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Arginine Transport via Cationic Amino Acid Transporter 2 Plays a Critical Regulatory Role in Classical or Alternative Activation of Macrophages¹

Andrée Yeramian^*, Lorena Martin, Neus Serrat^*, Luis Arpa^*, Concepció Soler^*, Joan Bertran, Carol McLeod, Manuel Palacín, Manuel Modolell, Jorge Lloberas^* and Antonio Celada^2,*

^* Macrophage Biology Group, Institute of Biomedical Research, Barcelona Science Park, and Department of Biochemistry and Molecular Biology, University of Barcelona and Institute of Biomedical Research, Barcelona Science Park, Barcelona, Spain; Cancer Center and Department of Medicine, University of California, San Diego, CA 92093; and Max Planck Institute for Immunobiology, Freiburg, Germany

Arginine is processed by macrophages in response to the cytokines to which these cells are exposed. Th1-type cytokines induce NO synthase 2, which metabolizes arginine into nitrites, while the Th2-type cytokines produce arginase, which converts arginine into polyamines and proline. Activation of bone marrow-derived macrophages by these two types of cytokines increases L-arginine transport only through the y⁺ system. Analysis of the expression of the genes involved in this system showed that Slc7A1, encoding cationic amino acid transporters (CAT)1, is constitutively expressed and is not modified by activating agents, while Slc7A2, encoding CAT2, is induced during both classical and alternative activation. Macrophages from Slc7A2 knockout mice showed a decrease in L-arginine transport in response to the two kinds of cytokines. However, while NO synthase 2 and arginase expression were unmodified in these cells, the catabolism of arginine was impaired by both pathways, producing smaller amounts of nitrites and also of polyamines and proline. In addition, the induction of Slc7A2 expression was independent of the arginine available and of the enzymes that metabolize it. In conclusion, the increased arginine transport mediated by activators is strongly regulated by CAT2 expression, which could limit the function of macrophages.

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