Sido Jessica Margaret, Yang Xiaoming, Nagarkatti Prakash S, Nagarkatti Mitzi
*Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA.
*Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA
J Leukoc Biol. 2015 Apr;97(4):677-88. doi: 10.1189/jlb.1A1014-479R. Epub 2015 Feb 20.
MDSCs are potent immunosuppressive cells that are induced during inflammatory responses, as well as by cancers, to evade the anti-tumor immunity. We recently demonstrated that marijuana cannabinoids are potent inducers of MDSCs. In the current study, we investigated the epigenetic mechanisms through which THC, an exogenous cannabinoid, induces MDSCs and compared such MDSCs with the naïve MDSCs found in BM of BL6 (WT) mice. Administration of THC into WT mice caused increased methylation at the promoter region of DNMT3a and DNMT3b in THC-induced MDSCs, which correlated with reduced expression of DNMT3a and DNMT3b. Furthermore, promoter region methylation was decreased at Arg1 and STAT3 in THC-induced MDSCs, and consequently, such MDSCs expressed higher levels of Arg1 and STAT3. In addition, THC-induced MDSCs secreted elevated levels of S100A8, a calcium-binding protein associated with accumulation of MDSCs in cancer models. Neutralization of S100A8 by use of anti-S100A8 (8H150) in vivo reduced the ability of THC to trigger MDSCs. Interestingly, the elevated S100A8 expression also promoted the suppressive function of MDSCs. Together, the current study demonstrates that THC mediates epigenetic changes to promote MDSC differentiation and function and that S100A8 plays a critical role in this process.
骨髓来源的抑制性细胞（MDSCs）是一种强大的免疫抑制细胞，在炎症反应以及癌症过程中被诱导产生，以逃避抗肿瘤免疫。我们最近证明大麻素是MDSCs的有效诱导剂。在当前研究中，我们研究了外源性大麻素四氢大麻酚（THC）诱导MDSCs的表观遗传机制，并将此类MDSCs与BL6（野生型）小鼠骨髓中发现的原始MDSCs进行了比较。向野生型小鼠施用THC会导致THC诱导的MDSCs中DNMT3a和DNMT3b启动子区域的甲基化增加，这与DNMT3a和DNMT3b的表达降低相关。此外，THC诱导的MDSCs中Arg1和STAT3的启动子区域甲基化降低，因此，此类MDSCs表达更高水平的Arg1和STAT3。此外，THC诱导的MDSCs分泌的S100A8水平升高，S100A8是一种与癌症模型中MDSCs积累相关的钙结合蛋白。在体内使用抗S100A8（8H150）中和S100A8可降低THC触发MDSCs的能力。有趣的是，S100A8表达的升高也促进了MDSCs的抑制功能。总之，当前研究表明THC介导表观遗传变化以促进MDSC分化和功能，并且S100A8在此过程中起关键作用。
