Sphingolipid signalling: molecular basis and role in TNF-alpha-induced cell death.
Various lipidic molecules serve as second messengers for transducing signals from the cell surface to the cell interior and trigger specific cellular responses. Sphingolipids represent a complex group of lipids that have recently emerged as new transducers in eukaryotic cells. Several sphingolipid molecules are able to modulate cell growth, differentiation and death. This review summarises current knowledge of the signalling functions of sphingolipids, especially in the regulation of tumour necrosis factor [alpha] (TNF-[alpha])-mediated cytotoxic effects. TNF-[alpha] is a multifaceted cytokine that controls a wide range of immune responses in mammals, including induction of programmed cell death (also called apoptosis). On the basis of recent observations, a working model is proposed for the molecular mechanisms underlying regulation of sphingolipid generation following TNF-[alpha] receptor 1 activation. The implications of these findings for the development of future pharmacological strategies to prevent the cytotoxic TNF-[alpha] response and subsequent cellular dysfunctions (as seen in various human diseases) are discussed.
INSERM U.466, Laboratoire de Biochimie, CHU Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse cedex 9, France. sophie.malagarie@toulouse.inserm.fr
Sophie
S
Malagarie-Cazenave
Nathalie
N
Andrieu-Abadie
Bruno
B
Ségui
Valérie
V
Gouazé
Claudine
C
Tardy
Olivier
O
Cuvillier
Thierry
T
Levade
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D022082:Cellular Structures / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013107:Sphingolipids / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D013107:Sphingolipids; D014409:Tumor Necrosis Factor-alpha