title: Increased levels of CCR7 ligands in carotid atherosclerosis: different effects in macrophages and smooth muscle cells.
abstract: OBJECTIVE
  The homeostatic chemokines, CCL19 and CCL21 and their receptor CCR7, have recently been linked to atherogenesis. We investigated the expression of CCL19/CCL21/CCR7 in carotid atherosclerosis as well as the ability of these chemokines to modulate lipid accumulation in macrophages and vascular smooth muscle cell (SMC) phenotype.
  
  
  RESULTS
  Our major findings were: (i) patients with carotid atherosclerosis (n = 158) had increased plasma levels of CCL21, but not of CCL19, compared with controls (n = 20), with particularly high levels in symptomatic (n = 99) when compared with asymptomatic (n = 59) disease. (ii) Carotid plaques showed markedly increased mRNA levels of CCL21 and CCL19 in symptomatic (n = 14) when compared with asymptomatic (n = 7) patients, with CCR7 localized to macrophages and vascular SMC (immunohistochemistry). (iii) In vitro, CCL21, but not CCL19, increased the binding of modified LDL and promoted lipid accumulation in THP-1 macrophages. (iv) CCL19, but not CCL21, increased proliferation and release and activity of matrix metalloproteinase (MMP) 1 in vascular SMC. (v) The differential effects of CCL19 and CCL21 in macrophages and SMC seem to be attributable to divergent signalling pathways, with CCL19-mediated activation of AKT in SMC- and CCL21-mediated activation of extracellular signal-regulated kinase 1/2 in macrophages.
  
  
  CONCLUSIONS
  CCL19 and CCL21 are up-regulated in carotid atherosclerosis. The ability of CCL21 to promote lipid accumulation in macrophages and of CCL19 to induce proliferation and MMP-1 expression in vascular SMC could contribute to their pro-atherogenic potential.
authors: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors: Bente
authors: B
authors: Halvorsen
authors: Tuva B
authors: TB
authors: Dahl
authors: Linda M
authors: LM
authors: Smedbakken
authors: Anjana
authors: A
authors: Singh
authors: Annika E
authors: AE
authors: Michelsen
authors: Mona
authors: M
authors: Skjelland
authors: Kirsten
authors: K
authors: Krohg-Sørensen
authors: David
authors: D
authors: Russell
authors: Uta E
authors: UE
authors: Höpken
authors: Martin
authors: M
authors: Lipp
authors: Jan K
authors: JK
authors: Damås
authors: Sverre
authors: S
authors: Holm
authors: Arne
authors: A
authors: Yndestad
authors: Erik A
authors: EA
authors: Biessen
authors: Pål
authors: P
authors: Aukrust
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002340:Carotid Artery Diseases / Q000378:metabolism*; D054415:Chemokine CCL19 / Q000276:immunology / Q000378:metabolism; D054421:Chemokine CCL21 / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation
chemical_list: C515460:CCL19 protein, human; C515478:CCL21 protein, human; C515370:CCR7 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D008024:Ligands; D054400:Receptors, CCR7; D048052:Mitogen-Activated Protein Kinase 3
keywords: Atherosclerosis; Chemokines; Inflammation; Macrophages; SMC