Inhibition of NF-kappaB and AP-1 activation by R- and S-flurbiprofen.

R-flurbiprofen is considered the 'inactive' isomer of the nonsteroidal anti-inflammatory drug (NSAID), flurbiprofen, because it does not inhibit cyclooxygenase (COX) activity. However, previous studies have revealed that it has antinociceptive and antitum or effects not due to epimerization to the cyclooxygenase-inhibiting S-isomer. Here, we show that R-flurbiprofen has additional anti-inflammatory activity comparable with that of dexamethasone in the zymosan-induced paw inflammation model in rats. Different criteria suggest that the observed effects are mediated at least in part through inhibition of NF-kB activation: R-flurbiprofen inhibited i) LPS-induced NF-kB DNA binding activity in RAW 264.7 macrophages, ii) translocation of the p65 subunit of NF-kB into the nucleus of these cells, and iii) zymosan-induced NF-kB-dependent gene transcription in the inflamed paw and spinal cord of rats. S-flurbiprofen produced similar effects but was less potent. In addition, R-flurbiprofen inhibited DNA binding activity of AP-1, another key regulatory transcription factor in inflammatory processes. Because R-flurbiprofen does not cause gastrointestinal mucosal damage or other side effects associated with long-term NSAID or glucocorticoid use, it might be a useful drug in inflammatory or other diseases in which increased or constitutive NF-kB and AP-1 activation are involved in the pathophysiological processes.