Increased CD74 expression in human atherosclerotic plaques: contribution to inflammatory responses in vascular cells.
OBJECTIVE
The purpose of this study was to analyse the expression of CD74 in human atherosclerotic plaques and peripheral blood mononuclear cells (PBMC) as well as its potential participation in proinflammatory responses in cultured human vascular smooth muscle cells (VSMC).


RESULTS
CD74 expression was analysed in human atherosclerotic plaques (immunohistochemistry), PBMC (real-time PCR), and human aortic VSMC (real-time PCR and western blotting). Nuclear factor-kappaB (NF-kappaB) activation was assessed by southwestern histochemistry and electrophoretic mobility shift assay. Monocyte chemoattractant protein-1 (MCP-1) levels were studied by both real-time PCR and enzyme-linked immunosorbent assay. CD74 immunostaining was increased in the inflammatory vs. the fibrous region of atherosclerotic plaques (n = 70, 18.2 +/- 1.3 vs. 7.8 +/- 0.6% positive staining/mm2, P < 0.001). CD74 colocalized with the transcription factor NF-kappaB in both VSMC and macrophages. In cultured VSMC, CD74 expression was induced by interferon gamma (IFNgamma). Incubation with an agonistic anti-CD74 antibody or with IFNgamma elicited MCP-1 expression, which was prevented by AKT and gamma-secretase inhibitors. Moreover, CD74 small-interfering RNA decreased NF-kappaB activation and MCP-1 production induced by IFNgamma in VSMC. Finally, CD74 mRNA levels in PBMC from patients with carotid stenosis were higher than in healthy subjects (n = 20, 3 +/- 0.5 vs. 2 +/- 0.5 AU, P < 0.001). Additionally, a linear trend between CD74 mRNA expression tertiles and intima-media thickness (IMT) was observed in PBMC from asymptomatic subjects (n = 185, P < 0.001).


CONCLUSIONS
CD74 levels are increased in plaques and PBMC from patients with carotid stenosis and are associated with IMT in subjects free from clinical cardiovascular diseases. CD74 could be a novel therapeutic target to decrease the inflammatory response in atherosclerosis.
Renal and Vascular Research Lab, Fundación Jimenez Diaz, Autonoma University, Madrid, Spain. jlmartin@fjd.es
José Luis
JL
Martín-Ventura
Julio
J
Madrigal-Matute
Begoña
B
Muñoz-Garcia
Luis Miguel
LM
Blanco-Colio
Melany
M
Van Oostrom
Guillermo
G
Zalba
Ana
A
Fortuño
Carmen
C
Gomez-Guerrero
Luis
L
Ortega
Alberto
A
Ortiz
Javier
J
Diez
Jesús
J
Egido
D000944:Antigens, Differentiation, B-Lymphocyte / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002339:Carotid Arteries / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D016893:Carotid Stenosis / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D016894:Endarterectomy, Carotid; D005355:Fibrosis; D000949:Histocompatibility Antigens Class II / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D032389:Myocytes, Smooth Muscle / Q000276:immunology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017539:Tunica Intima / Q000276:immunology; D017540:Tunica Media / Q000276:immunology; D015854:Up-Regulation
D000944:Antigens, Differentiation, B-Lymphocyte; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C045084:invariant chain; D007371:Interferon-gamma