The Role of Igf-1 and Il-4 in Myeloid Progenitor Cell Survival
Minshall, Christian
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https://hdl.handle.net/2142/83635
Description
Title
The Role of Igf-1 and Il-4 in Myeloid Progenitor Cell Survival
Author(s)
Minshall, Christian
Issue Date
1997
Doctoral Committee Chair(s)
Kelley, Keith W.
Department of Study
Animal Sciences
Discipline
Animal Sciences
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Cell
Language
eng
Abstract
The development of myeloid progenitor cells requires paracrine growth factors to mediate the proliferation, differentiation and survival of these cells. In this thesis, we demonstrate that IGF-I and IL-4, a cytokine produced by activated T-lymphocytes, enhance the survival of CSF-stimulated progenitor cells. One particular enzyme activated by both IGF-I and IL-4 is phosphatidylinositol 3$\sp\prime$-kinase, a lipid kinase which phosphorylates phosphatidylinositol on its 3$\sp\prime$ carbon. We demonstrate that activation of this enzyme is critical for IGF-I- and IL-4-mediated inhibition of apoptosis in CSF-deprived myeloid progenitor cells. Although IL-3 effectively induces PI 3-kinase activity, this is not required for IL-3-stimulated survival of FDCP cells. These data suggest that at least two distinct pathways enhance the survival of myeloid cells, one that is dependent upon PI 3-kinase and one that involves another mechanism. We also clearly demonstrate that the downstream mediator of PI 3-kinase-stimulated survival in IGF-I- and IL-4-treated cells is the anti-apoptotic protein Bcl-2. In IL-3-deprived FDCP cells the levels of Bcl-2 decrease in a time-dependent fashion, and this is negatively correlated with an increase in the apoptotic population of these cells. Treatment of IL-3-deprived FDCP cells with IGF-I or IL-4 increases the expression of Bcl-2 protein relative to cells incubated in medium alone. This enhanced expression of Bcl-2 is dependent upon IGF-I- or IL-4-activated PI 3-kinase. Treatment of these cells with either wortmannin or LY294002, two potent inhibitors of PI 3-kinase activity, abrogates the ability of IGF-I or IL-4 to maintain the expression of Bcl-2 in FDCP cells. As expected neither inhibitor affected the ability of IL-3 to maintain Bcl-2 expression or inhibit apoptosis. These data confirm our initial findings which demonstrate that two distinct ligand-dependent mechanisms are involved in mediating the survival of myeloid progenitor cells. We also demonstrate that S6-kinase, an enzyme which mediates the downstream proliferative signal of PI 3-kinase, does not transduce IGF-I- or IL-4-stimulated inhibition of apoptosis. The expression of the pro-apoptotic protein, Bax, does not change even after IL-3 withdrawal for 24 h, and is not regulated by IL-3, IGF-I or IL-4 in the presence or absence of PI 3-kinase inhibitors. These data confirm previous studies that demonstrate cell survival is regulated by relative Bcl-2 and Bax ratios. Collectively, these data demonstrate that IGF-I and IL-4 enhance myeloid cell survival by increasing the expression of Bcl-2 via activation of PI 3-kinase, while IL-3 utilizes an alternative signaling pathway.
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