High-density lipoproteins suppress chemokines and chemokine receptors in vitro and in vivo.
OBJECTIVE
To investigate whether high-density lipoproteins (HDLs) suppress chemokine (CCL2, CCL5, and CX(3)CL1) and chemokine receptor (CCR2 and CX(3)CR1) expression, a mechanism for the atheroprotective properties of HDLs.


RESULTS
Apolipoprotein (apo) E(-/-) mice were fed a high-fat diet for 12 weeks. Before being euthanized, the mice received 5 consecutive daily injections of lipid-free apoA-I, 40 mg/kg, or saline (control). The injection of apoA-I reduced CCR2 and CX(3)CR1 expression in plaques compared with controls (P<0.05). ApoA-I-injected mice had lower plasma CCL2 and CCL5 levels. Hepatic CCL2, CCL5, and CX(3)CL1 levels were also reduced (P<0.05). In vitro studies found that reconstituted HDL (rHDL) reduced monocyte CCR2 and CX(3)CR1 expression and inhibited their migration toward CCL2 and CX(3)CL1 (P<0.05). Preincubation with rHDL reduced CCL2, CCL5, and CX(3)CL1 expression in monocytes and human coronary artery endothelial cells. The stimulation of CX(3)CR1 with peroxisome proliferator-activated receptor gamma agonist CAY10410 was suppressed by preincubation with rHDL but did not affect the peroxisome proliferator-activated receptor gamma antagonist (GW9664)-mediated increase in CCR2. In monocytes and human coronary artery endothelial cells, rHDL reduced the expression of the nuclear p65 subunit, IkappaB kinase activity, and the phosphorylation of IkappaBalpha (P<0.05).


CONCLUSIONS
Lipid-free apoA-I and rHDL reduce the expression of chemokines and chemokine receptors in vivo and in vitro via modulation of nuclear factor kappaB and peroxisome proliferator-activated receptor gamma.
Bursill
Christina A
CA
Heart Research Institute, 7 Eliza St, Sydney, New South Wales 2042, Australia. bursillc@hri.org.au
Castro
Maria L
ML
Beattie
Douglas T
DT
Nakhla
Shirley
S
van der Vorst
Emiel
E
Heather
Alison K
AK
Barter
Philip J
PJ
Rye
Kerry-Anne
KA
D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000378:metabolism; D018925:Chemokines / Q000097:blood / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D047495:PPAR gamma / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism
C501048:3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethylisoxazole; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; C111835:CCL2 protein, human; C483024:CCL5 protein, human; C515538:CX3CL1 protein, human; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054428:Chemokine CX3CL1; D018925:Chemokines; C515539:Cx3cl1 protein, mouse; D020672:I-kappa B Proteins; D007555:Isoxazoles; D008075:Lipoproteins, HDL; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D047495:PPAR gamma; C498143:RELA protein, human; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D023062:Receptors, Interleukin-8A; C498144:Rela protein, mouse; D013450:Sulfones; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha