CC chemokine I-309 is the principal monocyte chemoattractant induced by apolipoprotein(a) in human vascular endothelial cells.
BACKGROUND
Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerosis; however, the mechanisms are unclear. We previously reported that Lp(a) stimulated human vascular endothelial cells to produce monocyte chemotactic activity. The apolipoprotein(a) [apo(a)] portion of Lp(a) was the active moiety.


RESULTS
We now describe the identification of the chemotactic activity as being due to the CC chemokine I-309. The carboxy-terminal domain of apo(a) containing 6 type-4 kringles (types 5 to 10), kringle V, and the protease domain was demonstrated to contain the I-309-inducing portion. Polyclonal and monoclonal anti-I-309 antibodies as well as an antibody against a portion of the extracellular domain of CCR8, the I-309 receptor, inhibited the increase in monocyte chemotactic activity induced by apo(a). I-309 antisense oligonucleotides also inhibited the induction of endothelial monocyte chemotactic activity by apo(a). I-309 mRNA was identified in human umbilical vein endothelial cells. Apo(a) induced an increase in I-309 protein in the endothelial cytoplasm and in the conditioned medium. Immunohistochemical studies have identified I-309 in endothelium, macrophages, and extracellular areas of human atherosclerotic plaques and have found that I-309 colocalized with apo(a).


CONCLUSIONS
These data establish that I-309 is responsible for the monocyte chemotactic activity induced in human umbilical vein endothelial cells by Lp(a). The identification of the endothelial cell as a source for I-309 suggests that this chemokine may participate in vessel wall biology. Our data also suggest that I-309 may play a role in mediating the effects of Lp(a) in atherosclerosis.
Haque
N S
NS
Division of Hematology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Zhang
X
X
French
D L
DL
Li
J
J
Poon
M
M
Fallon
J T
JT
Gabel
B R
BR
Taubman
M B
MB
Koschinsky
M
M
Harpel
P C
PC
D000906:Antibodies / Q000494:pharmacology; D001054:Apolipoproteins A / Q000494:pharmacology / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D054402:Chemokine CCL1; D019742:Chemokines, CC / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003470:Culture Media / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000276:immunology; D011994:Recombinant Proteins / Q000378:metabolism
D000906:Antibodies; D001054:Apolipoproteins A; C065971:CCL1 protein, human; C103330:CCR8 protein, human; D054402:Chemokine CCL1; D019742:Chemokines, CC; D002630:Chemotactic Factors; D003470:Culture Media; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D011994:Recombinant Proteins