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 PGE2 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.