Dual inhibitory effects of furonaphthoquinone compound on enzyme activity and lipopolysaccharide-induced expression of cyclooxygenase-2 in macrophages.
2-Methyl-2-(2-methylpropenyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (NFD-37) is a synthetic furonaphthoquinone compound. In the present study, the NFD-37 compound was found to inhibit prostaglandin (PG) E(2) production in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7. NFD-37 compound exhibited a preferred inhibition on enzyme activity of cyclooxygenase (COX)-2 over COX-1. Further, NFD-37 compound attenuated LPS-induced synthesis of both mRNA and protein of COX-2, and suppressed LPS-induced COX-2 promoter activity in the macrophages, indicating that the furonaphthoquinone compound could down-regulate LPS-induced COX-2 expression at the transcription level. Even though COX-2 promoter behaves as a sophisticated biosensor for host defense, nuclear factor (NF)-kappaB activation has been evidenced to play a major mechanism for LPS-induced COX-2 expression in macrophages. NFD-37 compound exhibited a dose-dependent inhibitory effect on LPS-induced phosphorylation of inhibitory kappaBalpha (IkappaBalpha) protein, and subsequently inhibited IkappaBalpha degradation, DNA binding activity of NF-kappaB complex as well as NF-kappaB transcriptional activity in macrophages RAW 264.7. In another experiment, NFD-37 compound inhibited both COX-2 promoter activity and GST-IkappaBalpha phosphorylation elicited by an expression vector encoding IkappaB kinase beta. Taken together, NFD-37 compound inhibited enzyme activity of COX-2 but also suppressed COX-2 expression depending on NF-kappaB activation, and thus could provide an invaluable tool to investigate pharmacological potential in the excess PG-related disorders.
Ahn
Ki Young
KY
College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University, Cheongju 361-763, Republic of Korea.
Kim
Byung Hak
BH
Lee
Yong Rok
YR
Hwang
Dong-Hyuck
DH
Chung
Eun Yong
EY
Min
Kyung Rak
KR
Kim
Youngsoo
Y
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D017931:DNA Primers; D015232:Dinoprostone / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D005663:Furans / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
C505240:2-methyl-2-(2-methylpropenyl)-2,3-dihydronaphtho(2,3-b)furan-4,9-dione; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D005663:Furans; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009285:Naphthoquinones; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone