Chemokine receptor-8 (CCR8) mediates human vascular smooth muscle cell chemotaxis and metalloproteinase-2 secretion.
The response of the arterial vascular wall to injury is characterized by vascular smooth muscle cell (VSMC) migration, a process requiring metalloproteinase production. This migration is induced by cytokines, however the agonists involved are not fully defined. The CC chemokine receptor 8 (CCR8) is expressed on monocytes and T lymphocytes and is the sole receptor for the human CC chemokine 1 (CCL1, I-309) and for the viral chemokine, vCCL1 (viral macrophage inflammatory protein 1 [vMIP-1]). We have reported that CCR8 is expressed on human umbilical vein endothelial cells (HUVECs) and mediates chemotaxis induced by CCL1. The conditioned medium from incubation mixtures of lipoprotein(a) (Lp(a)) and HUVECs (LCM) contained CCL1 and stimulated both monocyte and HUVEC chemotaxis, providing novel mechanisms for the atherogenicity of Lp(a). We now report that CCL1, vCCL1, and LCM stimulate chemotaxis of human VSMCs that is blocked by murine monoclonal antibody against CCR8 and by the G-protein inhibitor pertussis toxin. The effect of anti-CCR8 was specific, as this antibody failed to effect the chemotaxis of VSMCs in response to CCL3 or by platelet-derived growth factor BB (PDGF-BB). VSMCs contained CCR8 mRNA and CCR8 antigen coprecipitated with VSMC membranes. Antibodies against metalloproteinase-2 (MMP-2) inhibited the CCL1-induced chemotaxis of VSMCs, whereas anti-MMP-9 was less effective. CCL1 induced VSMC pro-MMP-2 mRNA and protein secretion. Poxvirus MC148 inhibited the increase in MMP-2 induced by CCL1, documenting that CCR8 was the receptor responsible. In mouse femoral arteries, CCR8 and TCA3 antigen colocalized with VSMCs and were up-regulated after injury. The induction of CCR8 and CCL1/TCA3 under conditions associated with VSMC proliferation and migration raises the possibility that CCR8 may play an important role in vessel wall pathology.
Haque
Nasreen S
NS
Department of Medicine, Mount Sinai School of Medicine, 1 Gustave L. Levy Pl, New York, NY 10029, USA. nasreen.haque@mssm.edu
Fallon
John T
JT
Pan
Jiang Jin
JJ
Taubman
Mark B
MB
Harpel
Peter C
PC
D000595:Amino Acid Sequence; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D054402:Chemokine CCL1; D019742:Chemokines, CC / Q000494:pharmacology; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000276:immunology; D008666:Metalloendopeptidases / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology; D037342:Pertussis Toxin / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology; D014471:Umbilical Veins / Q000166:cytology; D014764:Viral Proteins
D000906:Antibodies; C065971:CCL1 protein, human; C103330:CCR8 protein, human; C502258:Ccl1 protein, mouse; D054402:Chemokine CCL1; D019742:Chemokines, CC; D002630:Chemotactic Factors; D017077:Culture Media, Conditioned; D016207:Cytokines; D004792:Enzyme Precursors; C435144:MC148 protein, poxvirus molluscum contagiosum; D012333:RNA, Messenger; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D014764:Viral Proteins; D037342:Pertussis Toxin; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2