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 immune and central nervous systems. We withdrew growth factors from IL-3-dependent murine myeloid progenitor cells (factor dependent cell progenitors (FDCP)) and measured a time-dependent 80% reduction in endogenous expression of Bcl-2. This decline in Bcl-2 is directly associated with a fourfold increase in the apoptotic population after 12 h and an eightfold increase after 24 h. Since IL-4 and insulin-like growth factor-I (IGF-I) regulate myeloid cell growth, we used IL-3-deprived FDCP 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 IGF-I maintain 10-fold higher levels of Bcl-2 than in IL-3-deprived cells. Similarly, Western analysis of Bcl-2 in lysates of IL-3-deprived myeloid progenitors confirmed that both IL-4 and IGF-I share with IL-3 the ability to maintain intact Bcl-2 protein. However, IL-4 and IGF-I do not change expression of the apoptotic inducer, Bax, although they maintain high levels of Bcl-2 that coimmunoprecipitate with Bax. 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 convergence point in the signaling pathways used by IL-4 and IGF-I.
Minshall
C
C
Department of Animal Sciences, University of Illinois, Urbana 61801, USA.
Arkins
S
S
Straza
J
J
Conners
J
J
Dantzer
R
R
Freund
G G
GG
Kelley
K W
KW
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004338:Drug Combinations; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007377:Interleukin-3 / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology*; D007958:Leukocyte Count; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D016895:Culture Media, Serum-Free; D004338:Drug Combinations; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D015847:Interleukin-4; D007334:Insulin-Like Growth Factor I