title: Diarctigenin, a lignan constituent from Arctium lappa, down-regulated zymosan-induced transcription of inflammatory genes through suppression of DNA binding ability of nuclear factor-kappaB in macrophages.
abstract: Diarctigenin was previously isolated as an inhibitor of nitric oxide (NO) production in macrophages from the seeds of Arctium lappa used as an alternative medicine for the treatment of inflammatory disorders. However, little is known about the molecular basis of these effects. Here, we demonstrated that diarctigenin inhibited the production of NO, prostaglandin E(2), tumor necrosis factor-alpha, and interleukin (IL)-1beta and IL-6 with IC(50) values of 6 to 12 miciroM in zymosan- or lipopolysaccharide-(LPS) activated macrophages. Diarctigenin attenuated zymosan-induced mRNA synthesis of inducible NO synthase (iNOS) and also inhibited promoter activities of iNOS and cytokine genes in the cells. Because nuclear factor (NF)-kappaB plays a pivotal role in inflammatory gene transcription, we next investigated the effect of diarctigenin on NF-kappaB activation. Diarctigenin inhibited the transcriptional activity and DNA binding ability of NF-kappaB in zymosan-activated macrophages but did not affect the degradation and phosphorylation of inhibitory kappaB (IkappaB) proteins. Moreover, diarctigenin suppressed expression vector NF-kappaB p65-elicited NF-kappaB activation and also iNOS promoter activity, indicating that the compound could directly target an NF-kappa-activating signal cascade downstream of IkappaB degradation and inhibit NF-kappaB-regulated iNOS expression. Diarctigenin also inhibited the in vitro DNA binding ability of NF-kappaB but did not affect the nuclear import of NF-kappaB p65 in the cells. Taken together, diarctigenin down-regulated zymosan- or LPS-induced inflammatory gene transcription in macrophages, which was due to direct inhibition of the DNA binding ability of NF-kappaB. Finally, this study provides a pharmacological potential of diarctigenin in the NF-kappaB-associated inflammatory disorders.
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Korea.
authors.forename: Byung Hak
authors.initials: BH
authors.lastname: Kim
authors.forename: Seong Su
authors.initials: SS
authors.lastname: Hong
authors.forename: Soon Woo
authors.initials: SW
authors.lastname: Kwon
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Hyeran
authors.initials: H
authors.lastname: Sung
authors.forename: In-Jeong
authors.initials: IJ
authors.lastname: Lee
authors.forename: Bang Yeon
authors.initials: BY
authors.lastname: Hwang
authors.forename: Sukgil
authors.initials: S
authors.lastname: Song
authors.forename: Chong-Kil
authors.initials: CK
authors.lastname: Lee
authors.forename: Daehyun
authors.initials: D
authors.lastname: Chung
authors.forename: Byeongwoo
authors.initials: B
authors.lastname: Ahn
authors.forename: Sang-Yoon
authors.initials: SY
authors.lastname: Nam
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D031170:Arctium / Q000737:chemistry*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D004247:DNA / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D015850:Interleukin-6 / Q000235:genetics; D017705:Lignans / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015054:Zymosan / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D015850:Interleukin-6; D017705:Lignans; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D004247:DNA; D015054:Zymosan; D052247:Nitric Oxide Synthase Type II; C532887:diarctigenin; D015232:Dinoprostone