Macrophages require distinct arginine catabolism and transport systems for proliferation and for activation

Abstract

In murine macrophages, as a result of arginine catabolism during activation, citruline is produced under the effect of IFN‐γ 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.