Conjugated linoleic acid suppresses the migratory and inflammatory phenotype of the monocyte/macrophage cell.
OBJECTIVE
We have previously shown that conjugated linoleic acid (CLA) regresses pre-established murine atherosclerosis. Although the exact underlying mechanisms are unclear, accumulation of macrophages and expression of inflammatory markers were reduced in atherosclerotic plaques of CLA-fed mice, implicating the monocyte/macrophage as a target through which CLA may mediate anti-atherosclerotic effects. CLA mediates its effect at least in part via activation of the nuclear receptor, peroxisome proliferator activator receptor-gamma (PPARgamma). In this study we investigate if CLA mediates anti-atherogenic effects via modulation of monocyte/macrophage function and provide evidence for an additional PPARgamma-independent mechanism for CLA.


RESULTS
Migration of the human monocyte cell line THP-1, and primary blood monocytes (HPBMCs) was assessed using transwell migration assays. Monocyte chemoattractant protein-1 (MCP-1) mediates chemotaxis via interaction with the chemokine (C-C motif)-2 receptor (CCR-2), which is expressed on the monocyte cell surface, and is negatively regulated by PPARgamma agonists. Incubation of THP-1 monocytes with CLA-isomers and a PPARgamma agonist inhibited MCP-1-induced monocyte migration. Prior to monocyte recruitment, activated platelets accumulate and release the contents of their secretory granules ("platelet-releasate"). Here we demonstrate that platelet-releasate is a monocyte chemoattractant, and CLA, but not the PPARgamma agonist, inhibits platelet-releasate-induced migration of THP-1 and HPBMC monocytes. CLA-treatment also suppressed the inflammatory macrophage phenotype, demonstrated by decreased induction of monocyte migration by CLA-treated macrophage-conditioned-media, as well as by decreased cyclooxygenase (COX)-2 and cytosolic phospholipase-A2 (cPLA2) expression and MCP-1, prostaglandin E2 (PGE2) and matrix metalloprotease (MMP)-9 generation.


CONCLUSIONS
CLA-isomers inhibit monocyte migration and reduce the inflammatory output of the macrophage. These mechanisms may contribute to the potent anti-atherosclerotic effects of CLA in vivo.
McClelland
Sarah
S
School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Ireland.
Cox
Clare
C
O'Connor
Roisin
R
de Gaetano
Monica
M
McCarthy
Cathal
C
Cryan
Lorna
L
Fitzgerald
Des
D
Belton
Orina
O
D002465:Cell Movement / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D009000:Monocytes / Q000187:drug effects*; D047495:PPAR gamma; D054467:Phospholipases A2 / Q000096:biosynthesis; D054390:Receptors, CCR2 / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
D018932:Chemokine CCL2; D002839:Chromans; D044243:Linoleic Acids, Conjugated; D047495:PPAR gamma; D054390:Receptors, CCR2; D045162:Thiazolidinediones; D051546:Cyclooxygenase 2; D054467:Phospholipases A2; D020780:Matrix Metalloproteinase 9; D000077288:Troglitazone; D015232:Dinoprostone