Park Jung Hwa, Jang Jong-Hwa, Choi Eun Jung, Kim Young Seob, Lee Eun Ji, Jung In Duk, Han Hee Dong, Wu T-C, Hung Chien-Fu, Kang Tae Heung, Park Yeong-Min
Department of Immunology, KU open innovation center and School of Medicine, Konkuk University, Chungju 380-701, South Korea.
Department of Dental Hygiene, Hanseo University, Seosan 356-706, South Korea.
Mol Med. 2016 Sep;22:424-436. doi: 10.2119/molmed.2016.00026. Epub 2016 Jul 6.
The identification of HMGB1 as a late-mediator in sepsis has highlighted HMGB1 as a promising therapeutic target for sepsis treatment. Recent studies have revealed that annexin A5, a 35 kDa Ca-dependent phospholipid binding protein, exerts anti-inflammatory effect by inhibiting LPS binding to TLR4/MD2 complex. Annexin A5 administration has been shown to protect against endotoxin lethality even when the treatment was given after the early cytokine response, which prompted our group to suspect that annexin A5 may inhibit the binding of HMGB1, as well as endotoxin to TLR4. Here we suggest annexin A5 as a new inhibitor of HMGB1-mediated pro-inflammatory cytokine production and coagulation in sepsis. We first confirmed the inhibitory role of annexin A5 in LPS-induced production of pro-inflammatory cytokines both and . We observed that annexin A5 protects against tissue damage and organ dysfunction during endotoxemia . We then assessed the inhibiting role of annexin A5 in HMGB1/TLR4 interaction, and showed that annexin A5 treatment reduces HMGB1-mediated cytokines IL6 and TNFα both and . Finally, we confirmed that anticoagulant property of annexin A5 persists in various septic conditions including elevated HMGB1. Overall, we suggest annexin A5 as an alternative therapeutic approach for controlling HMGB1-mediated pro-inflammation and coagulation in patients with sepsis.
高迁移率族蛋白B1（HMGB1）被鉴定为脓毒症的晚期介质，这突出了HMGB1作为脓毒症治疗中一个有前景的治疗靶点。最近的研究表明，膜联蛋白A5，一种35 kDa的钙依赖性磷脂结合蛋白，通过抑制脂多糖（LPS）与Toll样受体4/髓样分化蛋白2（TLR4/MD2）复合物的结合发挥抗炎作用。已证明给予膜联蛋白A5可预防内毒素致死，即使在早期细胞因子反应后给予治疗也是如此，这促使我们团队怀疑膜联蛋白A5可能抑制HMGB1以及内毒素与TLR4的结合。在此，我们提出膜联蛋白A5作为脓毒症中HMGB1介导的促炎细胞因子产生和凝血的新抑制剂。我们首先证实了膜联蛋白A5在体内和体外对LPS诱导的促炎细胞因子产生的抑制作用。我们观察到膜联蛋白A5在内毒素血症期间可预防组织损伤和器官功能障碍。然后我们评估了膜联蛋白A5在HMGB1/TLR4相互作用中的抑制作用，并表明膜联蛋白A5治疗在体内和体外均降低了HMGB1介导的细胞因子白细胞介素6（IL6）和肿瘤坏死因子α（TNFα）。最后，我们证实膜联蛋白A5的抗凝特性在包括HMGB1升高在内的各种脓毒症条件下均持续存在。总体而言，我们提出膜联蛋白A5作为控制脓毒症患者中HMGB1介导的促炎和凝血的一种替代治疗方法。
