MyD88-dependent and independent pathways of Toll-Like Receptors are engaged in biological activity of Triptolide in ligand-stimulated macrophages

摘要

Background: Triptolide is a diterpene triepoxide from the Chinese medicinal plant Tripterygium wilfordii Hook F., withknown anti-inflammatory, immunosuppressive and anti-cancer properties.Results: Here we report the expression profile of immune signaling genes modulated by triptolide in LPS inducedmouse macrophages. In an array study triptolide treatment modulated expression of 22.5% of one hundred and ninetyfive immune signaling genes that included Toll-like receptors (TLRs). TLRs elicit immune responses through theircoupling with intracellular adaptor molecules, MyD88 and TRIF. Although it is known that triptolide inhibits NFκBactivation and other signaling pathways downstream of TLRs, involvement of TLR cascade in triptolide activity was notreported. In this study, we show that triptolide suppresses expression of proinflammatory downstream effectorsinduced specifically by different TLR agonists. Also, the suppressive effect of triptolide on TLR-induced NFκB activationwas observed when either MyD88 or TRIF was knocked out, confirming that both MyD88 and TRIF mediated NFκBactivation may be inhibited by triptolide. Within the TLR cascade triptolide downregulates TLR4 and TRIF proteins.Conclusions: This study reveals involvement of TLR signaling in triptolide activity and further increases understandingof how triptolide activity may downregulate NFκB activation during inflammatory conditions.