Modulation of transcription factor NF-κB by enantiomers of the nonsteroidal drug ibuprofen

Abstract

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-κB (NF-κB).

3. R(−)-ibuprofen (IC₅₀: 121.8 μM) as well as the S(+)-enantiomer (IC₅₀: 61.7 μM) inhibited the activation of NF-κB 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-κB by prostaglandin E₂ (PGE₂). Very high concentrations of ibuprofen (20 mM) did not prevent NF-κB 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-κB-IκB-complex.

4. Our data raise the possibility that R(−)-ibuprofen exerts some of its effects by inhibition of NF-κB activation.

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