C. Brodie et al., OUABAIN INDUCES INHIBITION OF THE PROGRESSION PHASE IN HUMAN T-CELL PROLIFERATION, Journal of cellular physiology, 165(2), 1995, pp. 246-253
Ouabain, a specific inhibitor of the Na-K ATPase, has been shown to ex
ert immunosuppressive effects. The goals of this study were to define
the stage of the proliferative response which is sensitive to ouabain
and to correlate the inhibitory action of ouabain on cell proliferatio
n with its effect on Na-K ATPase activity. We found that ouabain inhib
ited T-cell proliferation in a dose-dependent manner and this inhibiti
on was similar in CD4(+) and CD8(+) T cells. To define the role of the
Na-K ATPase in early activation of T lymphocytes, we examined the eff
ects of ouabain on the induction of competence (acquisition of respons
iveness to interleukin (IL)-2 or IL-4) by phytohemagglutinin (PHA) or
the combination of phorbol dibutyrate/ionomycin. Ouabain, at concentra
tions that completely inhibited the enzyme activity, did not interfere
with the induction of competence, suggesting that although activated
cells express increased activity of Na-K ATPase, this enzyme activity
does not play a role in early activation pathways. In contrast, ouabai
n inhibited the progression phase to DNA synthesis in a dose-dependent
manner even at concentrations that had little or no effect on Na-K AT
Pase activity. This inhibition was not due to a decrease in the produc
tion of IL-2 but rather to an inhibition of the expression of the p55
and p75 subunits of the IL-2 receptor (IL-2R). The inhibition of p55 a
ppeared to occur at the mRNA level. These results indicate that the ac
tivity of the Na-K ATPase is not essential for the induction of compet
ence or early activation. On the other hand, inhibition of cell prolif
eration and transcription of IL-2R subunits by low concentrations of o
uabain may be related to changes in intracellular K+ concentrations or
to inhibition of membranal phospholipid metabolism secondary to alter
ation in Na-K ATPase activity. (C) 1995 Wiley-Liss, Inc.