Le Vee Marc, Gripon Philippe, Stieger Bruno, Fardel Olivier
Institut National de la Santé et de la Recherche Médicale U620, Faculty of Pharmacy, Rennes, France.
Drug Metab Dispos. 2008 Feb;36(2):217-22. doi: 10.1124/dmd.107.016907. Epub 2007 Nov 8.
Interleukin (IL) 1beta is a proinflammatory cytokine known to markedly alter expression of major organic anion transporters in rodent hepatocytes. However, its effects toward human hepatic transporters remain poorly characterized. Therefore, the present study was aimed at determining IL-1beta effects on expression of organic anion transporters in primary human hepatocytes and highly differentiated human hepatoma HepaRG cells. Exposure to 1 ng/ml IL-1beta was first shown to markedly repress mRNA expression of sodium-taurocholate cotransporting polypeptide (NTCP), a major sinusoidal transporter handling bile acids, in both human hepatocytes and HepaRG cells. It concomitantly reduced NTCP protein levels and NTCP-mediated cellular uptake of taurocholate in HepaRG cells. Other transporters such as the influx transporters organic anion transporting polypeptide (OATP)-B, OATP-C, and OATP8 and the efflux pumps multidrug resistance-associated protein (MRP) 2, MRP3, MRP4, and breast cancer resistance protein were also down-regulated at mRNA levels in human hepatocytes treated by IL-1beta for 24 h, and most of these transporters were similarly repressed in IL-1beta-exposed HepaRG cells; the cytokine also reduced bile salt export pump (BSEP) and OATP-C protein expression in human hepatocytes. IL-1beta was further shown to activate the extracellular signal-regulated protein kinase (ERK) in human hepatocytes and HepaRG cells; however, chemical inhibition of this kinase failed to counteract repressing effects of IL-1beta toward NTCP, BSEP, OATP-B, and OATP-C. Taken together, these data indicate that IL-1beta treatment reduced expression of major organic anion transporters in human hepatic cells in an ERK-independent manner. Such IL-1beta effects may likely participate in both cholestasis and alterations of hepatic detoxification pathways caused by inflammation in humans.
白细胞介素(IL)-1β是一种促炎细胞因子,已知其可显著改变啮齿动物肝细胞中主要有机阴离子转运体的表达。然而,其对人类肝脏转运体的影响仍未得到充分表征。因此,本研究旨在确定IL-1β对原代人肝细胞和高度分化的人肝癌HepaRG细胞中有机阴离子转运体表达的影响。首先发现,暴露于1 ng/ml的IL-1β可显著抑制人肝细胞和HepaRG细胞中钠-牛磺胆酸盐共转运多肽(NTCP)的mRNA表达,NTCP是一种处理胆汁酸的主要窦状隙转运体。它同时降低了HepaRG细胞中NTCP的蛋白水平以及NTCP介导的牛磺胆酸盐细胞摄取。其他转运体,如摄取转运体有机阴离子转运多肽(OATP)-B、OATP-C和OATP8以及外排泵多药耐药相关蛋白(MRP)2、MRP3、MRP4和乳腺癌耐药蛋白,在经IL-1β处理24小时的人肝细胞中,其mRNA水平也下调,并且在暴露于IL-1β的HepaRG细胞中,这些转运体大多也受到类似的抑制;该细胞因子还降低了人肝细胞中胆盐输出泵(BSEP)和OATP-C的蛋白表达。进一步表明,IL-1β可激活人肝细胞和HepaRG细胞中的细胞外信号调节蛋白激酶(ERK);然而,该激酶的化学抑制未能抵消IL-1β对NTCP、BSEP、OATP-B和OATP-C的抑制作用。综上所述,这些数据表明,IL-1β处理以ERK非依赖性方式降低了人肝细胞中主要有机阴离子转运体的表达。这种IL-1β效应可能参与了人类炎症引起的胆汁淤积和肝脏解毒途径的改变。