Up-regulation of the high-affinity pyrimidine-preferring nucleoside transporter concentrative nucleoside transporter 1 by tumor necrosis factor-alpha and interleukin-6 in liver parenchymal cells

Background/Aims: Concentrative nucleoside transporter 1 (CNT1), a high affinity transporter for pyrimidine nucleosides, is responsible for their Na+-dependent concentrative uptake into hepatocytes. Though CNT1 protein amounts increase in rat liver soon after partial hepatectomy, the physiological regulators of CNT1 expression have not yet been identified. Methods: Rat hepatoma cell lines and hepatocytes isolated from fetuses and adult rats were used to identify single agents able to up-regulate CNT1 expression and activity in liver. TNF-alpha receptor-I (TNFRI) and IL-6 knock-out mice were also used to study CNT1 regulation in vivo. Results: TNF-alpha and IL-6 independently induced CNT1 protein expression in cultured liver parenchymal and FAO hepatoma cells by PI-3 kinase- and ERK-dependent mechanisms, respectively. In vivo data showed that transporter protein levels were low in livers from TNFRI knock-out mice, but not in those from IL-6 deficient animals. However, IL-6 administration only partially restored CNT1 expression in the former model. Conclusions: This study identifies TNF-alpha as a major in vivo modulator of the nucleoside transporter CNT1 and suggests a secondary role for IL-6 in mediating CNT1 up-regulation by TNF-alpha in vivo. Evidence is provided that two independent pathways are involved in the up-regulation of CNT1 by TNF-alpha and IL-6. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.