Mitra Poulami, Oskeritzian Carole A, Payne Shawn G, Beaven Michael A, Milstien Sheldon, Spiegel Sarah
Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16394-9. doi: 10.1073/pnas.0603734103. Epub 2006 Oct 18.
Mast cells play a pivotal role in inflammatory and immediate-type allergic reactions by secreting a variety of potent inflammatory mediators, including sphingosine-1-phosphate (S1P). However, it is not known how S1P is released from cells. Here, we report that S1P is exported from mast cells independently of their degranulation and demonstrate that it is mediated by ATP binding cassette (ABC) transporters. Constitutive and antigen-stimulated S1P release was inhibited by MK571, an inhibitor of ABCC1 (MRP1), but not by inhibitors of ABCB1 (MDR-1, P-glycoprotein). Moreover, down-regulation of ABCC1 with small interfering RNA, which decreased its cell surface expression, markedly reduced S1P export from both rat RBL-2H3 and human LAD2 mast cells. Transport of S1P by ABCC1 influenced migration of mast cells toward antigen but not degranulation. These findings have important implications for S1P functions in mast cell-mediated immune responses.
肥大细胞通过分泌多种强效炎症介质，包括1-磷酸鞘氨醇（S1P），在炎症和速发型过敏反应中起关键作用。然而，尚不清楚S1P是如何从细胞中释放出来的。在此，我们报告S1P从肥大细胞中输出与其脱颗粒无关，并证明其由ATP结合盒（ABC）转运蛋白介导。ABCC1（多药耐药相关蛋白1，MRP1）抑制剂MK571可抑制组成型和抗原刺激的S1P释放，但ABCB1（多药耐药蛋白1，MDR-1，P-糖蛋白）抑制剂则无此作用。此外，用小干扰RNA下调ABCC1，降低其细胞表面表达，可显著减少大鼠RBL-2H3和人LAD2肥大细胞中S1P的输出。ABCC1介导的S1P转运影响肥大细胞向抗原的迁移，但不影响其脱颗粒。这些发现对S1P在肥大细胞介导的免疫反应中的功能具有重要意义。
