Modulation of transcription factor NF-kappaB by enantiomers of the nonsteroidal drug ibuprofen.
1. The nonsteroidal drug ibuprofen exists as an R(-)- and S(+)-enantiomer. Only the S(+)-enantiomer is an effective cyclo-oxygenase inhibitor, while the R(-)-enantiomer is inactive in this respect. Thus the molecular mechanism by which R(-)-ibuprofen exerts its anti-inflammatory and antinociceptive effects remains unknown. 2. In this study the effects of the enantiomers of ibuprofen on modulation of transcription factors have been examined with electrophoretic mobility-shift assay (EMSA), transient transfection experiments, confocal immunofluorescence and nuclear import experiments, to determine their selectivity and potency as inhibitors of the activation of transcription factor nuclear factor-kappaB (NF-kappaB). 3. R(-)-ibuprofen (IC50: 121.8 microM) as well as the S(+)-enantiomer (IC50: 61.7 microM) inhibited the activation of NF-kappaB in response to T-cell stimulation. The effect of ibuprofen was specific because, at concentrations up to 10 mM, ibuprofen did not affect the heat shock transcription factor (HSF) and the activation of NF-kappaB by prostaglandin E2 (PGE2). Very high concentrations of ibuprofen (20 mM) did not prevent NF-kappaB binding to DNA in vitro. Immunofluorescence and nuclear import experiments indicate that the site of ibuprofen action appeared to be upstream of the dissociation of the NF-kappaB-IkappaB-complex. 4. Our data raise the possibility that R(-)-ibuprofen exerts some of its effects by inhibition of NF-kappaB activation.
Scheuren
N
N
Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Erlangen, Germany.
Bang
H
H
Münster
T
T
Brune
K
K
Pahl
A
A
D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry / Q000494:pharmacology*; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D007052:Ibuprofen