Macrophages require different nucleoside transport systems for proliferation and activation.
To evaluate the mechanisms involved in macrophage proliferation and activation, we studied the regulation of the nucleoside transport systems. In murine bone marrow-derived macrophages, the nucleosides required for DNA and RNA synthesis are recruited from the extracellular medium. M-CSF induced macrophage proliferation and DNA and RNA synthesis, whereas interferon gamma (IFN-gamma) led to activation, blocked proliferation, and induced only RNA synthesis. Macrophages express at least the concentrative systems N1 and N2 (CNT2 and CNT1 genes, respectively) and the equilibrative systems es and ei (ENT1 and ENT2 genes, respectively). Incubation with M-CSF only up-regulated the equilibrative system es. Inhibition of this transport system blocked M-CSF-dependent proliferation. Treatment with IFN-gamma only induced the concentrative N1 and N2 systems. IFN-gamma also down-regulated the increased expression of the es equilibrative system induced by M-CSF. Thus, macrophage proliferation and activation require selective regulation of nucleoside transporters and may respond to specific requirements for DNA and RNA synthesis. This report also shows that the nucleoside transporters are critical for macrophage proliferation and activation.
Soler
C
C
Departament de Fisiologia (Biologia del Macròfag) and Fundació August Pi i Sunyer, Campus de Bellvitge, E-08028 Barcelona, Spain.
García-Manteiga
J
J
Valdés
R
R
Xaus
J
J
Comalada
M
M
Casado
F J
FJ
Pastor-Anglada
M
M
Celada
A
A
Felipe
A
A
D000818:Animals; D001692:Biological Transport; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002453:Cell Cycle; D002455:Cell Division; D004247:DNA / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology; D008262:Macrophage Activation / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D033703:Nucleoside Transport Proteins; D009705:Nucleosides / Q000378:metabolism*; D011684:Purine Nucleosides / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis; D016196:S Phase
D002352:Carrier Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D011684:Purine Nucleosides; C065171:cif nucleoside transporter; D012313:RNA; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D004247:DNA