ROLE OF PHOSPHATIDYLINOSITOL 8-OH-KINASE ACTIVITY IN THE INHIBITION OF APOPTOSIS IN HEMATOPOIETIC-CELLS - PHOSPHATIDYLINOSITOL 3-OH-KINASE INHIBITORS REVEAL A DIFFERENCE IN SIGNALING BETWEEN INTERLEUKIN-3 AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR

Apoptosis of haemopoietic cells can be inhibited by various cytokines, but the specific signalling pathways involved are not well defined. I nterleukin (IL)-4 has unique actions since it is unable to activate p2 1(ras) or mitogen-activated protein kinase, but can activate PtdIns 3- OH-kinase (PtdIns 3-kinase), the latter effect being shared with most other cytokines. In many cases, IL-4 is able to maintain cell viabilit y by inhibiting apoptosis, but is unable to stimulate continuous proli feration of cells. This led us to investigate the role of PtdIns 3-kin ase in inhibition of apoptosis. Two potent inhibitors of PtdIns 3-kina se, wortmannin and LY294002, rapidly induced apoptosis in cells incuba ted in the presence of IL-4, at concentrations consistent with their a bility to inhibit PtdIns 3-kinase activity in whole cells. Interesting ly, the same effect was seen in cells in the presence of IL-3 and Stee l factor, while cells incubated in the presence of granulocyte-macroph age colony stimulating factor, and to a lesser extent, IL-5 could bypa ss the effect of wortmannin or LY294002. Therefore, this study suggest s that PtdIns 3-kinase activity provides an important, although not a unique signal, required to inhibit apoptosis in haemopoietic cells.