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J. Biol. Chem., Vol. 276, Issue 19, 15881-15885, May 11, 2001
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From the Cancer Center and Department of Medicine, University of
California, San Diego, La Jolla, California 92093-0064
The aberrant production of nitric oxide (NO)
contributes to the pathogenesis of diseases as diverse as cancer and
arthritis. Sustained NO production via the inducible enzyme,
nitric-oxide synthase 2 (NOS2), requires extracellular arginine uptake.
Three closely related cationic amino acid transporter genes
(Cat1-3) encode the transporters that mediate most
arginine uptake in mammalian cells. Because CAT2 is induced
coordinately with NOS2 in numerous cell types, we investigated a
possible role for CAT2-mediated arginine transport in regulating NO
production. The complexity of arginine transport systems and their
biochemically similar transport properties called for a genetic
approach to determine the role of CAT2. CAT2-deficient mice were
generated and found to be healthy and fertile in contrast to
Cat1
Sustained Nitric Oxide Production in Macrophages Requires the
Arginine Transporter CAT2*
,
/ animals. Analysis of
cytokine-activated macrophages from Cat2/
mice revealed a 92% reduction in NO production and a 95% reduction in
L-Arg uptake. The reduction in NO production was not due to differences in NOS2 protein expression, NOS2 activity, or intracellular L-arginine content. In conclusion, our results show that
sustained abundant NO synthesis by macrophages requires arginine
transport via the CAT2 transporter.
*
This work was supported by the Susan G. Komen Breast Cancer
Foundation, American Institute of Cancer Research Grant 9724, National
Institutes of Health Grant CA81376, and the California Breast Cancer
Research Program. Support for early phases of this study was provided
by the UCSD Academic Senate and the California Research Coordinating
Committee.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Susan G. Komen Breast Cancer Research Foundation Postdoctoral Fellow.
§
Howard Hughes Medical Institute Predoctoral Fellow.
¶
Clayton Foundation Investigator. To whom correspondence
should be addressed: UCSD Cancer Center, 9500 Gilman Dr., Mail Code 0064, La Jolla, CA 92093-0064. Tel.: 858-534-7251; Fax: 858-534-7340; E-mail: cmacleod@ucsd.edu.
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