Interferon-gamma regulates nucleoside transport systems in macrophages through signal transduction and activator of transduction factor 1 (STAT1)-dependent and -independent signalling pathways

Biochem J. 2003 Nov 1;375(Pt 3):777-83. doi: 10.1042/BJ20030260.


The expressions of CNT and ENT (concentrative and equilibrative nucleoside transporters) in macrophages are differentially regulated by IFN-gamma (interferon-gamma). This cytokine controls gene expression through STAT1-dependent and/or -independent pathways (where STAT1 stands for signal transduction and activator of transcription 1). In the present study, the role of STAT1 in the response of nucleoside transporters to IFN-gamma was studied using macrophages from STAT1 knockout mice. IFN-gamma triggered an inhibition of ENT1-related nucleoside transport activity through STAT1-dependent mechanisms. Such inhibition of macrophage growth and ENT1 activity by IFN-gamma is required for DNA synthesis. Interestingly, IFN-gamma led to an induction of the CNT1- and CNT2-related nucleoside transport activities independent of STAT1, thus ensuring the supply of extracellular nucleosides for the STAT1-independent RNA synthesis. IFN-gamma up-regulated CNT2 mRNA and CNT1 protein levels and down-regulated ENT1 mRNA in both wild-type and STAT1 knockout macrophages. This is consistent with a STAT1-independent, long-term-mediated, probably transcription-dependent, regulation of nucleoside transporter genes. Moreover, STAT1-dependent post-transcriptional mechanisms are implicated in the regulation of ENT1 activity. Although nitric oxide is involved in the regulation of ENT1 activity in B-cells at a post-transcriptional level, our results show that STAT1-dependent induction of nitric oxide by IFN-gamma is not implicated in the regulation of ENT1 activity in macrophages. Our results indicate that both STAT1-dependent and -independent pathways are involved in the regulation of nucleoside transporters by IFN-gamma in macrophages.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / drug effects
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Equilibrative Nucleoside Transporter 1
  • Gene Expression Regulation / drug effects
  • Interferon-gamma / pharmacology*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Nitric Oxide / metabolism
  • Nucleoside Transport Proteins
  • Purine Nucleosides / metabolism*
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • STAT1 Transcription Factor
  • Signal Transduction / drug effects*
  • Trans-Activators / genetics
  • Trans-Activators / physiology*


  • Carrier Proteins
  • DNA-Binding Proteins
  • Equilibrative Nucleoside Transporter 1
  • Membrane Transport Proteins
  • Nucleoside Transport Proteins
  • Purine Nucleosides
  • RNA, Messenger
  • SLC29A1 protein, mouse
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Trans-Activators
  • cif nucleoside transporter
  • Nitric Oxide
  • Interferon-gamma