Park Sun Hong, Baek Seung-Il, Yun Jieun, Lee Seungmin, Yoon Da Young, Jung Jae-Kyung, Jung Sang-Hun, Hwang Bang Yeon, Hong Jin Tae, Han Sang-Bae, Kim Youngsoo
College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea;
Bio-evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Korea; and.
J Immunol. 2015 Feb 1;194(3):1122-30. doi: 10.4049/jimmunol.1402101. Epub 2014 Dec 29.
Mice lacking the IL-1R-associated kinase 4 (IRAK4) are completely resistant to LPS-induced endotoxic disorder or the TLR9 agonist CpG DNA plus d-galactosamine-induced acute liver injury (ALI), whereas wild-type strains succumb. However, translational drugs against sepsis or ALI remain elusive. Lonicerae flos extract is undergoing the clinical trial phase I in LPS-injected healthy human volunteers for sepsis treatment. In the current study, chlorogenic acid (CGA), a major anti-inflammatory constituent of lonicerae flos extract, rescued endotoxic mortality of LPS-intoxicated C57BL/6 mice, as well as ameliorated ALI of LPS/d-galactosamine-challenged C57BL/6 mice. As a mechanism, CGA inhibited various TLR agonist-, IL-1α-, or high-mobility group box-1-stimulated autophosphorylation (activation) of IRAK4 in peritoneal macrophages from C57BL/6 or C3H/HeJ mice via directly affecting the kinase activity of IRAK4, a proximal signal transducer in the MyD88-mediated innate immunity that enhances transcriptional activity of NF-κB or AP-1. CGA consequently attenuated protein or mRNA levels of NF-κB/AP-1 target genes encoding TNF-α, IL-1α, IL-6, and high-mobility group box-1 in vivo under endotoxemia or ALI. Finally, this study suggests IRAK4 as a molecular target of CGA in the treatment of innate immunity-related shock and organ dysfunction following insult of various TLR pathogens from bacteria and viruses.
缺乏白细胞介素-1受体相关激酶4（IRAK4）的小鼠对脂多糖（LPS）诱导的内毒素紊乱或Toll样受体9（TLR9）激动剂CpG DNA加d-半乳糖胺诱导的急性肝损伤（ALI）完全具有抗性，而野生型品系则会死亡。然而，针对败血症或ALI的转化药物仍然难以捉摸。金银花提取物正在LPS注射的健康人类志愿者中进行治疗败血症的I期临床试验。在当前的研究中，金银花提取物的主要抗炎成分绿原酸（CGA）挽救了LPS中毒的C57BL/6小鼠的内毒素致死率，并改善了LPS/d-半乳糖胺攻击的C57BL/6小鼠的ALI。作为一种机制，CGA通过直接影响IRAK4的激酶活性，抑制了来自C57BL/6或C3H/HeJ小鼠腹腔巨噬细胞中各种TLR激动剂、白细胞介素-1α或高迁移率族蛋白盒1刺激的IRAK4自磷酸化（激活），IRAK4是髓样分化因子88（MyD88）介导的先天免疫中的近端信号转导器，可增强核因子κB（NF-κB）或激活蛋白-1（AP-1）的转录活性。因此，在体内内毒素血症或ALI情况下，CGA降低了编码肿瘤坏死因子-α（TNF-α）、白细胞介素-1α、白细胞介素-6和高迁移率族蛋白盒1的NF-κB/AP-1靶基因的蛋白质或mRNA水平。最后，本研究表明IRAK4是CGA治疗细菌和病毒等各种TLR病原体攻击后先天免疫相关休克和器官功能障碍的分子靶点。
