Role of phosphatidylinositol 3-OH-kinase activity in the inhibition of apoptosis in haemopoietic cells: phosphatidylinositol 3-OH-kinase inhibitors reveal a difference in signalling between interleukin-3 and granulocytre-macrophage colony stimulating

摘要

Apoptosis of haemopoietic cells can be inhibited by various cytokines, but the specific signalling pathways involved are not well defined. Interleukin (IL)-4 has unique actions since it is unable toactivate p21~(ras) or mitogen-activated protein kinase, but can activate Ptdlns 3-OH-kinase (Ptdlns 3-kinase), the latter effect being shared with most other cytokines. In many cases, IL-4 is able to maintain cell viability by inhibiting apoptosis, but is .unable to stimulate continuous proliferation of cells. This led us to investigate the role of Ptdlns. 3-kinase in inhibition of apoptosis. Two potent inhibitors of Ptdlns 3-kinase, wortmannin and LY294002. rapidly induced apoptosis in cells incubated in the presence of IL-4, at concentrations consistentwith then ability to inhibit Ptdlns 3-kinase activity in whole cells. Interestingly the same effect was seen in cells in the presence of IL-3 and Steel factor, while cells incubated in the presence of granulocyte-macrophage colony stimulating factor, and to a lesser extent, IL-5 could bypass the effect of wortmannin or LY294002. Therefore, this study suggests that Ptdlns 3-kinase activity provides an important, although not a unique signal, required to inhibit apoptosis in haemopoietic cells.