Drug-induced liver injury (DILI) represents one of the major causes why drugs have to be withdrawn from the market.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.

中文翻译：

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药物暴露的肝细胞增强了人NK细胞的活化。

药物性肝损伤（DILI）代表了必须将药物撤出市场的主要原因之一。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）细胞之间的新的相互作用。在先前已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多种药物（例如丙戊酸，酮康唑，异丙嗪，异烟肼）调节）。当暴露于许多不同的药物后，尤其是激活的NKG2D配体（MICA，MICB和ULBPs）和NKp30配体B7-H6的表达在原代人肝细胞中被上调。使用人类肝细胞细胞系Huh7和HepG2，我们证实，暴露于药物后，激活性NK细胞配体的蛋白质水平升高。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引起增强的NK细胞活化。通过增加对肝细胞的细胞毒性和干扰素（IFN）-γ的产生，可以明显增强NK细胞的活化。NK细胞活化可以被抗活化NK细胞受体的特异性抗体阻断。这些数据支持以下假设：NK细胞可以通过与肝细胞直接相互作用来调节药物诱导的肝损伤，从而导致细胞毒性和IFN-γ的产生。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引起增强的NK细胞活化。通过增加对肝细胞的细胞毒性和干扰素（IFN）-γ的产生，可以明显增强NK细胞的活化。NK细胞活化可以被抗活化NK细胞受体的特异性抗体阻断。这些数据支持以下假设：NK细胞可以通过与肝细胞直接相互作用来调节药物诱导的肝损伤，从而导致细胞毒性和IFN-γ的产生。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引起增强的NK细胞活化。通过增加对肝细胞的细胞毒性和干扰素（IFN）-γ的产生，可以明显增强NK细胞的活化。NK细胞活化可以被抗活化NK细胞受体的特异性抗体阻断。这些数据支持以下假设：NK细胞可以通过与肝细胞直接相互作用来调节药物诱导的肝损伤，从而导致细胞毒性和IFN-γ的产生。NK细胞活化可以被抗活化NK细胞受体的特异性抗体阻断。这些数据支持以下假设：NK细胞可以通过与肝细胞直接相互作用来调节药物诱导的肝损伤，从而导致细胞毒性和IFN-γ的产生。NK细胞活化可以被抗活化NK细胞受体的特异性抗体阻断。这些数据支持以下假设：NK细胞可以通过与肝细胞直接相互作用来调节药物诱导的肝损伤，从而导致细胞毒性和IFN-γ的产生。