The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65

J Biol Chem. 1998 Dec 11;273(50):33508-16. doi: 10.1074/jbc.273.50.33508.


The sesquiterpene lactone helenalin is a potent anti-inflammatory drug whose molecular mechanism of action remains unclear despite numerous investigations. We have previously shown that helenalin and other sesquiterpene lactones selectively inhibit activation of the transcription factor NF-kappaB, a central mediator of the human immune response. These drugs must target a central step in NF-kappaB pathway, since they inhibit NF-kappaB induction by four different stimuli. It has previously been reported that sesquiterpene lactones exert their effect by inhibiting degradation of IkappaB, the inhibitory subunit of NF-kappaB. These data contradicted our report that IkappaB is not detectable in helenalin-treated, ocadaic acid-stimulated cells. Here we use confocal laser scanning microscopy to demonstrate the presence of IkappaB-released, nuclear NF-kappaB in helenalin-treated, tumor necrosis factor-alpha stimulated cells. These data show that neither IkappaB degradation nor NF-kappaB nuclear translocation are inhibited by helenalin. Rather, we provide evidence that helenalin selectively alkylates the p65 subunit of NF-kappaB. This sesquiterpene lactone is the first anti-inflammatory agent shown to exert its effect by directly modifying NF-kappaB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Biological Transport
  • Cell Nucleus / metabolism
  • Dimerization
  • Humans
  • Jurkat Cells
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism*
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / pharmacology*
  • Sesquiterpenes, Guaiane
  • Structure-Activity Relationship
  • Transcription Factor RelA


  • Anti-Inflammatory Agents, Non-Steroidal
  • NF-kappa B
  • Sesquiterpenes
  • Sesquiterpenes, Guaiane
  • Transcription Factor RelA
  • helenalin