The effect of PPAR-Gamma Ligands on Monocyte Polarisation
University of Wales
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Pharmacological activation of the nuclear receptor PPARγ enhances differentiation of circulating monocytes towards an alternative anti-inflammatory M2 phenotype, linked to atherosclerosis and its cardiovascular complications. Previous work has shown that participation in low-intensity exercise significantly increases PPARγ expression and activity in the leukocytes of previously sedentary individuals. Seventeen sedentary adults (mean age 45.6 ± 11.1) years participated in an eight week low-intensity exercise programme consisting of walking 10000 steps, three times a week. Compared to controls there was a significant down-regulation in leukocytes mRNA gene expression of the pro-inflammatory M1 markers (MCP-1 and IL-6), and an up-regulation in gene expression of the M2 markers of monocyte polarisation: MR, CD163 and CX3CR1 after 8 weeks of exercise. This exercise regimen also resulted in a significant increase in mRNA gene expression of the Th2 cytokine IL-4. In-vitro differentiation of monocytes into the M2 phenotype by PPARγ activation was achieved by treating THP-1 monocytic cells for up to 72 hours with the Th2 cytokine IL-13 (15ng/ml), the dietary lipid CLA (20 or 100μM) and a specific PPARγ ligand Rosiglitazone (1μM). Monocytes were polarised to an M2 phenotype after IL-13 treatment, inducing an increase in mRNA gene expression of MR and a decrease in MCP-1 gene expression; these effects were further enhanced after 72 hours of incubation upon co-treatment of IL-13 with CLA or Rosiglitazone. Also, polarisation of differentiated THP-1 cells to an M2 phenotype and treatment with the various stimuli resulted in a significant increase in MR and CD163 surface expression. Interestingly the down-regulation of MCP-1 with Rosiglitazone and CLA was abolished by treatment with the PPARγ antagonist GW9662 (1μM). In conclusion, this study presents evidence that exercise and the dietary lipid CLA can induce monocyte polarisation towards a beneficial M2 phenotype partly through their ability to activate PPARγ.
Yakeu, G. Butcher, L., Isa, S., Webb, R. Roberts., A. Thomas., AW, Backx, K., James, PE., Morris, K. Low-intensity exercise triggers monocyte polarisation into the M2 anti-inflammatory phenotype. Submitted for publication to Atherosclerosis March 2010
Yakeu, G., Butcher, L., Webb, R., A, Thomas., Morris, K. 01/07/09. Low-intensity exercise induces PPARy mediated monocyte sub-type priming: an important anti-atherosclerotic mechanism. 8th Annual postgraduate Research and Knowledge Transfer Partnership Colloquium at Gregynog Hall 1-3rd July 2009
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