Diarctigenin, a Lignan Constituent from Arctium lappa, Down-Regulated Zymosan-Induced Transcription of Inflammatory Genes through Suppression of DNA Binding Ability of Nuclear Factor-κB 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 E₂, tumor necrosis factor-α, and interleukin (IL)-1β and IL-6 with IC₅₀ values of 6 to 12 μM 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)-κB plays a pivotal role in inflammatory gene transcription, we next investigated the effect of diarctigenin on NF-κB activation. Diarctigenin inhibited the transcriptional activity and DNA binding ability of NF-κB in zymosan-activated macrophages but did not affect the degradation and phosphorylation of inhibitory κB (IκB) proteins. Moreover, diarctigenin suppressed expression vector NF-κB p65-elicited NF-κB activation and also iNOS promoter activity, indicating that the compound could directly target an NF-κ-activating signal cascade downstream of IκB degradation and inhibit NF-κB-regulated iNOS expression. Diarctigenin also inhibited the in vitro DNA binding ability of NF-κB but did not affect the nuclear import of NF-κB 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-κB. Finally, this study provides a pharmacological potential of diarctigenin in the NF-κB-associated inflammatory disorders.