Macrophages require distinct arginine catabolism and transport systems for proliferation and for activation.
In murine macrophages, as a result of arginine catabolism during activation, citruline is produced under the effect of IFN-gamma and LPS, and ornithine and polyamines by IL-4 and IL-10. For proliferation, arginine is required from the extracellular medium and is used for protein synthesis. During activation, most arginine (>95% in 6 h) was metabolized, while under proliferation only half was incorporated into proteins. Under basal conditions, this amino acid was preferentially transported by y(+)L activity. During activation, arginine transport increased drastically (4-5-fold) through y(+) cationic amino acid transporter (CAT) activity. By contrast, M-CSF induced only a modest increase in uptake (0.5-fold). The increase in arginine transport during activation, but not proliferation, was mediated by the SLC7A2/Cat2 gene. SLC7A1/Cat1 is constitutively expressed, and is not modified by proliferating or activating agents. M-CSF-dependent proliferation was not affected in the macrophages of SLC7A2 knockout mice; however, these cells showed a drastic reduction in the production of citruline or ornithine and polyamines during activation. The data show that a large increase in a specific transport system (CAT2) is necessary for activation-induced arginine metabolism, while arginine is in excess for the requirements of proliferation and a modest increase in transport occurs.
Yeramian
Andrée
A
Macrophage Biology Group, Institute of Research in Biomedicine, Barcelona Science Park, Spain.
Martin
Lorena
L
Arpa
Luis
L
Bertran
Joan
J
Soler
Concepció
C
McLeod
Carol
C
Modolell
Manuel
M
Palacín
Manuel
M
Lloberas
Jorge
J
Celada
Antonio
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000378:metabolism*; D015317:Biogenic Polyamines / Q000378:metabolism; D027202:Cationic Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015317:Biogenic Polyamines; D027202:Cationic Amino Acid Transporter 2; D008070:Lipopolysaccharides; D016753:Interleukin-10; D015847:Interleukin-4; D009569:Nitric Oxide; D012313:RNA; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D001120:Arginine; D001119:Arginase