SUPPRESSION OF APOPTOTIC CELL-DEATH OF IL-3-DEPENDENT CELL-LINES BY ER SR CA2+-ATPASE INHIBITORS UPON IL-3 DEPRIVATION/

An ER/SR Ca2+-ATPase inhibitor, cyclopiazonic acid (CPA), was found to suppress apoptotic cell death of IL-3-dependent cell lines, FDC.P2, I C-2, and Ba/F3, upon IL-3 deprivation. Structurally unrelated ER/SR Ca 2+-ATPase inhibitors, thapsigargin and 2,5-di(tert-butyl)-1,4-benzohyd roquinone also maintained cell viability in the absence of IL-3. In th e Ca2+-free medium CPA failed to suppress apoptosis, suggesting that t he anti-apoptotic activity of CPA is dependent on extracellular calciu m, The culture supernatant of CPA-treated cells was able to prolong ce ll survival of FDC.P2 in the absence of IL-3. An anti-IL-4 antibody al most completely eliminated the anti-apoptotic activity of CPA. Indeed, a significant amount of IL-4 was detected in the supernatant of cells treated with ER/SE Ca2+-ATPase inhibitors. Thus, our present data cle arly demonstrate not only that EWSR Ca2+-ATPase inhibitors induce the secretion of IL-4 in IL-3-dependent cell lines, but also that IL-4 can replace IL-3 in protecting these cells from apoptotic cell death in a n autocrine manner. (C) 1996 Academic Press, Inc.