Regulation of Myeloid Growth and Differentiation by the Insulin-Like Growth Factor I Receptor¹

Abstract

Flow cytometry was used to examine the expression of type I insulin-like growth factor receptors (IGF-IR) on three types of human hematopoietic cells that represent different stages of myeloid lineage development. Both HL-60 (promyeloid) and U-937 (monocytic) cells express abundant IGF-IR protein (> 79% cells positive for the IGF-IR), whereas KG-1 myeloblasts express negligible levels of IGF-IR (< 1% IGF-IR-positive cells). Exogenous IGF-I, IGF-II, and an IGF-I analog that binds poorly to IGF-binding protein-3 (des-IGF-I) increased DNA synthesis of HL-60 and U-937 cells in a dose-dependent (1-25 ng/ml) fashion by 2- to 4-fold in serum-free medium, whereas KG-1 cells did not respond to any of these growth factors. The IGF-induced increase in proliferation of HL-60 promyeloid cells was inhibited by soluble IGF-binding protein-3 (500 ng/ml) when these cells were stimulated with 10 ng/ml of either IGF-I (53 +/- 8%) or IGF-II (59 +/- 8%), but not with des-IGF-I (3 +/- 1%). In contrast, the anti-IGF-IR monoclonal antibody (mAb; alpha IR-3) inhibited the DNA synthesis caused by 10 ng/ml exogenous IGF-I (67 +/- 6%), IGF-II (72 +/- 8%), and des-IGF-1 (82 +/- 9%). Proliferation of KG-1 myeloblasts, however, was neither stimulated by the IGFs nor inhibited by the anti-IGF-IR mAb. In the absence of exogenous IGF-I, the mAb directed against the IGF-IR significantly suppressed basal DNA synthesis of HL-60 promyeloid (72 +/- 5%) and U-937 monocytic (39 +/- 7%) cells, but did not affect DNA synthesis of KG-1 myeloblasts (8 +/- 1%) compared to an isotype-matched control mAb. Similarly, the alpha IR-3 mAb abrogated vitamin D3-induced differentiation of the HL-60 cells into macrophages in serum-free medium, as assessed by expression of the leucam surface protein, CD11b. As the alpha IR-3 mAb inhibits DNA synthesis in the presence and absence of exogenous IGF-I on receptor-bearing cells, but not IGF-IR-negative cells, these data demonstrate that both endocrine and autocrine IGF-I are potent growth factors in human myeloid cells where expression of the surface receptor, rather than the ligand, is the critical control element. More importantly, these data support the hypothesis that autocrine IGF-I may play a significant role in the differentiation of promyeloid cells into macrophages.

Epidermal growth factor–induced activation of the insulin-like growth factor I receptor in rat hepatocytes

“…1,28,45 Our current findings of IGF-IR activation by des( 1-3)-IGF-I, and surface coating by IGFBP-3, support an inhibitory role for this class of IGFBP in hepatocytes. Enhanced expression of the IGF-IR may be associated with malignant transformation.…”

Insulin/IGF-1 signaling promotes immunosuppression via the STAT3 pathway: impact on the aging process and age-related diseases

“…It is known that several cytokines, such as IL-6, IL-10, and TGF-β, which activate STAT3 signaling, are potent inducers of the differentiation and activation of MDSCs [97]. Interestingly, it is known that insulin/ IGF-1 signaling can control the growth of hematopoietic progenitor cells and myeloid differentiation both in Drosophila and mammalian species [98][99][100]. In Drosophila, insulin/TOR signaling regulates the size and differentiation of the hematopoietic niche [99].…”

Insulin-Like Growth Factor Binding Proteins: New Proteins, New Functions

“…The most powerful evidence supporting this sequestration mechanism has come from studies using the IGF-I analog des-(1-3)-IGF-I which binds IGF-I-R and stimulates DNA synthesis but does not bind IGFBP-3. In the human promyeloid cell line HL-60, adding IGFBP-3 to serum-free media inhibited cell proliferation induced by IGF-I and IGF-II but not by des- (1-3)-IGF-I [100]. Transfected Ishikawa endometrial cancer cells which overexpressed both IGF-I-R and cell membrane-bound IGFBP-3 demonstrated equal IGF-I-R binding by IGF-I and des-(1-3)-IGF-I [101].…”