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

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Abstract
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. 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). 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. Our data raise the possibility that R(−)‐ibuprofen exerts some of its effects by inhibition of NF‐κB activation. British Journal of Pharmacology (1998) 123, 645–652; doi:10.1038/sj.bjp.0701652