Received for publication May 29, 2007.
Revised September 21, 2007.
Accepted for publication November 6, 2007.

DOWN-REGULATION OF ORGANIC ANION TRANSPORTER EXPRESSION IN HUMAN HEPATOCYTES EXPOSED TO THE PRO-INFLAMMATORY CYTOKINE INTERLEUKIN-1

Abstract

Interleukin-1 (IL-1) is a pro-inflammatory cytokine known to markedly alter expression of major organic anion transporters in rodent hepatocytes. Its effects towards human hepatic transporters remain however poorly characterized. The present study was therefore aimed at determining IL-1 effects on expression of organic anion transporters in primary human hepatocytes and highly differentiated human hepatoma HepaRG cells. Exposure to 1 ng/ml IL-1 was first demonstrated to markedly repress mRNA expression of 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 OATP-B, OATP-C and OATP8 and the efflux pumps MRP2, MRP3, MRP4 and BCRP were also down-regulated at mRNA levels in human hepatocytes treated by IL-1 for 24 h and most of these transporters were similarly repressed in IL-1-exposed HepaRG cells; the cytokine also reduced BSEP and OATP protein expression in human hepatocytes. IL-1 was further shown to activate the extracellular signal-regulated protein kinase (ERK) in human hepatocytes and HepaRG cells; chemical inhibition of this kinase however failed to counteract repressing effects of IL-1 towards NTCP, BSEP, OATP-B and OATP-C. Taken together, these data indicate that IL-1 treatment reduced expression of major organic anion transporters in human hepatic cells in an ERK-independent manner. Such IL-1 effects may likely participate to both cholestasis and alterations of hepatic detoxication pathways caused by inflammation in humans.

Key words: ABC transporters, bile acid transport, cytokines, hepatic transport, hepatobiliary transport, hepatocytes, organic anion transport, transporters

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