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Repression of PPARγ reduces the ABCG2-mediated efflux activity of M2 macrophages
The International Journal of Biochemistry & Cell Biology ( IF 3.4 ) Pub Date : 2020-11-28 , DOI: 10.1016/j.biocel.2020.105895
Chae Eun Kim 1 , Ha Young Park 1 , Hae Jeong Won 2 , Minyoung Kim 3 , Byungsuk Kwon 4 , Su-Jun Lee 3 , Dong Hyun Kim 3 , Jae-Gook Shin 3 , Su-Kil Seo 1
Affiliation  

Even though subclasses of macrophage have distinct roles during progression of infectious diseases, it remains poorly understood whether there is a subset-specific difference in drug responses. Here, we report that ABCG2 was expressed specifically in M2-like macrophages and that it controlled their efflux activities. Abcg2 expression is markedly induced during polarization of PMA-primed macrophages toward an M2 type. IL-4 and IL-13 induced Pparg expression through STAT6 and PPARγ in turn acted on the Abcg2 promoter for its transcription activation. Once polarized to M2-like macrophages, these cells had sustained PPARγ transcription activation of Abcg2 gene. Accordingly, interruption of this machinery by T0070907, an inverse agonist of PPARγ, was shown to be effective in Abcg2 downregulation and its efflux activity in M2-like macrophages. Taken together, our results implicate that ABCG2 of M2 macrophages may function as an important pump that plays a potential role in drug efflux and that T0070907 may be used to increase the efficacy of M2 macrophage-targeting drugs such as antibiotics.



中文翻译:

PPARγ 的抑制降低了 M2 巨噬细胞的 ABCG2 介导的外排活性

尽管巨噬细胞的亚类在传染病的进展过程中具有不同的作用,但对药物反应是否存在亚类特异性差异仍知之甚少。在这里,我们报告 ABCG2 在 M2 样巨噬细胞中特异性表达,并且它控制着它们的外排活动。在 PMA 引发的巨噬细胞向 M2 型极化期间显着诱导了Abcg2表达。IL-4 和 IL-13通过 STAT6诱导Pparg表达,PPARγ 依次作用于Abcg2启动子以激活其转录。一旦极化为 M2 样巨噬细胞,这些细胞就会持续激活Abcg2 的PPARγ 转录激活基因。因此,PPARγ 的反向激动剂 T0070907 对这种机制的中断显示出对Abcg2下调及其在 M2 样巨噬细胞中的外排活性有效。总之,我们的结果表明 M2 巨噬细胞的 ABCG2 可能作为一个重要的泵发挥作用,在药物外流中发挥潜在作用,并且 T0070907 可用于提高 M2 巨噬细胞靶向药物(如抗生素)的功效。

更新日期:2020-12-01
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