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 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. Interleukin (IL)-4 has unique actions since it is unable to activate p21ras 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 viability by inhibiting apoptosis, but is unable to stimulate continuous proliferation of cells. This led us to investigate the role of PtdIns 3-kinase in inhibition of apoptosis. Two potent inhibitors of PtdIns 3-kinase, wortmannin and LY294002, rapidly induced apoptosis in cells incubated in the presence of IL-4, at concentrations consistent with their ability to inhibit PtdIns 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 PtdIns 3-kinase activity provides an important, although not a unique signal, required to inhibit apoptosis in haemopoietic cells.
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011233:Precipitin Tests; D015398:Signal Transduction / Q000187:drug effects*; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D016207:Cytokines; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D009025:Morpholines; D015847:Interleukin-4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000077191:Wortmannin