TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced "acidic" sphingomyelin breakdown

Cell. 1992 Nov 27;71(5):765-76. doi: 10.1016/0092-8674(92)90553-o.


In this paper, we describe a phospholipid transmission pathway mediating tumor necrosis factor (TNF) activation of the nuclear transcription factor kappa B (NF-kappa B). Central to this TNF signaling route is the second messenger-like molecule ceramide, which is generated by sphingomyelin (SM) breakdown catalyzed by a sphingomyelinase (SMase). SMase activation is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-specific phospholipase C (PC-PLC). The functional coupling of these two C type phospholipases is revealed by D609, a selective inhibitor of PC-PLC. SMase itself, or SMase-inducing regimens such as exogenous PLC or synthetic DAGs, induces NF-kappa B activation at pH 5.0, suggesting the operation of an acidic SMase. A model is proposed in which a TNF-responsive PC-PLC via DAG couples to an acidic SMase, resulting in the generation of ceramide, which eventually triggers rapid induction of nuclear NF-kappa B activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Ceramides / pharmacology
  • Diglycerides / pharmacology
  • Isoelectric Point
  • Molecular Sequence Data
  • NF-kappa B / metabolism*
  • Oligodeoxyribonucleotides / chemistry
  • Phosphatidylcholines / metabolism*
  • Receptors, Cell Surface / physiology
  • Receptors, Tumor Necrosis Factor
  • Regulatory Sequences, Nucleic Acid
  • Signal Transduction
  • Sphingomyelin Phosphodiesterase / metabolism
  • Sphingomyelins / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Type C Phospholipases / physiology*


  • Ceramides
  • Diglycerides
  • NF-kappa B
  • Oligodeoxyribonucleotides
  • Phosphatidylcholines
  • Receptors, Cell Surface
  • Receptors, Tumor Necrosis Factor
  • Sphingomyelins
  • Tumor Necrosis Factor-alpha
  • Type C Phospholipases
  • Sphingomyelin Phosphodiesterase