Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase mediate macrophage proliferation induced by oxidized low-density lipoprotein.
We previously reported that oxidized low-density lipoprotein (Ox-LDL)-induced expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) via PKC, leading to activation of phosphatidylinositol-3 kinase (PI-3K), was important for macrophage proliferation [J Biol Chem 275 (2000) 5810]. The aim of the present study was to elucidate the role of extracellular-signal regulated kinase 1/2 (ERK1/2) and of p38 MAPK in Ox-LDL-induced macrophage proliferation. Ox-LDL-induced proliferation of mouse peritoneal macrophages assessed by [3H]thymidine incorporation and cell counting assays was significantly inhibited by MEK1/2 inhibitors, PD98059 or U0126, and p38 MAPK inhibitors, SB203580 or SB202190, respectively. Ox-LDL-induced GM-CSF production was inhibited by MEK1/2 inhibitors but not by p38 MAPK inhibitors in mRNA and protein levels, whereas recombinant GM-CSF-induced macrophage proliferation was inhibited by p38 MAPK inhibitors but enhanced by MEK1/2 inhibitors. Recombinant GM-CSF-induced PI-3K activation and Akt phosphorylation were significantly inhibited by SB203580 but enhanced by PD98059. Our results suggest that ERK1/2 is involved in Ox-LDL-induced macrophage proliferation in the signaling pathway before GM-CSF production, whereas p38 MAPK is involved after GM-CSF release. Thus, the importance of MAPKs in Ox-LDL-induced macrophage proliferation was confirmed and the control of MAPK cascade could be targeted as a potential treatment of atherosclerosis.
Senokuchi
Takafumi
T
Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860 5886, Japan.
Matsumura
Takeshi
T
Sakai
Masakazu
M
Matsuo
Tomoko
T
Yano
Miyuki
M
Kiritoshi
Shinsuke
S
Sonoda
Kazuhiro
K
Kukidome
Daisuke
D
Nishikawa
Takeshi
T
Araki
Eiichi
E
D001161:Arteriosclerosis / Q000276:immunology / Q000503:physiopathology; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000494:pharmacology*; D010084:Oxidation-Reduction; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000494:pharmacology*
D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases