Molecular interactions among insulin-like growth factor, its receptor and binding proteins on myeloid cells
Li, Yongming
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Permalink
https://hdl.handle.net/2142/19576
Description
Title
Molecular interactions among insulin-like growth factor, its receptor and binding proteins on myeloid cells
Author(s)
Li, Yongming
Issue Date
1994
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, Molecular
Biology, Animal Physiology
Health Sciences, Immunology
Language
eng
Abstract
Atrophic thymus glands from old rats contained a greater population of CD4$\sp-$CD8$\sp-$ cells and a reduced percentage of CD4$\sp+$CD8$\sp+$ lymphocytes compared to those of young rats. These age-associated changes could be reversed by implanting the growth hormone (GH) secreting cells, GH$\sb3$. To understand the molecular mechanism by which insulin-like growth factor-I (IGF-I), a mediator of GH's action, acts on cells of immune system, the expression of IGF-I, IGF-I receptor (IGF-IR) and IGF binding proteins (IGFBP) in myeloid cells were studied. Human myeloid cell lines expressed IGF-I mRNA and probably secreted IGF-I peptides as evidenced by suppression of basal proliferation by an antibody to IGF-IR. Expression of the IGF-IR on myeloid cells was required for enhanced proliferation caused by both exogenous IGF-I and IGF-II. IGFBP-3 also inhibited IGF-I-induced cell proliferation. Furthermore, thymus and spleen contained IGFBPs. Among leukocytes, IGFBPs were primarily expressed in myeloid cells and their expression increased as myeloid cells were differentiated into mature macrophages. IGFBP levels from activated macrophages were down-regulated by proteases from these cells. Affinity cross-linking and protein binding immunomobility-shift assays, as well as Northern blotting, identified the 25 kDa IGFBP as IGFBP-4 that was expressed in a thymic macrophage cell line (TMC). TMC cells secrete IGFBP-4 at approximately 373 ng/10$\sp7$ cells/day as determined by ligand blot followed by PhosphorImager analysis. RT-PCR amplification of TMC mRNA with primers designed from rat and human IGFBP-4 sequences produced a 278 bp putative murine IGFBP-4 cDNA fragment which corresponded to 40% of the coding region. DNA sequencing revealed that this murine IGFBP-4 cDNA differed from the rat sequence at 6 residues (97% homology), but the deduced amino acid sequence was identical to that of the rat sequence. These results show that myeloid cells are the primary hematopoietic cells that synthesize and secrete IGFBP in leukocytes and that IGF-I together with IGFBP act in an autocrine fashion on these cells. Macrophage-derived IGFBP-4 may be a key regulator for the access of IGF-I to myeloid cells in thymic development and hematopoiesis.
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