Dendritic cells require multidrug resistance protein 1 (ABCC1) transporter activity for differentiation
Dendritic cells require multidrug resistance protein 1 (ABCC1) transporter activity for differentiation
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DOI：
10.4049/jimmunol.176.9.5191
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发表时间：
2006-05-01
影响因子：
4.4
通讯作者：
Scheper, Rik J.
中科院分区：
文献类型：
--
作者：
van de Ven, Rieneke;de Jong, Mariska C.;Scheper, Rik J.
树突状细胞（DC）表达ATP结合盒（ABC）转运蛋白P-糖蛋白（ABCB 1）和多药耐药蛋白1（MRP 1; ABCC 1）。在功能上，这两种转运蛋白已被描述为有效的DC和T细胞迁移所需的。在这项研究中，我们报告说，MRP 1活性也是至关重要的DC的分化。在体外DC分化过程中，用特异性拮抗剂抑制MRP 1（而非P-糖蛋白）转运体活性可干扰早期DC的发育。间质性和朗格汉斯DC分化受损的特征在于：1）形态学变化，通过流式细胞术分析中下降的侧向散射水平反映; 2）表型变化，通过单核细胞标志物CD 14的表达维持，CD 40、CD 86、HLA-DR的表达水平降低，以及表达CD 1a、CD 1c和朗格汉斯蛋白的细胞量显著减少来说明。缺陷的DC分化也导致其刺激同种异体T细胞的能力降低。我们确定了内源性CD 1配体硫苷脂和单唾液酸神经节苷脂GM 1作为MRP 1底物，但外源性添加这些底物不能恢复DC分化过程中阻断MRP 1活性所造成的缺陷。虽然据报道，白三烯C-4恢复小鼠Mrp 1缺陷DC的迁移，MRP 1抑制DC分化的影响似乎是独立的白三烯途径。虽然MRP 1转运体活性对DC分化很重要，但DC分化所需的相关MRP 1底物仍有待鉴定。总之，MRP 1似乎在DC发育和DC功能中发挥重要的生理作用。
Dendritic cells (DC) express the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and multidrug resistance protein 1 (MRP1; ABCC1). Functionally, both these transporters have been described to be required for efficient DC and T cell migration. In this study, we report that MRP1 activity is also crucial for differentiation of DC. Inhibition of MRP1, but not P-glycoprotein, transporter activity with specific antagonists during in vitro DC differentiation interfered with early DC development. Impaired interstitial and Langerhans DC differentiation was characterized by 1) morphological changes, reflected by dropped side scatter levels in flow cytometric analysis and 2) phenotypic changes illustrated by maintained expression of the monocytic marker CD14, lower expression levels of CD40, CD86, HLA-DR, and a significant decrease in the amount of cells expressing CD1a, CD1c, and Langerin. Defective DC differentiation also resulted in their reduced ability to stimulate allogeneic T cells. We identified the endogenous CD1 ligands sulfatide and monosialoganglioside GM1 as MRP1 substrates, but exogenous addition of these substrates could not restore the defects caused by blocking MRP1 activity during DC differentiation. Although leukotriene C-4 was reported to restore migration of murine Mrp1-deficient DC, the effects of MRP1 inhibition on DC differentiation appeared to be independent of the leukotriene pathway. Though MRP1 transporter activity is important for DC differentiation, the relevant MRP1 substrate, which is required for DC differentiation, remains to be identified. Altogether, MRP1 seems to fulfill an important physiological role in DC development and DC functions.