Inhibition Effect of Amaryllidaceae Alkaloids, Lycorine and Lycoricidinol on Macrophage TNF-α Production

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Abstract
We previously demonstrated that Amaryllidaceae alkaloids, lycorine and lycoricidinol, inhibit induction of apoptosis by calprotectin derived from neutrophils, and that the latter alkaloid showed suppression in rat adjuvant-induced arthritis model. These findings suggest that the alkaloids have a modulating activity against inflammatory reaction. To explore further the mechanism of the suppression for inflammation, we studied the effect of the alkaloids on macrophage tumor necrosis factor (TNF-alpha) production in vitro, since TNF-alpha is recognized as a pivotal cytokine to regulate inflammation. As a result of this study, lycorine and lycoricidinol inhibited TNF-alpha production of murine macrophages stimulated with lipopolysaccharide (ID50 were 0.2 microgram/ml and 0.002 microgram/ml, respectively). The inhibition was also observed in macrophages treated by Gram-positive bacteria, Enterococcus faecalis. Both lycorine and lycoricidinol reportedly have inhibitory activity for protein biosynthesis. Although the inhibition of TNF-alpha production by lycoricidinol was mainly due to the inhibition of protein biosynthesis, lycorine showed inhibition against TNF-alpha production at lower concentrations than the case that they inhibited 35S-Cysteine/35S-Methionine incorporation into macrophages. These facts suggest that the inhibition of TNF-alpha production is not due to the inhibitory activity against protein translation at least at lower concentrations. From these results, it was concluded that these alkaloids exert inhibitory effects not only on neutrophil apoptosis-inducing protein, calprotectin, but also on macrophage TNF-alpha production.