Conjugated linoleic acid suppresses the migratory and inflammatory phenotype of the monocyte/macrophage cell

McClelland, Sarah; Cox, Clare; O’Connor, Roisin; de Gaetano, Monica; McCarthy, Cathal; Cryan, Lorna; Fitzgerald, Des; Belton, Orina

doi:10.1016/j.atherosclerosis.2010.02.003

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Volume 211, Issue 1 , Pages 96-102, July 2010

Conjugated linoleic acid suppresses the migratory and inflammatory phenotype of the monocyte/macrophage cell

Sarah McClelland
- School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Ireland
Clare Cox
- School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Ireland
Roisin O’Connor
- Wolfson Institute for Biomedical Research, University College London, UK
Monica de Gaetano
- School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Ireland
Cathal McCarthy
- School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Ireland
Lorna Cryan
- Vascular Biology Programme, Boston Children's Hospital, Boston, MA, USA
Des Fitzgerald
- School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Ireland
Orina Belton
- School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Ireland
- Corresponding author. Tel.: +353 1 7166748; fax: +353 1 7166701.

Received 19 November 2009; received in revised form 18 January 2010; accepted 2 February 2010. published online 11 March 2010.

Abstract

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-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.

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.

Keywords: Conjugated linoleic acid, Monocyte migration, PPARs, Cyclooxygenase