title: Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids.
abstract: Calcium influx through store-operated calcium release-activated calcium channels (CRAC) is required for T cell activation, cytokine synthesis, and proliferation. The CD95 (Apo-1/Fas) receptor plays a role in self-tolerance and tumor immune escape, and it mediates apoptosis in activated T cells. In this paper we show that CD95-stimulation blocks CRAC and Ca(2+) influx in lymphocytes through the activation of acidic sphingomyelinase (ASM) and ceramide release. The block of Ca(2+) entry is lacking in CD95-defective lpr lymphocytes as well as in ASM-defective cells and can be restored by retransfection of ASM. C2 ceramide, C6 ceramide, and sphingosine block CRAC reversibly, whereas the inactive dihydroceramide has no effect. CD95-stimulation or the addition of ceramide prevents store-operated Ca(2+) influx, activation of the transcriptional regulator NFAT, and IL-2 synthesis. The block of CRAC by sphingomyelinase metabolites adds a function to the repertoire of the CD95 receptor inhibiting T cell activation signals.
authors.affiliation: Department of Physiology I, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany. alepplew@uni-tuebingen.de
authors.forename: A
authors.initials: A
authors.lastname: Lepple-Wienhues
authors.forename: C
authors.initials: C
authors.lastname: Belka
authors.forename: T
authors.initials: T
authors.lastname: Laun
authors.forename: A
authors.initials: A
authors.lastname: Jekle
authors.forename: B
authors.initials: B
authors.lastname: Walter
authors.forename: U
authors.initials: U
authors.lastname: Wieland
authors.forename: M
authors.initials: M
authors.lastname: Welz
authors.forename: L
authors.initials: L
authors.lastname: Heil
authors.forename: J
authors.initials: J
authors.lastname: Kun
authors.forename: G
authors.initials: G
authors.lastname: Busch
authors.forename: M
authors.initials: M
authors.lastname: Weller
authors.forename: M
authors.initials: M
authors.lastname: Bamberg
authors.forename: E
authors.initials: E
authors.lastname: Gulbins
authors.forename: F
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D002518:Ceramides / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D013107:Sphingolipids / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002518:Ceramides; D013107:Sphingolipids; D019014:fas Receptor; D013108:Sphingomyelin Phosphodiesterase; D002118:Calcium