Oxysterol-induced up-regulation of MCP-1 expression and synthesis in macrophage cells.
To investigate the proinflammatory potential of cholesterol and cholesterol oxidation products (oxysterols), which are present in oxidized low-density lipoproteins, foam cells, and fibrotic plaque, we used an in vitro model mimicking the challenge of macrophage cells by the cholesterol accumulating within the central core of atheroma. A biologically representative oxysterol mixture was shown to be potentially able to sustain a chronic inflammatory process within the vascular wall by up-regulating the expression of defined proinflammatory genes. In particular, expression and synthesis of the major chemokine for monocytes/macrophages, namely monocyte chemotactic protein-1 (MCP-1), were consistently increased when cells of the macrophage lineage (U937 cell line) were incubated with this mixture. On the contrary, an identical concentration of unoxidized cholesterol in no case modified expression or synthesis of the chemokine. Up-regulated expression and synthesis of MCP-1 by the oxysterol mixture was clearly dependent on a net increment of phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor kappaB (NF-kappaB) nuclear binding. The results indicate that cholesterol may contribute to the progression of atherosclerotic lesions by strongly up-regulating crucial proinflammatory factors like MCP-1, but only after having been oxidized to oxysterols.
Leonarduzzi
Gabriella
G
Department of Clinical and Biological Sciences, University of Turin, S. Luigi Hospital, 10043 Orbassano (Turin), Italy.
Gamba
Paola
P
Sottero
Barbara
B
Kadl
Alexandra
A
Robbesyn
Fanny
F
Calogero
Raffaele A
RA
Biasi
Fiorella
F
Chiarpotto
Elena
E
Leitinger
Norbert
N
Sevanian
Alex
A
Poli
Giuseppe
G
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D015854:Up-Regulation
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016328:NF-kappa B; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases