Effects of macrophage colony-stimulating factor (M-CSF) on protease production from monocyte, macrophage and foam cell in vitro: a possible mechanism for anti-atherosclerotic effect of M-CSF.
M-CSF is a growth factor that stimulates proliferation and differentiation of monocyte/macrophage-lineage cells. In our previous studies, M-CSF regresses atherosclerotic lesions preformed in aorta of high cholesterol-fed rabbit. Immunohistochemical analysis indicated that extracellular matrix (ECM), such as collagen, was especially eliminated in the intima of atherosclerotic lesion. To define the collagen-lowering potential of M-CSF, we have studied the effects of M-CSF on production of collagen-degrading proteases, such as MMP-1, -9 and urokinase in vitro. Monocytes freshly isolated from human peripheral blood produced MMP-9, but not urokinase, and M-CSF enhanced MMP-9 production. Macrophages were prepared by culturing monocytes for 10 days in the presence or absence of M-CSF, and protease production was assayed. M-CSF augmented production of MMP-9 and urokinase in a dose-dependent manner. M-CSF also enhanced MMP-1 production of macrophages, but not significantly. Foam cells were prepared by culturing macrophages in the presence of acetyl LDL, and protease production from these cells were also elevated by M-CSF. These results suggest that M-CSF exogenously administered in atherosclerotic rabbits might regress the thickened intima by activating macrophages to degrade collagen accumulated in the lesion.
Tojo
N
N
Drug Discovery Pharmaceutical Research Division, Yoshitomi Pharmaceutical Industries, Ltd., 2-25-1, Shodai-Ohtani, Hirakata, Osaka 573, Japan.
Asakura
E
E
Koyama
M
M
Tanabe
T
T
Nakamura
N
N
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D002470:Cell Survival; D002478:Cells, Cultured; D002791:Cholesterol, Dietary; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000096:biosynthesis*; D005487:Foam Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis
D002791:Cholesterol, Dietary; D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor; D010450:Endopeptidases; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1