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.
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.
Kim
Byung Hak
BH
College of Pharmacy, Chungbuk National University, Cheongju, Korea.
Hong
Seong Su
SS
Kwon
Soon Woo
SW
Lee
Hwa Young
HY
Sung
Hyeran
H
Lee
In-Jeong
IJ
Hwang
Bang Yeon
BY
Song
Sukgil
S
Lee
Chong-Kil
CK
Chung
Daehyun
D
Ahn
Byeongwoo
B
Nam
Sang-Yoon
SY
Han
Sang-Bae
SB
Kim
Youngsoo
Y
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
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