An investigation into the role of PPARγ and IL-6 in exercise-induced alterations in monocyte gene expression

Abstract

The pro-inflammatory M1 macrophage phenotype is linked to insulin resistance, T2D and associated cardiovascular co-morbidities, whereas M2 macrophages regulate the M1 inflammatory response and are, thus, believed to be preventative of these diseases. Exercise may induce markers of M2 polarisation and downregulate M1 markers in mononuclear cells but this has not yet been demonstrated in macrophage precursors, monocytes. Thus, the present research aimed to investigate the effects of exercise on M1/M2 marker expression in monocytes and to elucidate potential mechanisms for any observed changes. Participation in exercise was found to beneficially alter T2D and CVD risk factors, including insulin sensitivity, in high-risk females. Exercise participation was also shown to induce markers of M2 polarisation and reduce expression of the M1 marker, MCP-1, in isolated monocytes. Additionally, a ‘key regulator’ of M2 polarisation, PPARγ was upregulated in monocytes and PPARγ activating properties were elevated in serum samples obtained immediately after exercise participation. Finally, IL-6 was also found to be upregulated immediately after participation in exercise. In THP-1 monocytes, PPARγ was shown to have no effect on M1/M2 marker expression. However, IL-6 was found to downregulate expression of MCP-1, in human monocytes co-cultured with lymphocytes. In conclusion, PPARγ activation does not appear to play a role in the upregulation of M2 markers observed in monocytes following exercise participation. Instead, IL-6 generation may contribute to the impact of exercise on monocyte/macrophage phenotype. It is likely, however, that other exercise-associated factors may also contribute to the observed elevations in monocyte M2 marker expression following exercise participation but these are yet to be elucidated. Nonetheless, this research provides evidence that participation in an exercise intervention, such as the one administered in this study, may impact upon monocyte-macrophage polarisation towards the M2 phenotype, and that this may contribute to the improvements in insulin sensitivity and T2D/CVD risk which support prescription of physical activity in the prevention and management of T2D.