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Total methanol extract of Saussurea lappa radix (Compositae) showed potent inhibitory effect on the production of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, in murine macrophage-like cell (RAW264.7 cells) in our previous screening studies on 120 Korean medicinal plants. The activity-guided purification of the plant resulted in the isolation of three components. The chemical structures of the components isolated were established by spectroscopic analyses as sesquiterpene lactones [cynaropicrin (1), reynosin (2), and santamarine (3)]. These three compounds inhibited TNF-alpha production in a dose-dependent manner. The molar concentrations of cynaropicrin, reynosin, and santamarine producing 50% inhibition (IC50) of TNF-alpha production were 2.86 micrograms/ml (8.24 microM), 21.7 micrograms/ml (87.4 microM), and 26.2 micrograms/ml (105 microM), respectively. However, treatment with sulphydryl (SH) compounds such as L-cysteine, dithiothreitol, and 2-mercaptoethanol abrogated the inhibitory effect of cynaropicrin on TNF-alpha production. Therefore, we conclude that the principal inhibitory component of Saussurea lappa is cynaropicrin and its inhibitory effect is mediated through conjugation with SH-groups of target proteins.

Ginsenosides are the major principles of Panax ginseng C. A. Meyer (Araliaceae) used as a mild oriental folk medicine. In this report, we have examined the inhibitory potency of protopanaxadiol ginsenosides (PPDGs) such as Rb1, Rb2 and Rc, and their co-treatment effect with known tumor necrosis factor (TNF)-alpha antagonists on TNF-alpha production in either murine (RAW264.7) or human (U937) macrophages stimulated with lipopolysaccharide (LPS). Rb1, and Rb2 strongly suppressed TNF-alpha production in RAW264.7 cells with an IC50 of 56.5 and 27.5 microM, respectively, and in differentiated U937 cells with an IC50 of 51.3, and 26.8 microM, respectively. The inhibitory activity of Rb1 and Rb2 was significantly increased by pharmacological agents against protein kinase C, protein tyrosine kinase, and protein kinase A, and anti-rheumatoid arthritis drugs, such as chloroquine and steroid drugs. In contrast, only cyclic AMP phosphodiesterase (cAMP PDE) inhibitors among cAMP-elevating agents did not change the inhibitory potency of PPDGs. These data suggest that PPDGs may possess potential therapeutic efficacy against TNF-alpha mediated disease and the therapeutic potency of PPDGs may be enhanced when co-treated with various kinds of known TNF-alpha antagonists but not with cAMP PDE inhibitors.

We have investigated the immunomodulatory effects of arctigenin, a dibenzyl butyrolactone lignan compound, on tumour necrosis factor (TNF)-alpha and nitric oxide (NO) production, and lymphocyte proliferation. Arctigenin inhibited strongly TNF-alpha production by lipopolysaccharide-stimulated murine macrophage RAW264.7 and differentiated human macrophage U937 with IC50 values of 5.0 and 3.9 microM, respectively, without displaying cytotoxicity. The TNF-alpha inhibitory effect of arctigenin in lipopolysaccharide-triggered RAW264.7 cells was increased by co-treatment with several known TNF-alpha inhibitors. It also potently attenuated T and B cell proliferation stimulated by concanavalin A and lipopolysaccharide in a dose-dependent manner with IC50 values of 2.9 and 14.6 microM, respectively. In contrast, the compound showed a different pattern in lipopolysaccharide- and interferon (IFN)-gamma-induced NO production from RAW264.7 cells. Arctigenin inhibited NO release by IFN-gamma signal, whereas it significantly enhanced lipopolysaccharide-triggered NO production in RAW264.7 cells. The results suggested that arctigenin may regulate immune responses in activated macrophages and lymphocytes including TNF-alpha and NO production and lymphocyte proliferation.