Glucocorticoid inhibits oxidized LDL-induced macrophage growth by suppressing the expression of granulocyte/macrophage colony-stimulating factor.
Glucocorticoid, an anti-inflammatory agent, inhibits the development of atherosclerosis in various experimental animal models. This is partially explained by its ability to inhibit smooth muscle cell migration and proliferation in the intima and to reduce chemotaxis of circulating monocytes and leukocytes into the subendothelial spaces. We have recently demonstrated that oxidized LDL (Ox-LDL) has a mitogenic activity for macrophages in vitro in which Ox-LDL-induced granulocyte/macrophage colony-stimulating factor (GM-CSF) production plays an important role. Proliferation of cellular components is one of the characteristic events in the development and progression of atherosclerotic lesions. In the present study, we investigated the effects of glucocorticoids on Ox-LDL-induced macrophage growth. Dexamethasone, prednisolone, and cortisol inhibited Ox-LDL-induced thymidine incorporation into macrophages by 85%, 70%, and 50%, respectively. Ox-LDL induced a significant production of GM-CSF by macrophages, which was effectively inhibited by dexamethasone, prednisolone, and cortisol by 80%, 65%, and 50%, respectively. Dexamethasone-mediated inhibition of Ox-LDL-induced GM-CSF mRNA expression and macrophage growth was significantly abrogated by RU-486, a glucocorticoid receptor antagonist. Our results suggest that the inhibitory effects of glucocorticoids on macrophage growth may be due to the inhibition of Ox-LDL-induced GM-CSF production through transactivation of the glucocorticoid receptor.
Sakai
M
M
Department of Metabolic Medicine, Kumamoto University School of Medicine, Division of Cardiology, Kumamoto National Hospital, Kumamoto, Japan.
Biwa
T
T
Matsumura
T
T
Takemura
T
T
Matsuda
H
H
Anami
Y
Y
Sasahara
T
T
Kobori
S
S
Shichiri
M
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D015735:Mifepristone / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis
D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D015735:Mifepristone; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor