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

J Hepatol. 2004 Oct;41(4):538-44. doi: 10.1016/j.jhep.2004.06.008.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Interleukin-6 / deficiency
  • Interleukin-6 / pharmacology*
  • Interleukin-6 / physiology
  • Liver / cytology
  • Liver / drug effects
  • Liver / metabolism*
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Rats
  • Receptors, Tumor Necrosis Factor / deficiency
  • Receptors, Tumor Necrosis Factor / physiology
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Up-Regulation


  • Interleukin-6
  • Membrane Transport Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha
  • cif nucleoside transporter
  • recombinant human tumor necrosis factor-binding protein-1