Cyclosporine A inhibits Ca2+-dependent stimulation of the Na+/H+ antiport in human T cells.
Abstract
The cyclic undecapeptide cyclosporine A (CsA) is a potent immunosuppressive agent
that inhibits the initial activation of T lymphocytes. This agent appears to be most
effective in blocking the action of mitogens such as concanavalin A and the calcium
ionophore A23187, which cause an influx of Ca2+, but not those that may act by alternate
mechanisms. These observations suggest that CsA may block a Ca2+-dependent step in
T cell activation. We have shown that stimulation of the T3-T cell receptor complex-associated
Ca2+ transporter activates the Na+/H+ antiport (Rosoff, P. M., and L. C. Cantley,
1985, J. Biol. Chem., 260: 14053-14059). The tumor-promoting phorbol esters, which
are co-mitogenic for T cells, activate the exchanger by a separate pathway which is
mediated by protein kinase C. Both the rise in intracellular Ca2+ and intracellular
pH may be necessary for the successful triggering of cellular activation. In this
report we show that CsA blocks the T3-T cell receptor-stimulated, Ca2+ influx-dependent
activation of Na+/H+ exchange, but not the phorbol ester-mediated pathway in a transformed
human T cell line. CsA inhibited mitogen-stimulation of interleukin-2 production in
a separate cell line. CsA also inhibited vasopressin stimulation of the antiporter
in normal rat kidney fibroblasts, but had no effect on serum or 12-O-tetradecanoyl
phorbol 13-acetate stimulation. CsA did not affect serum or vasopressin or serum stimulation
of normal rat kidney cell proliferation. CsA also had no effect on lipopolysaccharide
or phorbol ester stimulation of Na+/H+ exchange activity or induction of differentiation
in 70Z/3 pre-B lymphocytes in which these events are initiated by the protein kinase
C pathway. These data suggest that mechanisms of activation of Na+/H+ exchange that
involve an elevation in cytosolic Ca2+ are blocked by CsA but that C kinase-mediated
regulation is unaffected. The importance of the Na+/H+ antiport in the regulation
of growth and differentiation of T cells is discussed.
Type
Journal articleSubject
B-LymphocytesCalcium
Carrier Proteins
Cell Differentiation
Cell Line
Cyclosporins
Fibroblasts
Humans
Hydrogen-Ion Concentration
In Vitro Techniques
Interleukin-2
Lymphocyte Activation
Mitogens
Receptors, Antigen, T-Cell
Sodium
Sodium-Hydrogen Antiporter
T-Lymphocytes
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Show full item recordScholars@Duke
Philip Martin Rosoff
Professor Emeritus of Pediatrics
My main interests are clinical ethics with a concentration on the equitable allocation
of scarce resources (rationing). In this area, I have done work on planning for pandemic
influenza and allocation of drugs during shortages. Before retirement I played a major
role in the Clinical Ethics Service at Duke Hospital and chair the hospital's Ethics
Committee.

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