Functional expression of the Na/K pump is controlled via a cyclosporin A-sensitive signalling pathway in activated human lymphocytes.
An immunosuppressant cyclosporin A (CsA) inhibits T-cell proliferation by blocking the nuclear factor of activated T-cells (NFAT) required for expression of the interleukin-2 (IL-2) gene. This work has demonstrated for the first time that in human blood lymphocytes (HBLs) activated by phytohemagglutinin (PHA), CsA at anti-proliferative doses inhibits the late sustained increase in ouabain-sensitive Rb(K) influxes, which accompanies the growth phase of G0/G1/S transition. CsA affects neither the initial, transient activation of the pump in response to PHA nor the ouabain-resistant ion fluxes during cell cycle progression. When the HBLs were rendered competent to proliferate by phorbol 12,13-dibutyrate ester and ionomycin in the presence of CsA, the exogenous IL-2 did not bypass the initial inhibitory effect of CsA on the long-term pump enhancement. When applied after the competence induction, CsA produced no effect on the sustained increase in ouabain-sensitive Rb influxes during the IL-2-induced progression phase. These results indicate that in activated HBLs, (1) IL-2 is involved in functional expression of the Na/K pump during cell transition from quiescence to proliferation, (2) the cell cycle-associated upregulation of the pump is related to a CsA-sensitive signalling pathway.
Marakhova
I I
II
Institute of Cytology, Russian Academy of Sciences, St. Petersburg. iim@mail.cytspb.rssi.ru
Ivanova
A E
AE
Toropova
F V
FV
Vereninov
A A
AA
Vinogradova
T A
TA
D016572:Cyclosporine / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D010042:Ouabain / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D012413:Rubidium / Q000378:metabolism; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010835:Phytohemagglutinins; D015240:Phorbol 12,13-Dibutyrate; D015759:Ionomycin; D010042:Ouabain; D016572:Cyclosporine; D004247:DNA; D000254:Sodium-Potassium-Exchanging ATPase; D012413:Rubidium