Potent anti-inflammatory effect of a novel furan-2,5-dione derivative, BPD, mediated by dual suppression of COX-2 activity and LPS-induced inflammatory gene expression via NF-?B inactivation.

ABSTRACT: We previously reported that 3-(benzo[d]-1,3-dioxol-5-yl)-4-phenylfuran-2,5-dione (BPD) showed strong inhibitory effects on PGE(2) production. However, the exact mechanism for the anti-inflammatory effect of BPD is not completely understood. In this study, we investigated the molecular mechanism involved in the effects of BPD on inflammatory mediators in LPS-stimulated macrophages and animal models of inflammation.The expressions of COX-2, inducible NOS (iNOS), TNF-?, IL-6 and IL-1?, in LPS-stimulated RAW 264.7 cells and murine peritoneal macrophages, were determined by Western blot and/or qRT-PCR, respectively. NF-?B activation was investigated by EMSA, reporter gene assay and Western blotting. Anti-inflammatory effects of BPD were evaluated in vivo in carrageenan-induced paw oedema in rats and LPS-induced septic shock in mice.BPD not only inhibited COX-2 activity but also reduced the expression of COX-2. In addition, BPD inhibited the expression of iNOS, TNF-?, IL-6 and IL-1? at the transcriptional level. BPD attenuated LPS-induced DNA-binding activity and the transcription activity of NF-?B; this was associated with a decrease in the phosphorylation level of inhibitory ?B-? (I?B-?) and reduced nuclear translocation of NF-?B. Furthermore, BPD suppressed the formation of TGF-?-activated kinase-1 (TAK1)/TAK-binding protein1 (TAB1), which was accompanied by a parallel reduction of phosphorylation of TAK1 and I?B kinase (IKK). Pretreatment with BPD inhibited carrageenan-induced paw oedema and LPS-induced septic death.Taken together, our data indicate that BPD is involved in the dual inhibition of COX-2 activity and TAK1-NF-?B pathway, providing a molecular basis for the anti-inflammatory properties of BPD.

SUBMITTER: Shin JS 

PROVIDER: S-EPMC3372841 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other