title: Acid sphingomyelinase is required for protection of effector memory T cells against glucocorticoid-induced cell death.
abstract: The activity of acid sphingomyelinase (aSMase) was previously reported to be involved in glucocorticoid-induced cell death (GICD) of T lymphocytes. This mechanism in turn is believed to contribute to the therapeutic efficacy of glucocorticoids (GCs) in the treatment of inflammatory diseases. In this study, we reassessed the role of aSMase in GICD by using aSMase knockout mice. The absence of aSMase largely abolished the partial protection that effector memory CD4(+) T cells in wild-type mice possess against GICD. Reduced IL-2 secretion by aSMase-deficient CD4(+) T cells suggested that a lack of this important survival factor might be the cause of these cells' enhanced susceptibility to GICD. Indeed, addition of IL-2 restored the protection against GICD, whereas neutralization of IL-2 abrogated the otherwise protective effect seen in wild-type effector memory CD4(+) T cells. The therapeutic implications of the altered sensitivity of aSMase-deficient T cells to GICD were assessed in models of inflammatory disorders; namely, experimental autoimmune encephalomyelitis and acute graft-versus-host disease. Surprisingly, GC treatment was equally efficient in both models in terms of ameliorating the diseases, regardless of the genotype of the T cells. Thus, our data reveal a hitherto unrecognized contribution of aSMase to the sensitivity of effector memory CD4(+) T cells to GICD and call into question the traditionally attributed importance of GICD of T cells to the treatment of inflammatory diseases by GCs.
authors.affiliation: Department of Cellular and Molecular Immunology, University of Göttingen Medical School, Göttingen 37073, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Tischner
authors.forename: Jennifer
authors.initials: J
authors.lastname: Theiss
authors.forename: Anna
authors.initials: A
authors.lastname: Karabinskaya
authors.forename: Jens
authors.initials: J
authors.lastname: van den Brandt
authors.forename: Sybille D
authors.initials: SD
authors.lastname: Reichardt
authors.forename: Ulrike
authors.initials: U
authors.lastname: Karow
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.forename: Olaf
authors.initials: O
authors.lastname: Utermöhlen
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D006086:Graft vs Host Disease / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000235:genetics; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*
chemical_list: D007376:Interleukin-2; D003907:Dexamethasone; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase