Background and purpose: 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.
Experimental approach: The expressions of COX-2, inducible NOS (iNOS), TNF-α, IL-6 and IL-1β, in LPS-stimulated RAW 264.7 cells and murine peritoneal macrophages, were determined by Western blot and/or qRT-PCR, respectively. NF-κB 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.
Key results: BPD not only inhibited COX-2 activity but also reduced the expression of COX-2. In addition, BPD inhibited the expression of iNOS, TNF-α, IL-6 and IL-1β at the transcriptional level. BPD attenuated LPS-induced DNA-binding activity and the transcription activity of NF-κB; this was associated with a decrease in the phosphorylation level of inhibitory κB-α (IκB-α) and reduced nuclear translocation of NF-κB. Furthermore, BPD suppressed the formation of TGF-β-activated kinase-1 (TAK1)/TAK-binding protein1 (TAB1), which was accompanied by a parallel reduction of phosphorylation of TAK1 and IκB kinase (IKK). Pretreatment with BPD inhibited carrageenan-induced paw oedema and LPS-induced septic death.
Conclusion and implications: Taken together, our data indicate that BPD is involved in the dual inhibition of COX-2 activity and TAK1-NF-κB pathway, providing a molecular basis for the anti-inflammatory properties of BPD.
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.