Stress-induced sphingolipid signaling: role of type-2 neutral sphingomyelinase in murine cell apoptosis and proliferation.
BACKGROUND
Sphingomyelin hydrolysis in response to stress-inducing agents, and subsequent ceramide generation, are implicated in various cellular responses, including apoptosis, inflammation and proliferation, depending on the nature of the different acidic or neutral sphingomyelinases. This study was carried out to investigate whether the neutral Mg(2+)-dependent neutral sphingomyelinase-2 (nSMase2) plays a role in the cellular signaling evoked by TNFalpha and oxidized LDLs, two stress-inducing agents, which are mitogenic at low concentrations and proapoptotic at higher concentrations.


RESULTS
For this purpose, we used nSMase2-deficient cells from homozygous fro/fro (fragilitas ossium) mice and nSMase2-deficient cells reconstituted with a V5-tagged nSMase2. We report that the genetic defect of nSMase2 (in fibroblasts from fro/fro mice) does not alter the TNFalpha and oxidized LDLs-mediated apoptotic response. Likewise, the hepatic toxicity of TNFalpha is similar in wild type and fro mice, thus is independent of nSMase2 activation. In contrast, the mitogenic response elicited by low concentrations of TNFalpha and oxidized LDLs (but not fetal calf serum) requires nSMase2 activation.


CONCLUSIONS
nSMase2 activation is not involved in apoptosis mediated by TNFalpha and oxidized LDLs in murine fibroblasts, and in the hepatotoxicity of TNFalpha in mice, but is required for the mitogenic response to stress-inducing agents.
Devillard
Raphael
R
INSERM U858, CHU Rangueil, Toulouse, France.
Galvani
Sylvain
S
Thiers
Jean-Claude
JC
Guenet
Jean-Louis
JL
Hannun
Yusuf
Y
Bielawski
Jacek
J
Nègre-Salvayre
Anne
A
Salvayre
Robert
R
Augé
Nathalie
N
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D006868:Hydrolysis; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D013107:Sphingolipids / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000096:biosynthesis / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008077:Lipoproteins, LDL; D013107:Sphingolipids; D014409:Tumor Necrosis Factor-alpha; C491483:Smpd3 protein, mouse; D013108:Sphingomyelin Phosphodiesterase