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Colony-Stimulating Factors Signal for Increased Transport of Vitamin
C in Human Host Defense Cells
Juan Carlos Vera,
Coralia I. Rivas,
Rong H. Zhang, and
David W. Golde
From the Program in Molecular Pharmacology and Therapeutics, Memorial
Sloan-Kettering Cancer Center, New York, NY.
Although serum concentrations of ascorbic acid seldom exceed 150 µmol/L, mature neutrophils and mononuclear phagocytes accumulate millimolar concentrations of vitamin C. Relatively little is known about the mechanisms regulating this process. The colony-stimulating factors (CSFs), which are central modulators of the production, maturation, and function of human granulocytes and mononuclear phagocytes, are known to stimulate increased glucose uptake in target
cells. We show here that vitamin C uptake in neutrophils, monocytes,
and a neutrophilic HL-60 cell line is enhanced by the CSFs. Hexose
uptake studies and competition analyses showed that dehydroascorbic
acid is taken up by these cells through facilitative glucose
transporters. Human monocytes were found to have a greater capacity to
take up dehydroascorbic acid than neutrophils, related to more
facilitative glucose transporters on the monocyte cell membrane.
Ascorbic acid was not transported by these myeloid cells, indicating
that they do not express a sodium-ascorbate cotransporter. Granulocyte
(G)- and granulocyte-macrophage colony-stimulating factor (GM-CSF)
stimulated increased uptake of vitamin C in human neutrophils,
monocytes, and HL-60 neutrophils. In HL-60 neutrophils, GM-CSF
increased both the transport of dehydroascorbic acid and the
intracellular accumulation of ascorbic acid. The increase in transport
was related to a decrease in Km for transport of dehydroascorbic acid
without a change in Vmax. Increased ascorbic acid accumulation was a
secondary effect of increased transport. Triggering the neutrophils
with the peptide fMetLeuPhe led to enhanced vitamin C uptake by
increasing the oxidation of ascorbic acid to the transportable moiety
dehydroascorbic acid, and this effect was increased by priming the
cells with GM-CSF. Thus, the CSFs act at least at two distinct
functional loci to increase cellular vitamin C uptake: conversion of
ascorbic acid to dehydroascorbic acid by enhanced oxidation in the
pericellular milieu and increased transport of DHA through the
facilitative glucose transporters at the cell membrane. These results
link the regulated uptake of vitamin C in human host defense cells to
the action of CSFs.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2536-2546
© 1998 by The American Society of Hematology.
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