A novel triptolide derivative ZT01 exerts anti-inflammatory effects by targeting TAK1 to prevent macrophage polarization into pro-inflammatory phenotype - 19/04/20
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Graphical abstract |
Highlights |
• | ZT01, an analogue of triptolide, exerts anti-inflammatory activities and with low toxicity. |
• | ZT01 inhibits M1 subtype macrophage polarization in vivo and in vitro. |
• | ZT01 bind to TAK1 to prevent the formation of TAK1-TAB1 complex. |
• | ZT01 exhibits anti-inflammation activity by inhibiting TAK1/MKK4/JNK signaling pathway. |
Abstract |
Sepsis is a main reason for death in intensive care units, inflammation is closely related to sepsis. Anti-inflammation plays an important role in treating of sepsis. ZT01 is a triptolide derivative with strong anti-inflammatory activity and low toxicity. The purpose of this study is to evaluate the anti-inflammatory activity of ZT01 under the sepsis condition and explore the underlying molecular mechanisms. Two in vivo model of sepsis, caecal ligation and puncture or intraperitoneal injection of LPS in C57BL/6, were used to evaluate the therapeutic effects of ZT01. In vitro, the anti-inflammatory properties of ZT01 were assessed in IFN-γ or LPS-induced macrophages by ELISA, RT-PCR, western blotting and co-immunoprecipitation. Macrophages were used to investigate the polarization phenotype by flow cytometry. The results showed, ZT01 significantly attenuated inflammatory response of sepsis in serum or lung tissue by inhibiting production of pro-inflammatory factors and improved the survival rate of septic mice in vivo. In cultured macrophages, ZT01 not only decreased the levels of TNF-α and IL-6 but also prevented the TKA1-TAB1 complex formation, thereby inhibiting the phosphorylation expression of MKK4 and JNK, which were all stimulated by LPS. Moreover, ZT01 inhibited the LPS-induced polarization of macrophages into pro-inflammatory phenotype. Adoptive transfer ZT01 pretreated bone marrow-derived macrophages obviously reduced the pro-inflammatory factors in mice after LPS challenge. Our findings suggested that ZT01 exhibited anti-inflammation activity via preventing the pro-inflammatory phenotype of macrophages by blocking the formation of the TAK1-TAB1 complex and subsequently phosphorylation of MKK4 and JNK.
Le texte complet de cet article est disponible en PDF.Keywords : Triptolide derivative, Sepsis, Anti-inflammation, Macrophage polarization, JNK, TAK1-TAB1
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