A novel triptolide derivative ZT01 exerts anti-inflammatory effects by targeting TAK1 to prevent macrophage polarization into pro-inflammatory phenotype
A novel triptolide derivative ZT01 exerts anti-inflammatory effects by targeting TAK1 to prevent macrophage polarization into pro-inflammatory phenotype
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DOI：
10.1016/j.biopha.2020.110084
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发表时间：
2020-06-01
影响因子：
7.5
通讯作者：
Zhang, Tiantai
中科院分区：
文献类型：
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作者：
Fu, Junmin;Zang, Yingda;Zhang, Tiantai
脓毒症是重症监护病房死亡的主要原因，炎症与脓毒症密切相关。抗炎在脓毒症的治疗中起着重要作用。ZT01是一种具有较强抗炎活性、低毒的雷公藤甲素衍生物。本研究的目的是评价ZT01在脓毒症条件下的抗炎作用，并探讨其分子机制。采用C57BL/6大鼠盲肠结扎穿孔或腹腔注射脂多糖两种体内脓毒症模型，评价ZT01的治疗作用。在体外，用ELISA法、RT-PCR法、免疫印迹法和免疫共沉淀法检测ZT01对干扰素-γ和脂多糖诱导的巨噬细胞的抗炎作用。用流式细胞仪检测巨噬细胞的极化表型。结果表明，ZT01通过抑制促炎因子的产生，明显减轻脓毒症小鼠血清或肺组织的炎症反应，提高体内脓毒症小鼠的存活率。在培养的巨噬细胞中，ZT01不仅能降低TNF-α和IL-6的水平，而且还能阻止TKA1-TAB1复合体的形成，从而抑制MKK4和JNK的磷酸化表达，而MKK4和JNK都是内毒素刺激的。此外，ZT01还能抑制内毒素诱导的巨噬细胞向促炎表型的极化。过继转移ZT01预处理的骨髓巨噬细胞可明显降低内毒素攻击后小鼠的促炎因子水平。我们的研究结果表明，ZT01通过阻断TAK1-TAB1复合体的形成以及随后MKK4和JNK的磷酸化来抑制巨噬细胞的促炎表型，从而发挥抗炎作用。
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-gamma 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-alpha 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 marrowderived 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.