Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan.
Int Immunopharmacol. 2024 Jan 5;126:111254. doi: 10.1016/j.intimp.2023.111254. Epub 2023 Nov 22.
Toxoplasma gondii (T. gondii)-derived heat shock protein 70 (T.g.HSP70) is a toxic protein that downregulates host defense responses against T. gondii infection. T.g.HSP70 was proven to induce fatal anaphylaxis in T. gondii infected mice through cytosolic phospholipase A (cPLA) activated-platelet-activating factor (PAF) production via Toll-like receptor 4 (TLR4)-mediated signaling. In this study, we investigated the effect of arctiin (ARC; a major lignan compound of Fructus arctii) on allergic liver injury using T.g.HSP70-stimulated murine liver cell line (NCTC 1469) and a mouse model of T. gondii infection. Localized surface plasmon resonance, ELISA, western blotting, co-immunoprecipitation, and immunofluorescence were used to investigate the underlying mechanisms of action of ARC on T. gondii-induced allergic acute liver injury. The results showed that ARC suppressed the T.g.HSP70-induced allergic liver injury in a dose-dependent manner. ARC could directly bind to T.g.HSP70 or TLR4, interfering with the interaction between these two factors, and inhibiting activation of the TLR4/mitogen-activated protein kinase/nuclear factor-kappa B signaling, thereby inhibiting the overproduction of cPLA, PAF, and interferon-γ. This result suggested that ARC ameliorates T.g.HSP70-induced allergic acute liver injury by disrupting the TLR4-mediated activation of inflammatory mediators, providing a theoretical basis for ARC therapy to improve T.g.HSP70-induced allergic liver injury.
刚地弓形虫（Toxoplasma gondii）来源的热休克蛋白 70（T.g.HSP70）是一种毒性蛋白，可下调宿主对刚地弓形虫感染的防御反应。已证明 T.g.HSP70 通过细胞溶质磷脂酶 A（cPLA）激活血小板激活因子（PAF）的产生，通过 Toll 样受体 4（TLR4）介导的信号转导，在刚地弓形虫感染的小鼠中诱导致命的过敏反应。在这项研究中，我们使用刚地弓形虫 HSP70 刺激的鼠肝细胞系（NCTC 1469）和刚地弓形虫感染的小鼠模型，研究了牛蒡子苷（ARC；牛蒡子的主要木脂素化合物）对过敏性肝损伤的影响。局部表面等离子体共振、ELISA、western blot、共免疫沉淀和免疫荧光用于研究 ARC 对刚地弓形虫诱导的过敏急性肝损伤的作用机制。结果表明，ARC 以剂量依赖性方式抑制 T.g.HSP70 诱导的过敏肝损伤。ARC 可以直接与 T.g.HSP70 或 TLR4 结合，干扰这两个因素之间的相互作用，并抑制 TLR4/丝裂原活化蛋白激酶/核因子-κB 信号的激活，从而抑制 cPLA、PAF 和干扰素-γ的过度产生。这一结果表明，ARC 通过破坏 TLR4 介导的炎症介质的激活来改善 T.g.HSP70 诱导的过敏急性肝损伤，为 ARC 治疗改善 T.g.HSP70 诱导的过敏肝损伤提供了理论依据。
