IL-4 AND INSULIN-LIKE GROWTH-FACTOR-I INHIBIT THE DECLINE IN BCL-2 AND PROMOTE THE SURVIVAL OF IL-3-DEPRIVED MYELOID PROGENITORS

The proto-oncogene product Bcl-2 regulates cell survival in both the i mmune and central nervous systems, We withdrew growth factors from IL- 3-dependent murine myeloid progenitor cells (factor dependent cell pro genitors (FDCP)) and measured a time-dependent 80% reduction in endoge nous expression of Bcl-2, This decline in Bcl-2 is directly associated with a fourfold increase in the apoptotic population after 12 h and a n eightfold increase after 24 h, Since IL-4 and insulin-like growth fa ctor-I (IGF-I) regulate myeloid cell growth, we used IL-3-deprived FDC P cells to determine whether IL-4 and IGF-I maintain Bcl-2 expression and prevent apoptosis, We demonstrate that IL-4, like IGF-I and IL-3, promotes survival of FDCP cells by reducing the apoptotic population, Flow cytometric measurement of intracellular Bcl-2 established that IL -4 and ICF-I maintain 10-fold higher levels of Bcl-2 than in IL-3-depr ived cells, Similarly, Western analysis of Bcl-2 in lysates of IL-3-de prived myeloid progenitors confirmed that both IL-4 and ICF-I share wi th IL-3 the ability to maintain intact Bcl-2 protein. However, IL-4 an d IGF-I do not change expression of the apoptotic inducer, Bar, althou gh they maintain high levels of Bcl-2 that coimmunoprecipitate with Ba r. Collectively, these data demonstrate that IL-4 and IGF-I, like IL-3 , inhibit apoptosis in myeloid progenitors and maintain high levels of Bcl-2/Bax heterodimers, suggesting that Bcl-2 is a critical convergen ce point in the signaling pathways used by IL-4 and IGF-I.