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Originally published online as doi:10.1189/jlb.0403142 on August 1, 2003

Published online before print August 1, 2003
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(Journal of Leukocyte Biology. 2003;74:923-931.)
© 2003 by Society for Leukocyte Biology

Phosphatidylinositol 3-kinase is essential for kit ligand-mediated survival, whereas interleukin-3 and flt3 ligand induce expression of antiapoptotic Bcl-2 family genes

Richard Karlsson*, Maria Engström*, Maria Jönsson*, Peter Karlberg*, Cornelis J.H. Pronk*, Johan Richter{dagger} and Jan-Ingvar Jönsson*,1

* Division of Molecular Medicine, Department of Laboratory Medicine, Lund University, University Hospital MAS, Malmö, and
{dagger} Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden

1Correspondence: Department of Laboratory Medicine University Hospital MAS, Entrance 78, 3rd floor SE-205 02, Malmö, Sweden. E-mail: Jan-Ingvar.Jonsson{at}molmed.mas.lu.se

Cytokines such as interleukin 3 (IL-3), kit ligand (KL), and flt3 ligand (FL) promote survival of hematopoietic stem cells and myeloid progenitor cells. In many cell types, members of the Bcl-2 gene family are major regulators of survival, but the mediating mechanisms are not fully understood. Using two myeloid progenitor cell lines, FDCP-mix and FDC-P1, as well as primary mouse bone marrow progenitors, we demonstrate that KL-mediated survival is dependent on the activation of phosphatidylinositol-3 (PI-3) kinase. The inhibitor LY294002 was able to completely abolish survival mediated by KL, whereas IL-3 and FL were only partially affected. Although all three cytokines induced phosphorylation of protein kinase B (PKB), only KL required PI-3 kinase activity to elicit survival in hematopoietic progenitors. In contrast, pretreatment of cells with inhibitors to the MAP kinase pathway did not affect the survival. We next established if IL-3 and FL activated antiapoptotic Bcl-2 and the related genes Bcl-XL and Mcl-1. By RNA protection assay and Western blot analysis, we show that all three genes are induced by IL-3, whereas FL induces Bcl-2 and to some extent Bcl-XL. Importantly, KL could not sustain their expression. Moreover, use of inhibitors implied that IL-3 was mainly exerting its effect on Bcl-2 at the level of transcription. The addition of LY294002 did not affect the expression of Bcl-2 and Bcl-XL, and thus, we conclude that expression of antiapoptotic Bcl-2 family member genes is not dependent on PI-3 kinase activity. Our results indicate that cytokines exert distinct survival effects and that FL and IL-3 are capable of sustaining progenitor survival by up-regulating the expression of Bcl-2 and related genes.

Key Words: Hematopoiesis • Progenitor • Cytokines • Apoptosis • PKB • Bcl-2




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