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Expression of platelet-derived growth factor beta receptor on human monocyte-derived macrophages and effects of
1Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Abstract:
Platelet-derived growth factor (PDGF) plays an important role in the process of atherosclerosis which is characterized by the presence of macrophage-derived foam cells. In the present study, the induction of the mRNA of PDGF-beta receptor was demonstrated during cell differentiation of human monocyte-macrophages, whereas no mRNA was detected in the cells during the early days of culture. Flow cytometry analysis using antibodies specific for PDGF-beta receptor and CD14 showed the presence of both PDGF-beta receptor and CD14 on human monocyte-derived macrophages, whereas no PDGF-beta receptor was detected on human monocytes 4 h after cell adhesion to a culture dish. In the binding assay of PDGF-BB on human monocyte-derived macrophages, a saturable and high affinity binding site with Kd of 27.5 pM and Bmax of 23.3 fmol/mg of cell protein was demonstrated. When human monocytes were cultured in the presence of the protein kinase C inhibitor staurosporine, PDGF-beta receptor induction was inhibited, and tetradecanoylphorbol acetate enhanced PDGF-beta receptor expression in human monocyte-derived macrophages, indicating that PDGF-beta receptor expression is associated with maturation and differentiation of monocyte-macrophages through the activation of protein kinase C. In response to PDGF-BB homodimer, PDGF-beta receptor was phosphorylated, and thymidine uptake and inositol trisphosphate production were stimulated in monocyte-derived macrophages. Furthermore, PDGF-BB suppressed the production of macrophages colony-stimulating factor in macrophages. The expression of PDGF-beta receptor on human monocyte-derived macrophages suggests that PDGF influences the process of atherosclerosis by regulating the function of macrophages as well as smooth muscle cells in the vascular wall.
Insights
Platelet-derived growth factor-beta receptor (PDGF-beta receptor) is expressed on differentiating human macrophages, influencing their function in atherosclerosis. This research highlights PDGF
Area of Science:
- Cardiovascular Biology
- Cellular and Molecular Medicine
- Immunology
Background:
- Atherosclerosis involves macrophage-derived foam cells.
- Platelet-derived growth factor (PDGF) is implicated in atherosclerosis.
Purpose of the Study:
- To investigate the expression and function of PDGF-beta receptor during human monocyte-macrophage differentiation.
- To elucidate the role of PDGF in macrophage function relevant to atherosclerosis.
Main Methods:
- RT-PCR to detect PDGF-beta receptor mRNA.
- Flow cytometry for receptor and CD14 expression analysis.
- Ligand binding assays for PDGF-BB.
- Inhibition and enhancement studies using protein kinase C modulators.
- Measurement of downstream signaling events (phosphorylation, thymidine uptake, IP3 production) and cytokine production.
Main Results:
- PDGF-beta receptor mRNA and protein are induced during human monocyte-macrophage differentiation.
- Macrophages exhibit high-affinity binding sites for PDGF-BB.
- PDGF-beta receptor expression is regulated by protein kinase C.
- PDGF-BB stimulates intracellular signaling pathways and suppresses M-CSF production in macrophages.
- PDGF-BB signaling influences macrophage function.
Conclusions:
- PDGF-beta receptor is expressed on differentiated human monocyte-derived macrophages.
- PDGF signaling pathways are active in macrophages and modulate their function.
- PDGF may influence atherosclerosis by regulating macrophage behavior in the vascular wall.