Down-regulation of organic anion transporter expression in human hepatocytes exposed to the proinflammatory cytokine interleukin 1beta.

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.