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

Abstract

1 The nonsteroidal drug ibuprofen exists as an R(7)-and S(+)-enantiomer. Only the S(+)-enantiomer is an e ective cyclo-oxygenase inhibitor, while the R(7)-enantiomer is inactive in this respect. Thus the molecular mechanism by which R(7)-ibuprofen exerts its anti-in¯ammatory and antinociceptive e ects remains unknown. 2 In this study the e ects of the enantiomers of ibuprofen on modulation of transcription factors have been examined with electrophoretic mobility-shift assay (EMSA), transient transfection experiments, confocal immuno¯uorescence and nuclear import experiments, to determine their selectivity and potency as inhibitors of the activation of transcription factor nuclear factor-kB (NF-kB). 3 R(7)-ibuprofen (IC 50 : 121.8 mM) as well as the S(+)-enantiomer (IC 50 : 61.7 mM) inhibited the activation of NF-kB in response to T-cell stimulation. The e ect of ibuprofen was speci®c because, at concentrations up to 10 mM, ibuprofen did not a ect the heat shock transcription factor (HSF) and the activation of NF-kB by prostaglandin E 2 (PGE 2 ). Very high concentrations of ibuprofen (20 mM) did not prevent NF-kB binding to DNA in vitro. Immuno¯uorescence and nuclear import experiments indicate that the site of ibuprofen action appeared to be upstream of the dissociation of the NF-kB-IkBcomplex. 4 Our data raise the possibility that R(7)-ibuprofen exerts some of its e ects by inhibition of NF-kB activation.

Selective inhibition of Aβ42 production by NSAID R‐enantiomers

“…One known COX-independent activity of both R-ibuprofen and R-flurbiprofen in the same range of Ab42 reduction dosage is NF-jB inhibition (Scheuren et al 1998;Tegeder et al 2001a) and NF-jB has been reported to selectively induce Ab42 production (Tomita et al 2000). Therefore, we tested the Ab42 lowering activity of a specific NF-jB inhibitor (SN-50) at doses which effectively inhibit translocation of the NF-jB active complex into the nucleus (Lin et al 1995).…”

“…High doses of ibuprofen and both S-and R-enantiomers inhibit NF-jB (Scheuren et al 1998;Tegeder et al 2001a) and NF-jB has been reported to specifically induce Ab42 production (Tomita et al 2000). Therefore, we tested the ability of an NF-jB peptide inhibitor to inhibit Ab42 production.…”

Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-κB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation

“…The significance of results when compared with the TNF-treated cells are *P>0.1, **Po0.1, ***Po0.01, ****Po0.001 Downregulation of NF-jB, COX-2, cyclin D1, and proliferation by NSAID Y Takada et al Bryant et al, 2003). Scheuren et al (1998) showed that R(À)-ibuprofen as well as the S( þ )-enantiomer inhibited the activation of NF-kB in response to T-cell stimulation. One recent report showed that low doses of celecoxib inhibit IL-1-induced NF-kB activation and high doses stimulate it (Niederberger et al, 2001), whereas in our system, celecoxib alone did not activate NF-kB.…”

“…Thus, both antiproliferative and anti-inflammatory effects of NSAID can be explained through their ability to suppress NF-kB. Although aspirin was the first NSAID shown to suppress NF-kB (Kopp and Ghosh, 1994), now several NSAID have been shown to suppress NF-kB activation (Kazmi et al, 1995;Scheuren et al, 1998;Yamamoto et al, 1999;Chuang et al, 2002;Bryant et al, 2003).…”

Interleukin-8 Up-regulation by Neutrophil Elastase Is Mediated by MyD88/IRAK/TRAF-6 in Human Bronchial Epithelium

“…Adenovirus-mediated overexpression of IB␣ and liposome-mediated transfection with decoy oligonucleotides in a CF airway epithelial cell line has been shown to decrease TNF␣-induced IL-8 secretion and NFB activity (50). In addition, the nonsteroidal anti-inflammatory drug ibuprofen has been shown to inhibit NFB activity, thereby preventing the expression of inflammatory cytokines (51)(52)(53). These studies have yielded promising results that suggest that NFB may indeed be a key target for development of anti-inflammatory therapeutics for CF.…”