Inhibition of breast cancer resistance protein (ABCG2) in human myeloid dendritic cells induces potent tolerogenic functions during LPS stimulation.
Inhibition of breast cancer resistance protein (ABCG2) in human myeloid dendritic cells induces potent tolerogenic functions during LPS stimulation.
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DOI：
10.1371/journal.pone.0104753
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Jin JO;Zhang W;Wong KW;Kwak M;van Driel IR;Yu Q
乳腺癌耐药蛋白（ABCG 2）是ATP结合盒转运蛋白的一个成员，是肿瘤细胞多药耐药（MDR）的主要决定因素，但ABC转运蛋白抑制剂在体内的治疗价值有限。在这项研究中，我们证明了外排转运蛋白ABCG 2的抑制诱导从人外周血髓样DC（mDC）产生致耐受性DC。ABCG 2表达存在于mDC中，并且通过LPS刺激进一步增加。在LPS刺激期间，用ABCG 2抑制剂Ko 143处理CD 1c + mDCs导致IL-10的产生增加，促炎细胞因子的产生减少，CD 83和CD 86的表达减少。此外，在单核细胞衍生的DC（MDDC）中抑制ABCG 2消除了这些细胞中响应于LPS的共刺激分子的上调和促炎细胞因子的产生。此外，LPS加Ko 143刺激的CD 1c + mDCs以IL-10依赖的方式抑制同种异体和超抗原特异性同系CD 4 + T细胞的增殖，并促进CD 25 + FOXP 3+调节性T（Treg）细胞的扩增。ABCG 2抑制的这些致耐受性作用可以通过ERK抑制来消除。因此，我们证明了在LPS刺激的mDC中抑制ABCG 2可以有效地诱导这些细胞中的耐受性潜力，提供了重要的新信息，可以导致开发更好的策略来对抗MDR癌症。
Breast cancer resistance protein (ABCG2), a member of the ATP-binding cassette transporters has been identified as a major determinant of multidrug resistance (MDR) in cancer cells, but ABC transporter inhibition has limited therapeutic value in vivo. In this research, we demonstrated that inhibition of efflux transporters ABCG2 induced the generation of tolerogenic DCs from human peripheral blood myeloid DCs (mDCs). ABCG2 expression was present in mDCs and was further increased by LPS stimulation. Treatment of CD1c+ mDCs with an ABCG2 inhibitor, Ko143, during LPS stimulation caused increased production of IL-10 and decreased production of pro-inflammatory cytokines and decreased expression of CD83 and CD86. Moreover, inhibition of ABCG2 in monocyte-derived DCs (MDDCs) abrogated the up-regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in these cells in response to LPS. Furthermore, CD1c+ mDCs stimulated with LPS plus Ko143 inhibited the proliferation of allogeneic and superantigen-specific syngenic CD4+ T cells and promoted expansion of CD25+FOXP3+ regulatory T (Treg) cells in an IL-10-dependent fashion. These tolerogenic effects of ABCG2 inhibition could be abolished by ERK inhibition. Thus, we demonstrated that inhibition of ABCG2 in LPS-stimulated mDCs can potently induce tolerogenic potentials in these cells, providing crucial new information that could lead to development of better strategies to combat MDR cancer.
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