title: 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.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.forename: Seung Ryel
authors.initials: SR
authors.lastname: Baek
authors.forename: Se-Il
authors.initials: SI
authors.lastname: Sohn
authors.forename: Young-Wuk
authors.initials: YW
authors.lastname: Cho
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D008070:Lipopolysaccharides; D016328:NF-kappa B