The Role of Insulin-Like Growth Factor-I in Myeloid Cell Differentiation

183 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1997.IGF-I transcripts and its protein are specifically induced as myeloid progenitor cells undergo differentiation toward macrophages. However, the potential role of IGF-I in myeloid cell differentiation has not yet been investigated. The data in this thesis demonstrate that IGF-I combined with either RA or vitamin D$\sb3$ enhances myeloid cell differentiation. IGF-I rescues myeloid progenitors from apoptosis and permits granulocytic differentiation in the presence of RA. IGF-I-induced activation of PI 3-kinase is responsible for this enhancement of differentiation and prevention of apoptosis. IGF-I also promotes vitamin D$\sb3$-induced macrophage differentiation via acting through its own receptor. Indeed, IGF-I is a critical element in serum inducing normal macrophage differentiation. IGF-I activates the PI 3-kinase-dependent PKC-$\zeta$ pathway during differentiation along the macrophage lineage. Inhibition of IGF-I-inducible PI 3-kinase leads to a complete block in PKC-$\zeta$ activation and abrogation of macrophage differentiation. Finally, it is demonstrated that the early events associated with IGF-I-promoted macrophage differentiation induced by vitamin D$\sb3$ occurs concomitantly with progression through the cell cycle. Indeed, IGF-I increases expression of CD11b, CD14 and the $\alpha$-naphthyl acetate esterase of mature macrophage. Cell growth and cell cycle analysis revealed that IGF-I promoted cells advancing through the cell cycle as well as enhances macrophage differentiation. Western blot analysis demonstrated that IGF-I-induced proliferating cells express high cyclin E and low p27$\rm\sp{KIP1}.$ As a result, Rb protein is hyperphosphorylated in IGF-I-treated proliferating cells. These IGF-I-induced events are similar during the initial stages of macrophage differentiation triggered by vitamin D3, suggesting that withdrawal from the cell cycle is not required for initiation of myeloid cell differentiation. Simultaneous cell cycle and cell surface antigen analysis showed that the CD11b marker is expressed in all phases of the cell cycle. Similarly, analysis of CD11b coupled with the intranuclear proliferation antigens, PCNA and Brdu, revealed that proliferation antigens are also expressed in differentiating promyeloid cells. Collectively, the present results establish new and important roles of IGF-I acting as a survival as well as a differentiation factor during both RA and vitamin D$\sb3$-induced myeloid differentiation processes.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD