Kupffer cell-mediated down regulation of rat hepatic CMOAT/MRP2 gene expression

Lipopolysaccharides (LPS) induces intrahepatic cholestasis and canalicular multispecific organic anion transporter (CMOAT/MRP2) plays a central role i n hepatic bilirubin transport. This study examined the role of Kupffer cell in LPS-induced cholestasis. Rats were injected intravenously with LPS. Kup ffer cells were inactivated with gadolinium chloride (Gd). CMOAT/MRP2 mRNA expression was time- and dose-dependently decreased by LPS injection with a decrease in bile dow and an increase in serum bilirubin level. Gd pretreat ment inhibited decrease in CMOAT/MRP2 mRNA and bile dow, and increase in se rum bilirubin. Kupffer cell-conditioned medium decreased CMOAT/MRP2 express ion. Addition of anti-IL-l or anti-TNF alpha antibody restored CMOAT/MRP2 e xpression, whereas IL-1 and TNF alpha decreased the expression. MAP kinases were activated by addition of the conditioned medium, and addition of PD98 059 or SB203580 restored CMOAT/MRP2 expression. These results suggest that LPS activates Kupffer cells to secrete IL-1 and TNF alpha, which in turn ac tivate MAP kinases and decrease CMOAT/MRP2 expression. (C) 1999 Academic Pr ess.