In murine macrophages, as a result of arginine catabolism during activation, citruline is produced under the effect of IFN-c 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.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35694_s.pdf
IntroductionMacrophages originate from undifferentiated stem cells in the bone marrow, and are transported through the blood to all body tissues where, in most cases, they undergo apoptosis [1]. Depending on the stimuli received, in tissues these phagocytes differentiate in numerous cell types including liver Kupffer cells, dermal Langerhans cells, bone osteoclasts, brain microglia, and Cell proliferation and activation require high concentrations of arginine either for protein synthesis or to elaborate either NO in classical activation or to produce polyamines and praline in alternative activation [3]. The extracellular milieu is the main source of arginine and several transport systems are involved in carrying this amino acid across the plasma membrane. Depending on the cell type, a number of transport activities may be expressed [6]. The SLC7 (solute carrier) family is divided into two subgroups, the cationic amino acid transporters (the CAT family, SLC7A1-4) and the glycoprotein-associated amino acid transporters SLC7A5-11, also called light chains or catalytic chains of the hetero(di)meric amino acid transporters. The CAT group includes four members, CAT-1 to CAT-4, whose gene products are SLC7A1 to SLC7A4. The first three members transport cationic L-amino acids, whereas the function of CAT-4 is not known. The hetero(di)meric amino acid transporters family is composed of seven proteins, whose genes are SLC7A5 to SLC7A11, but only y + LAT2, y + LAT1 and b o+ AT transport cationic amino acids [6].Macrophages require arginine to proliferate ...