Ca(2+)-ATPase inhibitors induce interleukin-2 synthesis and T cell proliferation.
In Jurkat cells, the three Ca(2+)-ATPase blockers, thapsigargin, cyclopiazonic acid, and di-tert-butylhydroquinone (DtBuHQ) induced both a release of Ca2+ from intracellular stores and a Ca2+ influx. In contrast to CD3 mAb, the Ca(2+)-ATPase inhibitors did not induce the formation of inositol trisphosphate from the hydrolysis of phosphatidylinositides. Emptying intracellular Ca2+ stores was accompanied by a decrease of phosphatidylserine (PtdSer) synthesis as previously observed in PHA- or CD3 mAb-treated Jurkat cells. In the presence of a phorbol ester able to activate protein kinase C, TPA, the three Ca(2+)-ATPase inhibitors induced Jurkat cells to synthesize large amounts of interleukin-2 demonstrating that early signal transduction mechanisms can be bypassed by Ca(2+)-ATPase inhibitors. In purified human peripheral blood T lymphocytes, the same inhibitors induced moderate if any cytosolic Ca2+ rise, in the absence of external calcium. Nevertheless analysis of PtdSer synthesis suggested that intracellular stores were efficiently depleted by DtBuHQ and cyclopiazonic acid but not by thapsigargin. In contrast, the three compounds induced similar Ca2+ influx. However, in the presence of TPA, cyclopiazonic acid and DtBuHQ induce highly purified T cells to proliferate while thapsigargin did not, suggesting that the status of internal Ca2+ store may have a decisive role in T cell activation.
Breittmayer
J P
JP
INSERM U343, Faculté de Médecine, Nice, France.
Ticchioni
M
M
Ferrua
B
B
Bernard
A
A
Aussel
C
C
D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects*; D010703:Phorbol Esters; D010718:Phosphatidylserines / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects*; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin
D006873:Hydroquinones; D007211:Indoles; D007376:Interleukin-2; D010703:Phorbol Esters; D010718:Phosphatidylserines; D013729:Terpenes; C019359:2,5-di-tert-butylhydroquinone; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D002118:Calcium; C000543:cyclopiazonic acid