Role for ceramide as an endogenous mediator of Fas-induced cytotoxicity

Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8443-7. doi: 10.1073/pnas.92.18.8443.

Abstract

Triggering of the Fas/APO-1 cell-surface receptor induces apoptosis through an uncharacterized chain of events. Exposure of Fas-sensitive cells to an agonist monoclonal antibody induced cell death and a 200-300% elevation in endogenous levels of the sphingolipid ceramide, a proposed intracellular mediator of apoptosis. In contrast, similar treatment of Fas-resistant cells caused insignificant changes in ceramide levels. Because resistant cell lines expressed the Fas antigen, these results indicate that these cells have a defect in the proximal signaling events leading to ceramide generation. Exposure of the resistant cell lines to a synthetic analog of ceramide induced apoptosis, thus bypassing Fas resistance and indicating that the signaling pathways downstream of ceramide were intact. Furthermore, activation of protein kinase C with the diacylglycerol analog phorbol 12-myristate 13-acetate significantly reduced Fas-induced cytotoxicity, suggesting opposing roles for ceramide and protein kinase C in regulation of apoptosis. These results provide evidence for ceramide as a necessary and sufficient lipid mediator of Fas-mediated apoptosis and suggest this process may be modulated via activation of additional signal-transduction pathways.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigens, Surface / physiology*
  • Apoptosis / physiology*
  • Cell Line
  • Cell Survival / physiology
  • Ceramides / biosynthesis
  • Ceramides / physiology*
  • Enzyme Activation
  • Hydrolysis
  • Phenotype
  • Protein Kinase C / metabolism
  • Sphingomyelins / metabolism
  • fas Receptor

Substances

  • Antigens, Surface
  • Ceramides
  • Sphingomyelins
  • fas Receptor
  • Protein Kinase C