Anti-inflammatory effect of pelubiprofen, 2-[4-(oxocyclohexylidenemethyl)-phenyl]propionic acid, mediated by dual suppression of COX activity and LPS-induced inflammatory gene expression via NF-κB inactivation

Pelubiprofen is a non‐steroidal anti‐inflammatory drugs (NSAIDs) that is related both structurally and pharmacologically to ibuprofen. Anti‐inflammatory properties of ibuprofen are due to its ability to both decrease prostaglandin synthesis by inhibiting the activities of cyclooxygenases (COXs) and IκB kinase‐β (IKK‐β). However, the exact mechanisms that accounts for the anti‐inflammatory effects of pelubiprofen are not reported. In this study, we investigated the molecular mechanisms how pelubiprofen modulates the inflammatory mediators in LPS‐induced macrophages and carrageenan‐induced acute inflammatory rat model. Pelubiprofen potently diminished PGE2 productions through inhibition of COX enzyme activity (IC50 values for COX‐1 and COX‐2 are 10.66 ± 0.99 and 2.88 ± 1.01 µM, respectively), but also reduced the expressions of COX‐2, inducible nitric oxide (iNOS), tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), and IL‐6 at transcriptional level in LPS‐induced RAW 264.7 cells. In addition, pelubiprofen attenuated the LPS‐induced transcription activity and the DNA binding activity of NF‐κB, which was accompanied by a parallel reduction of degradation and phosphorylation of inhibitory kappa B‐α (IκB‐α) and consequently by decreased nuclear translocation of NF‐κB. Furthermore, pelubipofen inhibited the LPS‐induced phosphorylation of IKK‐β and transforming growth factor‐β activated kinase‐1 (TAK1). In acute inflammatory rat model, pretreatment with pelubiprofen inhibited carrageenan‐induce edema, neutrophil migration, PGE2 production, and p65, a subunit of NF‐κB, nuclear translocation in inflamed paw. Taken together, our data indicated that pelubiprofen is involved in the dual inhibition of COX activity and TAK1‐IKK‐NF‐κB pathway, revealing molecular basis for the anti‐inflammatory properties of pelubiprofen. J. Cell. Biochem. 112: 3594–3603, 2011. © 2011 Wiley Periodicals, Inc.