title: Role of ABCC1 in export of sphingosine-1-phosphate from mast cells.
abstract: 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.
authors.affiliation: Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Poulami
authors.initials: P
authors.lastname: Mitra
authors.forename: Carole A
authors.initials: CA
authors.lastname: Oskeritzian
authors.forename: Shawn G
authors.initials: SG
authors.lastname: Payne
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beaven
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D001692:Biological Transport; D002465:Cell Movement; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000941:Antigens; D008246:Lysophospholipids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D034741:RNA, Small Interfering; D013110:Sphingosine; C060506:sphingosine 1-phosphate; C421109:multidrug resistance-associated protein 1