抄録
Macrophages and T lymphocytes are ubiquitous in all stages of atherogenesis. It has been postulated that altering the endothelial function leads to the increased adhesion of monocytes and lymphocytes to the endothelium, followed by their chemoattraction into the artery wall, where the monocytes are converted to macrophages. The macrophages and their secretory products, including platelet-derived growth factor (PDGF), may then play a role in inducing smooth muscle migration and proliferation within the intima, ultimately leading to the fibroproliferative advanced lesions of atherosclerosis. Furthermore, we postulated that T lymphocytes may regulate the growth factor production and secretion from macrophages.
We examined developing lesions in nonhuman primates to study the levels of gene expression in the growth factors and cytokines and were positive for PDGF-A, PDGF-B, and IL-lβ. We also examined the lesions of both nonhuman primates and humans immunohistochemically using a monoclonal anti-peptide antibody (PGF-007) with residues 73-97 of the mature PDGF B-chain. Immunohistochemical staining of macrophages (using monoclonal antibody HAM56, specific for macrophages) and PGF-007 demonstrated co-localization of PDGF-B within the macrophages in a perinuclear region. Immuno-staining of PDGF-B was observed in macrophages in all phases of atherogenesis in both humans and nonhuman primates.
We also examined the regulatory effect of interferon-γ (IFN-γ), a cytokine secreted by activated T lymphocytes, on growth factor production and secretion from macrophages. THP-1 cells, a monocytic leukemic cell line, were activated by incubation with phorbol 12-myristate 13-acetate (PMA). After 24 hours, IFN-γ was added to the culture medium and the effect on the levels of PDGF mRNA expression in THP-1 cells and the amount of PDGF secreted into the culture medium were examined. The levels of mRNA for both the A- and B-chains of PDGF decreased in a dose- and time-dependent fashion. A culture medium collected 48 hours after the addition of IFN-γ demonstrated a decrease of PDGF-dependent mitogenic activity, estimated by preincubation with anti-PDGF antibody, as well as the values of radioimmunoassay for PDGF.
These results suggest that macrophages can serve as a source of PDGF, which can act both as a chemoattractant and as a potent mitogen for smooth muscle cells, and thus play a putative role in the proliferative lesions of atherosclerosis. Furthermore, IFN-γ modulates PDGF production and secretion from macrophages, and the concomitant appearance of T cells and macrophages in atherosclerotic lesions may imply the cellular interaction of the regulatory mechanism for growth factor secretion from macrophages through the action of INF-γ.
