Amiloride-induced suppression of lymphocyte proliferation: inhibition of IL 2 receptor expression after blockade of early sodium influx.
Increased rates of monovalent cation fluxes are implicated in the activation of lymphocytes by mitogens. Our report shows that amiloride and dimethylamiloride, two inhibitors of the Na+/H+ antiport, dose dependently prevent the proliferation of mitogen-activated human peripheral blood lymphocytes. The action of these drugs follows several mechanisms, since their inhibitory effect can be reversed by extensive washing when they are used at low concentrations (150 microM for amiloride, 40 microM for dimethylamiloride), while at higher non cytotoxic concentrations this reversibility is no longer observed. We have studied the mechanism whereby amiloride inhibits the blastogenesis by measuring their effect on: 1) IL 2 production, 2) acquisition of IL 2 responsiveness and induction of IL 2 receptors, 3) IL 2-induced proliferation. Unlike the expression of IL 2 receptors, IL 2 production and IL 2-dependent proliferation were not inhibited by the low drug concentrations which indeed prevent blastogenesis. Moreover under these conditions, an enhanced accumulation of IL 2 was observed in the supernatants of stimulated cells. These results show that the drugs interact differently with the different cell populations involved in T cell proliferation: increase of an amiloride-dependent sodium influx is an obligatory step required to induce the early increase of the ouabain-dependent potassium influx which is needed for the expression of IL 2 receptors. On the contrary, the influx of potassium necessary for the IL 2-dependent proliferation does not seem to be controlled by the amiloride-dependent sodium flux.
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D007473:Ion Channels / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D015375:Receptors, Interleukin-2; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D007473:Ion Channels; D010835:Phytohemagglutinins; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; C039465:5-dimethylamiloride; D000584:Amiloride; D011188:Potassium