title: CCL20 is increased in hypercholesterolemic subjects and is upregulated by LDL in vascular smooth muscle cells: role of NF-κB.
abstract: OBJECTIVE
  Our aim was to analyze the regulation of CC Chemokine ligand 20 (CCL20) by LDL in human vascular smooth muscle cells (VSMC).
  
  
  RESULTS
  In asymptomatic subjects, circulating CCL20 levels were higher in patients with hypercholesterolemia (18.5±3.2 versus 9.1±1.3 pg/mL; P<0.01). LDL induced the expression of CCL20 in VSMC in a dose- and time-dependent manner. Increased levels of CCL20 secreted by LDL-treated VSMC significantly induced human lymphocyte migration, an effect reduced by CCL20 silencing. The upregulation of CCL20 by LDL was dependent on the activation of kinase signaling pathways and NF-κB. By site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we identified a NF-κB site (-80/-71) in CCL20 promoter critical for LDL responsiveness. Lysophosphatidic acid mimicked the upregulation of CCL20 induced by LDL, and minimal oxidation of LDL increased the ability of LDL to induce CCL20 through a mechanism that involves lysophosphatidic acid receptors. CCL20 was overexpressed in atherosclerotic lesions from coronary artery patients, colocalizing with VSMC. CCL20 was detected in conditioned media from healthy human aorta and its levels were significantly higher in secretomes from carotid endarterectomy specimens.
  
  
  CONCLUSIONS
  This study identifies CCL20 in atherosclerotic lesions and recognizes this chemokine as a mediator highly sensitive to the inflammatory response elicited by LDL.
authors.affiliation: Centro de Investigación Cardiovascular, Consejo Superior de Investigaciones Científicas, Institut Català de Ciències Cardiovasculars, Instituto de Investigaciones Biomédicas Sant Pau, Barcelona, Spain.
authors.forename: Olivier
authors.initials: O
authors.lastname: Calvayrac
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rodríguez-Calvo
authors.forename: Judith
authors.initials: J
authors.lastname: Alonso
authors.forename: Josune
authors.initials: J
authors.lastname: Orbe
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Martín-Ventura
authors.forename: Anna
authors.initials: A
authors.lastname: Guadall
authors.forename: Maurizio
authors.initials: M
authors.lastname: Gentile
authors.forename: Oriol
authors.initials: O
authors.lastname: Juan-Babot
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Oscar
authors.initials: O
authors.lastname: Beloqui
authors.forename: José A
authors.initials: JA
authors.lastname: Paramo
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
mesh_terms: D000328:Adult; D000368:Aged; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D004691:Endarterectomy; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; D008077:Lipoproteins, LDL; D016328:NF-kappa B