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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Granulocyte-macrophage colony-stimulating factor increases L-arginine transport through the induction of CAT2 in bone marrow-derived macrophages

¹Department of Biochemistry and Molecular Biology, University of Barcelona and Institute of Biomedical Research, Barcelona; ²Macrophage Biology Group, Institute of Biomedical Research, Barcelona Spain; ³Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany; ⁴Cancer Center and Department of Medicine, University of California, San Diego, La Jolla, California; ⁵Hospital Ramón y Cajal, Madrid, Spain; and ⁶Max Planck Institute for Immunobiology, Freiburg, Germany

Submitted 18 October 2005 ; accepted in final form 16 December 2005

L-Arginine transport is crucial for macrophage activation because it supplies substrate for the key enzymes nitric oxide synthase 2 and arginase I. These enzymes participate in classic and alternative activation of macrophages, respectively. Classic activation of macrophages is induced by type I cytokines, and alternative activation is induced by type II cytokines. The granulocyte macrophage colony-stimulating factor (GM-CSF), in addition to inducing proliferation and differentiation of macrophages, activates arginase I, but its action on L-arginine transport is unknown. We studied the L-arginine transporters that are active in mouse primary bone marrow-derived macrophages (BMM) and examined the effect of GM-CSF treatment on transport activities. Under basal conditions, L-arginine entered mainly through system y⁺L (>75%). The remaining transport was explained by system y⁺ (<10%) and a diffusion component (10–15%). In response to GM-CSF treatment, transport activity increased mostly through system y⁺ (>10-fold), accounting for about 40% of the total L-arginine transport. The increase in y⁺ activity correlated with a rise in cationic amino acid transporter (CAT)-2 mRNA and protein. Furthermore, GM-CSF induced an increase in arginase activity and in the conversion of L-arginine to ornithine, citrulline, glutamate, proline, and polyamines. BMM obtained from CAT2-knockout mice responded to GM-CSF by increasing arginase activity and the expression of CAT1 mRNA, which also encodes system y⁺ activity. Nonetheless, the increase in CAT1 activity only partially compensated the lack of CAT2 and L-arginine metabolism was hardly stimulated. We conclude that BMM present mainly y⁺L activity and that, in response to GM-CSF, L-arginine transport augments through CAT2, thereby increasing the availability of this amino acid to the cell.

system y⁺, cationic amino acid transporter; system y⁺L; L-arginine transporter

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