Raised MCP-4 levels in symptomatic carotid atherosclerosis: an inflammatory link between platelet and monocyte activation.
OBJECTIVE
Several studies suggest a pro-atherogenic role for the CC chemokine receptor 2 (CCR2), thought to reflect interaction with monocyte chemoattractant protein (MCP)-1. Based on its ability to attract leucocytes into inflamed tissue, we hypothesized a pro-atherogenic role for MCP-4, another CCR2 ligand.


RESULTS
Our main findings were: (i) patients with symptomatic carotid stenosis (n = 29), but not those with asymptomatic plaques (n = 31), had significantly raised plasma levels of MCP-4 compared with healthy controls (n = 20); (ii) in vitro, releasate from activated platelets markedly increased the expression of MCP-4 and CCR2 in THP-1 monocytes, and enhanced the MCP-4-mediated effect on interleukin-8 secretion in these cells, involving the platelet-derived chemokine RANTES; (iii) while MCP-1 had no effect on the release of RANTES and interferon-inducible protein of 10 kDa in tumour necrosis factor alpha-pre-activated THP-1 monocytes, MCP-4 profoundly enhanced the release of these pro-atherogenic chemokines; and (iv) the data indicate an inflammatory interaction between RANTES and MCP-4, involving CCR2, and mRNA levels of these mediators were markedly up-regulated within symptomatic atherosclerotic carotid plaque (n = 81).


CONCLUSIONS
Our findings suggest that the pro-atherogenic effects of CCR2 may not be restricted to interaction with MCP-1, but could also involve activation by MCP-4, being an inflammatory link between platelet and monocyte activation.
Research Institute for Internal Medicine, University of Oslo, Oslo, Norway.
Unni M
UM
Breland
Annika E
AE
Michelsen
Mona
M
Skjelland
Lasse
L
Folkersen
Kirsten
K
Krohg-Sørensen
David
D
Russell
Thor
T
Ueland
Arne
A
Yndestad
Gabrielle
G
Paulsson-Berne
Jan K
JK
Damås
Erik
E
Oie
Gøran K
GK
Hansson
Bente
B
Halvorsen
Pål
P
Aukrust
D000368:Aged; D000369:Aged, 80 and over; D016893:Carotid Stenosis / Q000097:blood / Q000150:complications / Q000276:immunology*; D016022:Case-Control Studies; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000276:immunology*; D018836:Inflammation Mediators / Q000097:blood*; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018945:Monocyte Chemoattractant Proteins / Q000097:blood*; D009000:Monocytes / Q000276:immunology*; D015539:Platelet Activation; D054390:Receptors, CCR2 / Q000378:metabolism; D012720:Severity of Illness Index; D015854:Up-Regulation
C099677:CCL13 protein, human; C483024:CCL5 protein, human; C515334:CCR2 protein, human; C508606:CXCL8 protein, human; D018946:Chemokine CCL5; D018836:Inflammation Mediators; D016209:Interleukin-8; D018945:Monocyte Chemoattractant Proteins; D054390:Receptors, CCR2