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Involvement of P-glycoprotein in the transmembrane transport of
interleukin-2 (IL-2), IL-4, and interferon-gamma in normal human T
lymphocytes
J Drach, A Gsur, G Hamilton, S Zhao, J Angerler, M Fiegl, N Zojer, M Raderer, I Haberl, M Andreeff and H Huber
University of Vienna, First Department of Internal Medicine, Austria.
The physiological role of the multidrug resistance P-glycoprotein (P- gp),
which is expressed by normal human T lymphocytes, is still largely unknown.
To investigate whether or not P-gp is involved in the transport of
cytokines, peripheral blood lymphocytes were stimulated with
phytohemagglutinin (PHA) in the absence or presence of P-gp inhibitors, and
concentrations of cytokines (interleukin-2 [IL-2], IL- 4, IL-6,
interferon-gamma [IFN-gamma]) in the supernatants of these cultures were
quantitated by enzyme-linked immunosorbent assay. P-gp inhibitors included
verapamil (Ver), tamoxifen (Tmx), and the P-gp specific monoclonal antibody
UIC2. Release of IL-2 was significantly suppressed by these inhibitors at
concentrations that were also effective in blocking efflux of Rhodamine-123
from normal T lymphocytes. IL-2 mRNA expression in lymphocytes was not
different between PHA control and the cultures with P-gp inhibitors. Ver
and Tmx did not interfere with T-cell activation as determined by CD25 and
CD69 expression. In a nonhematological model, the P-gp expressing HCT-8
adenocarcinoma cell line, exogenously added IL-2 was shown to exert an
inhibitory effect on P-gp mediated Rhodamine-123 efflux. In addition,
transepithelial transport of IL-2 by electrophysiologically tight and
polarized HCT-8 monolayers was examined. A time-dependent flux of IL-2
across dense monolayers, which was partially inhibited by Ver, was
observed. We also investigated whether or not P-gp inhibitors suppressed
release of other cytokines produced by activated T cells (IL- 4, IL-6,
IFN-gamma). Release of IL-4 and IFN-gamma was significantly inhibited by
Ver, Tmx, and UIC2; however, release of IL-6 remained unaffected. These
data show P-gp mediated transmembrane flux of IL-2 in T lymphocytes and
HCT-8 cells. We conclude that P-gp participates in the transport of
cytokines (IL-2, IL-4, and IFN-gamma) in normal peripheral T lymphocytes.
Volume 88,
Issue 5,
pp. 1747-1754,
09/01/1996
Copyright © 1996 by The American Society of Hematology
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