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 PGE(2) productions through inhibition of COX enzyme activity (IC(50) 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, PGE(2) 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.
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