Enhanced activation of human NK cells by drug-exposed hepatocytes
Enhanced activation of human NK cells by drug-exposed hepatocytes
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DOI：
10.1007/s00204-020-02668-8
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发表时间：
2020-02-14
影响因子：
6.1
通讯作者：
Watzl, Carsten
中科院分区：
文献类型：
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作者：
Fasbender, Frank;Obholzer, Martin;Watzl, Carsten
药物性肝损伤（DILI）是药物不得不从市场上撤回的主要原因之一。在这项研究中，我们描述了药物暴露的肝细胞和自然杀伤（NK）细胞之间的一种新的相互作用。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的全基因组表达分析中，我们发现NK细胞受体的几种活化配体受各种药物调节（例如，丙戊酸、酮康唑、异丙嗪、异烟肼）。尤其是在暴露于许多不同药物后，活化NKG 2D配体（云母、MICB和ULBP）和NKp 30配体B7-H6的表达在原代人肝细胞中上调。使用人肝细胞系Huh 7和HepG 2，我们证实了药物暴露后活化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细胞系或原代人肝细胞引起NK细胞活化增强。增强的NK细胞活化通过增加对肝细胞的细胞毒性和干扰素（IFN）-γ产生而明显。NK细胞的活化可被针对活化NK细胞受体的特异性抗体阻断。这些数据支持NK细胞可以通过与肝细胞直接相互作用调节药物诱导的肝损伤的假设，导致细胞毒性和IFN-γ的产生。
Drug-induced liver injury (DILI) represents one of the major causes why drugs have to be withdrawn from the market.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)-gamma 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-gamma production.