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-α receptor-I (TNFRI) and IL-6 knock-out mice were also used to study CNT1 regulation in vivo. Results TNF-α 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-α 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-α in vivo. Evidence is provided that two independent pathways are involved in the up-regulation of CNT1 by TNF-α and IL-6.