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Published on: March 2, 2014
Interferon-gamma attenuates the survival activity of G-CSF through PI3K/Akt signaling pathway in mouse multipotent
Hong Liu1, Keichiro Mihara, Guoqi Song
1Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Abstract:
Apoptosis plays an important role in the injury to stem and progenitor compartments associated with aberrant interferon-gamma (IFN-gamma) in aplastic anemia (AA), which is characterized by the loss of stem cells; however, its molecular mechanism is poorly understood. In this study, we have addressed the mechanism of the apoptotic function of IFN-gamma against hematopoietic stem and/or progenitors. Although granulocyte colony-stimulating factor (G-CSF) augmented survival and proliferative and differentiating activity in 32D cells, mouse multipotent progenitor cells, these effects were abolished by IFN-gamma and were susceptible to apoptosis with IFN-gamma. IFN-gamma attenuated Akt phosphorylated by G-CSF in a dose- and time-dependent manner. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), enhanced the inhibitory effect on Akt phosphorylated by G-CSF in collaboration with IFN-gamma, suggesting that the activity of IFN-gamma might converge on the PI3K pathway. We examined the expression of Bcl-2-associated death (Bad), which works downstream of Akt. IFN-gamma increased the Bad protein reduced by G-CSF. IFN-gamma induced apoptosis in 32D cells through the caspase pathway. Taken together, these results suggest that IFN-gamma could exert inhibitory action on stem cells and/or progenitors by interference with the PI3K/Akt signaling pathway. Our findings may contribute to understanding the decreased number of stem cells characteristic of AA.
Insights
Interferon-gamma (IFN-gamma) induces apoptosis in hematopoietic stem and progenitor cells by interfering with the PI3K/Akt pathway. This mechanism contributes to stem cell loss in aplastic anemia.
Area of Science:
- Hematology
- Molecular Biology
- Cell Biology
Background:
- Aplastic anemia (AA) is characterized by stem cell loss.
- Aberrant interferon-gamma (IFN-gamma) is implicated in stem and progenitor cell injury in AA.
- The molecular mechanisms underlying IFN-gamma-induced apoptosis in hematopoietic stem and progenitor cells are not well understood.
Purpose of the Study:
- To elucidate the molecular mechanism of IFN-gamma-induced apoptosis in hematopoietic stem and progenitor cells.
- To investigate the role of the PI3K/Akt signaling pathway in IFN-gamma's apoptotic effects.
Main Methods:
- Utilized 32D cells and mouse multipotent progenitor cells.
- Investigated the effects of granulocyte colony-stimulating factor (G-CSF) and IFN-gamma on cell survival, proliferation, and differentiation.
- Assessed Akt phosphorylation, PI3K inhibition using wortmannin, and Bcl-2-associated death (Bad) protein expression.
- Examined apoptosis induction via the caspase pathway.
Main Results:
- IFN-gamma abolished G-CSF-augmented survival and proliferation in progenitor cells, rendering them susceptible to apoptosis.
- IFN-gamma attenuated G-CSF-induced Akt phosphorylation in a dose- and time-dependent manner.
- IFN-gamma increased Bad protein levels and induced apoptosis through the caspase pathway, suggesting convergence on the PI3K pathway.
Conclusions:
- IFN-gamma inhibits stem and progenitor cells by interfering with the PI3K/Akt signaling pathway.
- This mechanism contributes to the understanding of stem cell loss in aplastic anemia.
- Findings highlight IFN-gamma's critical role in the pathogenesis of AA.
