Induction of murine macrophage growth by oxidized low density lipoprotein is mediated by granulocyte macrophage colony-stimulating factor.
We have examined whether certain secreted factor(s) is involved in oxidized low density lipoprotein (Ox-LDL)-induced murine macrophage growth. An antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) effectively inhibited Ox-LDL-induced macrophage growth by >80%. Ox-LDL as well as phospholipase A2-treated acetylated LDL enhanced mRNA levels and protein release of GM-CSF from macrophages, while neither acetylated LDL nor lysophosphatidylcholine (lyso-PC) showed such effects. The maximal induction of GM-CSF by Ox-LDL was noted at 4 h, followed by a time-dependent decrease to a basal level within 24 h. Ox-LDL-induced macrophage growth was inhibited by 75% by replacement of the culture medium at 24 h by a fresh medium containing the same concentration of Ox-LDL, when GM-CSF had already returned to the basal level. Thus, a cytokine(s) other than GM-CSF is also expected to participate in Ox-LDL-induced macrophage growth in a later phase. The Ox-LDL-induced GM-CSF release was inhibited by calphostin C, a protein kinase C inhibitor, and was significantly reduced in macrophages from the knockout mice lacking class A, type I and type II macrophage scavenger receptors (MSR-AI/AII). These results taken together indicate that effective endocytosis of lyso-PC of Ox-LDL by macrophages through MSR-AI/AII and subsequent protein kinase C activation have led to GM-CSF release into the medium which may play a priming role in conjunction with other cytokines in Ox-LDL-induced macrophage growth.
Department of Biochemistry, Kumamota University School of Medicine, Kumamota 860-0811, Japan.
T
T
Biwa
H
H
Hakamata
M
M
Sakai
A
A
Miyazaki
H
H
Suzuki
T
T
Kodama
M
M
Shichiri
S
S
Horiuchi
D000818:Animals; D002455:Cell Division; D017077:Culture Media, Conditioned; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D004789:Enzyme Activation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007377:Interleukin-3 / Q000037:antagonists & inhibitors; D015848:Interleukin-5 / Q000037:antagonists & inhibitors; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D015398:Signal Transduction
D017077:Culture Media, Conditioned; D007377:Interleukin-3; D015848:Interleukin-5; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; C495140:Msr1 protein, mouse; D009281:Naphthalenes; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; C061465:calphostin complex; C099252:oxidized low density lipoprotein; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011493:Protein Kinase C