The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65.
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.
Lyss
G
G
Institute of Pharmaceutical Biology, Albert-Ludwigs-Universität Freiburg, Schänzlestr. 1, 79104 Freiburg, Germany.
Knorre
A
A
Schmidt
T J
TJ
Pahl
H L
HL
Merfort
I
I
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D045789:Sesquiterpenes, Guaiane; D013329:Structure-Activity Relationship; D051996:Transcription Factor RelA
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D051996:Transcription Factor RelA; C001329:helenalin