Abstract
Activated macrophages require l-arginine uptake to sustain NO synthesis. Several transport systems could mediate this l-arginine influx. Using competition analysis and gene-expression studies, amino acid transport system y+ was identified as the major carrier responsible for this activity. To identify which of the four known y+ transport-system genes is involved in macrophage-induced l-arginine uptake, we used a hybrid-depletion study in Xenopus oocytes. Cationic amino acid transporter (CAT) 2 antisense oligodeoxyribonucleotides abolished the activated-macrophage-mRNA-induced l-arginine transport. Together with expression studies documenting that CAT2 mRNA and protein levels are elevated with increased l-arginine uptake, our data demonstrate that CAT2 mediates the l-arginine transport that is required for the raised NO production in activated J774 macrophages.
Full Text
The Full Text of this article is available as a PDF (207.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Baydoun A. R., Bogle R. G., Pearson J. D., Mann G. E. Arginine uptake and metabolism in cultured murine macrophages. Agents Actions. 1993;38(Spec No):C127–C129. doi: 10.1007/BF01991160. [DOI] [PubMed] [Google Scholar]
- Baydoun A. R., Bogle R. G., Pearson J. D., Mann G. E. Discrimination between citrulline and arginine transport in activated murine macrophages: inefficient synthesis of NO from recycling of citrulline to arginine. Br J Pharmacol. 1994 Jun;112(2):487–492. doi: 10.1111/j.1476-5381.1994.tb13099.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baydoun A. R., Mann G. E. Selective targeting of nitric oxide synthase inhibitors to system y+ in activated macrophages. Biochem Biophys Res Commun. 1994 Apr 29;200(2):726–731. doi: 10.1006/bbrc.1994.1511. [DOI] [PubMed] [Google Scholar]
- Beasley D., Schwartz J. H., Brenner B. M. Interleukin 1 induces prolonged L-arginine-dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells. J Clin Invest. 1991 Feb;87(2):602–608. doi: 10.1172/JCI115036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bogle R. G., Baydoun A. R., Pearson J. D., Moncada S., Mann G. E. L-arginine transport is increased in macrophages generating nitric oxide. Biochem J. 1992 May 15;284(Pt 1):15–18. doi: 10.1042/bj2840015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Caivano M. Role of MAP kinase cascades in inducing arginine transporters and nitric oxide synthetase in RAW264 macrophages. FEBS Lett. 1998 Jun 16;429(3):249–253. doi: 10.1016/s0014-5793(98)00578-x. [DOI] [PubMed] [Google Scholar]
- Closs E. I., Albritton L. M., Kim J. W., Cunningham J. M. Identification of a low affinity, high capacity transporter of cationic amino acids in mouse liver. J Biol Chem. 1993 Apr 5;268(10):7538–7544. [PubMed] [Google Scholar]
- Devés R., Boyd C. A. Transporters for cationic amino acids in animal cells: discovery, structure, and function. Physiol Rev. 1998 Apr;78(2):487–545. doi: 10.1152/physrev.1998.78.2.487. [DOI] [PubMed] [Google Scholar]
- Ding A. H., Nathan C. F., Stuehr D. J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol. 1988 Oct 1;141(7):2407–2412. [PubMed] [Google Scholar]
- Finley K. D., Kakuda D. K., Barrieux A., Kleeman J., Huynh P. D., MacLeod C. L. A mammalian arginine/lysine transporter uses multiple promoters. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9378–9382. doi: 10.1073/pnas.92.20.9378. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ito K., Groudine M. A new member of the cationic amino acid transporter family is preferentially expressed in adult mouse brain. J Biol Chem. 1997 Oct 17;272(42):26780–26786. doi: 10.1074/jbc.272.42.26780. [DOI] [PubMed] [Google Scholar]
- Kakuda D. K., Finley K. D., Maruyama M., MacLeod C. L. Stress differentially induces cationic amino acid transporter gene expression. Biochim Biophys Acta. 1998 Nov 11;1414(1-2):75–84. doi: 10.1016/s0005-2736(98)00155-2. [DOI] [PubMed] [Google Scholar]
