Department of Immunology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany.
Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany.
Arch Toxicol. 2020 Feb;94(2):439-448. doi: 10.1007/s00204-020-02668-8. Epub 2020 Feb 14.
Drug-induced liver injury (DILI) represents one of the major causes why drugs have to be withdrawn from the market. In this study, we describe a new interaction between drug-exposed hepatocytes and natural killer (NK) cells. In a previous genome-wide expression analysis of primary human hepatocytes that had been exposed to clinically relevant concentrations of 148 drugs, we found that several activating ligands for NK cell receptors were regulated by various drugs (e.g., valproic acid, ketoconazole, promethazine, isoniazid). Especially expression of the activating NKG2D ligands (MICA, MICB and ULBPs) and the NKp30 ligand B7-H6 were upregulated in primary human hepatocytes upon exposure to many different drugs. Using the human hepatocyte cell lines Huh7 and HepG2, we confirmed that protein levels of activating NK cell ligands were elevated after drug exposure. Hepatocyte cell lines or primary human hepatocytes co-cultivated with NK cells caused enhanced NK cell activation after pretreatment with drugs at in vivo relevant concentrations compared to solvent controls. Enhanced NK cell activation was evident by increased cytotoxicity against hepatocytes and interferon (IFN)-γ production. NK cell activation could be blocked by specific antibodies against activating NK cell receptors. These data support the hypothesis that NK cells can modulate drug-induced liver injury by direct interaction with hepatocytes resulting in cytotoxicity and IFN-γ production.
药物性肝损伤（DILI）是导致药物退出市场的主要原因之一。在本研究中，我们描述了一种药物暴露的肝细胞与自然杀伤（NK）细胞之间的新相互作用。在先前对暴露于临床相关浓度的 148 种药物的原代人肝细胞进行的全基因组表达分析中，我们发现多种 NK 细胞受体的激活配体受到各种药物的调节（例如，丙戊酸、酮康唑、异丙嗪、异烟肼）。特别是，多种药物暴露后，原代人肝细胞中激活型 NKG2D 配体（MICA、MICB 和 ULBPs）和 NKp30 配体 B7-H6 的表达上调。使用人肝细胞系 Huh7 和 HepG2，我们证实药物暴露后激活型 NK 细胞配体的蛋白水平升高。与溶剂对照相比，用体内相关浓度的药物预处理后，与 NK 细胞共培养的肝细胞系或原代人肝细胞会引起 NK 细胞的激活增强。NK 细胞的激活可以通过针对激活型 NK 细胞受体的特异性抗体来阻断。这些数据支持了这样一种假设，即 NK 细胞可以通过与肝细胞的直接相互作用来调节药物性肝损伤，从而导致细胞毒性和 IFN-γ 的产生。
