The Signaling Pathways of Erythropoietin and Interferon-γ Differ in Preventing the Apoptosis of Mature Erythroid Progenitor Cells

Interferon (IFN)-γ is a survival factor for mature erythroid progenitor cells. To elucidate related survival mechanisms, we compared the role of phosphatidylinositol 3-kinase (PI3-kinase) in the survival signals of IFN-γ and erythropoietin (EPO). Human erythroid colony-forming cells (ECFCs) purified from peripheral blood were used, and Ly294002 was used as a PI3-kinase inhibitor. Treating ECFCs with a high concentration of Ly294002 (50 μmol/L) in the presence of EPO and/or IFN-γ reduced cell viability by inducing apoptosis. However, treating cells with a lower concentration of Ly294002 (10 μmol/L) did not affect the antiapoptotic function of IFN-γ and abolished the antiapoptotic effect of EPO. Adding IFN-γ or EPO induced Bcl-x expression in ECFCs, as determined by Western blotting, and expression was suppressed in the presence of Ly294002. We also examined the phosphorylation of the protein kinase Akt, the downstream target of PI3-kinase. EPO stimulation significantly increased the level of Akt phosphorylation, but IFN-γ did not. These results suggest that IFN-γ plays a role in preventing the apoptosis of erythroid progenitor cells by affecting Bcl-x expression, thereby reducing the disruption of the mitochondrial transmembrane potential via PI3-kinase pathways that are related to but distinct from the EPO pathway.