- Kim J. W., Closs E. I., Albritton L. M., Cunningham J. M. Transport of cationic amino acids by the mouse ecotropic retrovirus receptor. Nature. 1991 Aug 22;352(6337):725–728. doi: 10.1038/352725a0. [DOI] [PubMed] [Google Scholar]
- Lowenstein C. J., Alley E. W., Raval P., Snowman A. M., Snyder S. H., Russell S. W., Murphy W. J. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9730–9734. doi: 10.1073/pnas.90.20.9730. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MacLeod C. L., Finley K. D., Kakuda D. K. y(+)-type cationic amino acid transport: expression and regulation of the mCAT genes. J Exp Biol. 1994 Nov;196:109–121. doi: 10.1242/jeb.196.1.109. [DOI] [PubMed] [Google Scholar]
- MacLeod C. L., Finley K., Kakuda D., Kozak C. A., Wilkinson M. F. Activated T cells express a novel gene on chromosome 8 that is closely related to the murine ecotropic retroviral receptor. Mol Cell Biol. 1990 Jul;10(7):3663–3674. doi: 10.1128/mcb.10.7.3663. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MacLeod C. L. Regulation of cationic amino acid transporter (CAT) gene expression. Biochem Soc Trans. 1996 Aug;24(3):846–852. doi: 10.1042/bst0240846. [DOI] [PubMed] [Google Scholar]
- Markovich D., Bissig M., Sorribas V., Hagenbuch B., Meier P. J., Murer H. Expression of rat renal sulfate transport systems in Xenopus laevis oocytes. Functional characterization and molecular identification. J Biol Chem. 1994 Jan 28;269(4):3022–3026. [PubMed] [Google Scholar]
- Markovich D., Stange G., Bertran J., Palacin M., Werner A., Biber J., Murer H. Two mRNA transcripts (rBAT-1 and rBAT-2) are involved in system b0,(+)-related amino acid transport. J Biol Chem. 1993 Jan 15;268(2):1362–1367. [PubMed] [Google Scholar]
- Nicholson B., Sawamura T., Masaki T., MacLeod C. L. Increased Cat3-mediated cationic amino acid transport functionally compensates in Cat1 knockout cell lines. J Biol Chem. 1998 Jun 12;273(24):14663–14666. doi: 10.1074/jbc.273.24.14663. [DOI] [PubMed] [Google Scholar]
- Sato H., Ishii T., Sugita Y., Bannai S. Induction of cationic amino acid transport activity in mouse peritoneal macrophages by lipopolysaccharide. Biochim Biophys Acta. 1991 Oct 14;1069(1):46–52. doi: 10.1016/0005-2736(91)90102-e. [DOI] [PubMed] [Google Scholar]
- Schmidt K., List B. M., Klatt P., Mayer B. Characterization of neuronal amino acid transporters: uptake of nitric oxide synthase inhibitors and implication for their biological effects. J Neurochem. 1995 Apr;64(4):1469–1475. doi: 10.1046/j.1471-4159.1995.64041469.x. [DOI] [PubMed] [Google Scholar]
- Schott C. A., Gray G. A., Stoclet J. C. Dependence of endotoxin-induced vascular hyporeactivity on extracellular L-arginine. Br J Pharmacol. 1993 Jan;108(1):38–43. doi: 10.1111/j.1476-5381.1993.tb13436.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sperandeo M. P., Borsani G., Incerti B., Zollo M., Rossi E., Zuffardi O., Castaldo P., Taglialatela M., Andria G., Sebastio G. The gene encoding a cationic amino acid transporter (SLC7A4) maps to the region deleted in the velocardiofacial syndrome. Genomics. 1998 Apr 15;49(2):230–236. doi: 10.1006/geno.1998.5252. [DOI] [PubMed] [Google Scholar]
- Stevens B. R., Kakuda D. K., Yu K., Waters M., Vo C. B., Raizada M. K. Induced nitric oxide synthesis is dependent on induced alternatively spliced CAT-2 encoding L-arginine transport in brain astrocytes. J Biol Chem. 1996 Sep 27;271(39):24017–24022. doi: 10.1074/jbc.271.39.24017. [DOI] [PubMed] [Google Scholar]
- Stuehr D. J., Nathan C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sweet M. J., Stacey K. J., Kakuda D. K., Markovich D., Hume D. A. IFN-gamma primes macrophage responses to bacterial DNA. J Interferon Cytokine Res. 1998 Apr;18(4):263–271. doi: 10.1089/jir.1998.18.263. [DOI] [PubMed] [Google Scholar]
- Teixeira S., Di Grandi S., Kühn L. C. Primary structure of the human 4F2 antigen heavy chain predicts a transmembrane protein with a cytoplasmic NH2 terminus. J Biol Chem. 1987 Jul 15;262(20):9574–9580. [PubMed] [Google Scholar]