在巨噬细胞的免疫调节中提供了新的证据，并可能为基于TRAIL的人类患者的抗肿瘤治疗提供线索。
This study reveals that tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces expression of IL-1β, IL-6, and tumor necrosis factor α in macrophages, especially in tumor-associated macrophages (TAMs). TRAIL re-educates TAMs to an M1-like phenotype and induces their cytotoxicity to tumor cells. This study provides new evidence for TRAIL in immune regulation of macrophages and sheds light on TRAIL-based antitumor therapy in human patients. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, because it can induce apoptosis in various tumor cells but not in most normal cells. Although it is well known that TRAIL and its receptors are expressed in many types of normal cells, including immune cells, their immunological effects and regulatory mechanisms are still obscure. In the present study, we demonstrated that TRAIL affected the activity of NF-κB (nuclear factor-κB) and the expression of its downstream proinflammatory cytokines IL-1β (interleukin-1β), IL-6, and tumor necrosis factor α in macrophages. TRAIL also induced microRNA-146a (miR-146a) expression in an NF-κB–dependent manner. As a result, miR-146a was involved as a negative-feedback regulator in the down-regulation of proinflammatory cytokine expression. In addition, the suppression of histone deacetylase (HDAC) activities by trichostatin A improved miR-146a expression due to the up-regulation of the DNA-binding activity of NF-κB at the miR-146a promoter in TRAIL-induced macrophages, suggesting that histone acetylation was involved in the suppression of miR-146a expression. Further investigation revealed that the HDAC subtype HDAC1 directly regulated the expression of miR-146a in TRAIL-stimulated macrophages. Finally, the TRAIL-sensitive human non small cell lung carcinoma cell line NCI-H460 was used to elucidate the physiological significance of TRAIL with respect to tumor-associated macrophages (TAMs). We demonstrated that TRAIL re-educated TAMs to an M1-like phenotype and induced cytotoxic effects in the tumor cells. These data provide new evidence for TRAIL in the immune regulation of macrophages and may shed light on TRAIL-based antitumor therapy in human patients.