title: Role of sphingosine kinase 1 and sphingosine-1-phosphate in CD40 signaling and IgE class switching.
abstract: The tumor necrosis factor (TNF) receptor family member CD40 plays an essential role in the activation of antigen-presenting cells, B cell maturation, and immunoglobulin (Ig) class switching critical for adaptive immunity. Although the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) and the kinase that produces it, sphingosine kinase 1 (SphK1), have long been implicated in the actions of TNF mediated by engagement of TNFR1, nothing is yet known of their role in CD40-mediated events. We have now found that ligation of CD40 activates and translocates SphK1 to the plasma membrane, leading to generation of S1P. SphK1 inhibition in human tonsil B cells, as well as inhibition or deletion of SphK1 in mouse splenic B cells, significantly reduced CD40-mediated Ig class switching and plasma cell differentiation ex vivo. Optimal activation of downstream CD40 signaling pathways, including NF-κB, p38, and JNK, also required SphK1. In mice treated with a SphK1 inhibitor or in SphK1(-/-) mice, isotype switching to antigen-specific IgE was decreased in vivo by 70 and 55%, respectively. Our results indicate that SphK1 is important for CD40-mediated B cell activation and regulation of humoral responses and suggest that targeting SphK1 might be a useful therapeutic approach to control antigen-specific IgE production.
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, and.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Sturgill
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Nitai C
authors.initials: NC
authors.lastname: Hait
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Dorit
authors.initials: D
authors.lastname: Avni
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Evelyn C
authors.initials: EC
authors.lastname: Valencia
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Michael
authors.initials: M
authors.lastname: Maceyka
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Santiago
authors.initials: S
authors.lastname: Lima
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Allegood
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.affiliation: Department of Microbiology and Immunology, and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Conrad
authors.affiliation: Department of Biochemistry and Molecular Biology, sspiegel@vcu.edu.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000235:genetics* / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D019013:CD40 Antigens; D007073:Immunoglobulin E; D008246:Lysophospholipids; D048670:MAP Kinase Kinase 4; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D048051:p38 Mitogen-Activated Protein Kinases; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
keywords: B cells; NF-κB; inflammation; sphingolipids