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-γ (PPARγ). In this study we investigate if CLA mediates anti-atherogenic effects via modulation of monocyte/macrophage function and provide evidence for an additional PPARγ-independent mechanism for CLA.
Methods and 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 PPARγ agonists. Incubation of THP-1 monocytes with CLA-isomers and a PPARγ 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 PPARγ 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.
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.
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Published online: March 11, 2010
Accepted: February 2, 2010
Received in revised form: January 18, 2010
Received: November 19, 2009
© 2010 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.