Abstract

Triptolide, a Chinese plant medicine from Tripterygium wilfordii Hook F, has been shown to have inhibitory effects on macrophage activities, and we recently found that it induces sudden macrophage cell death in the presence of bacterial lipopolysaccharide (LPS). In this present study, we examined precise mechanisms underlying induction of the cytotoxicity of triptolide toward macrophages in relation to the action of LPS, and thereby showed that the cytotoxic effects depended on the concentrations of both triptolide and LPS. More than 10 ng/mL LPS was necessary in combination with 300 ng/mL triptolide. However, pre-treatment with 1 ng/mL LPS for 60 min abolished the cytotoxicity induced by 100 ng/mL LPS and 300 ng/mL triptolide, showing that the cytotoxicity was regulated by LPS-tolerance. Besides, in primary macrophages obtained from mouse peritoneum, those from C3H/HeN mice, an LPS-responder, showed similar susceptibility to triptolide and LPS-induced cell damage; whereas those from C3H/HeJ mice, an LPS hypo-responder, did not, suggesting that the cytotoxic effect of triptolide was linked to the LPS/Toll-like receptor 4 (TLR4)-signaling cascade. These results suggest that the cytotoxicity of triptolide toward macrophages was regulated by the LPS-signaling cascade through both down-regulation known as LPS-tolerance and the TLR4 receptor.

Keywords: Macrophage cell death; Triptolide; Lipopolysaccharide (LPS); Apoptosis; C3H/HeN mouse; C3H/HeJ mouse