Atherosclerosis 212 (2010) 668–673 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Low-intensity exercise enhances expression of markers of alternative activation in circulating leukocytes: Roles of PPAR and Th2 cytokines G. Yakeu a , L. Butcher a , S. Isa a , R. Webb a , A.W. Roberts b , A.W. Thomas a , K. Backx c , P.E. James d , K. Morris a,∗ a Centre for Biomedical Sciences, Cardiff School of Health Sciences, University of Wales Institute Cardiff, Cardiff CF5 2YB, UK b School of Medicine, Cardiff University, Heath Park Campus, Cardiff CF14 4XN, UK c Cardiff School of Sport, UWIC, Cardiff CF23 6XD, UK d Welsh Heart Institute Cardiff University, Heath Park Campus, Cardiff CF14 4XN, UK article info Article history: Received 25 August 2009 Received in revised form 2 July 2010 Accepted 7 July 2010 Available online 16 July 2010 Keywords: Exercise Monocyte polarisation Anti-inflammatory Anti-atherogenic PPAR abstract Objective: Pharmacological activation of the nuclear receptor PPAR is linked to numerous beneficial effects in the contexts of inflammation, lipid homeostasis, Type-2 Diabetes (T2D) and atherosclerosis. These beneficial effects include priming of circulating monocytes for differentiation towards an ‘alter- native’ anti-inflammatory M2 macrophage phenotype. As we have recently shown that participation in low-intensity exercise increases PPAR expression and activity in leukocytes from previously sedentary individuals, we aimed to elucidate whether low-intensity exercise elicited a pattern of gene expression similar to that reported for M2 monocyte-macrophage differentiation. Methods: 17 sedentary individuals undertook an 8-week low-intensity exercise programme (walking 10,000 steps/day, three times/week). Changes in expression of PPARs and the PPAR co-activators PGC- 1  and PGC-1  ; Th2 (IL-4; IL-10) and Th1 (IL-6) cytokines; and markers for the M2 (AMAC1, CD14, MR, IL-4) and the ‘classical’ pro-inflammatory M1 (MCP-1, TNF, IL-6) phenotypes, were determined using RT-PCR (to assess leukocyte mRNA expression) and ELISA (to assess plasma cytokine levels). Results: Exercise was associated with upregulation of M2 markers, PGC-1  and PGC-1  , and with down- regulation of M1 markers. Moreover, plasma levels of Th2 cytokines increased after exercise, while those of Th1 cytokines decreased. However, other PPARs (PPAR; PPAR/) did not undergo marked exercise- induced activation or upregulation. Thus, participation in low-intensity exercise may prime monocytes for differentiation towards an M2 macrophage phenotype via PPAR/PGC-1 / . Conclusion: Given the similarities between these effects and pharmacologically induced M2 polarisation, we propose that exercise-induced PPAR/PGC-1 / -mediated M2 polarisation may constitute a novel anti-inflammatory benefit of low-intensity exercise. © 2010 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The importance of inflammation and of the monocyte-derived macrophage in atherosclerosis is widely recognised [1,2]. It has been known for several years that peripheral blood monocytes con- stitute a heterogeneous population of circulating leukocytes [3], while recent studies have noted that different monocyte subsets can differentiate into functionally distinct macrophage subpop- ulations in vivo [4]. Controversy currently exists as to whether monocytes should be viewed as being ‘locked into’ a particu- lar subset: although each monocyte is a highly plastic cell that can theoretically differentiate into one of a variety of different ∗ Corresponding author. Tel.: +44 2920 416871; fax: +44 2920 416982. E-mail address: kmorris@uwic.ac.uk (K. Morris). macrophage sub-types, it has also been argued that the general fate of monocytes can be influenced by systemic factors such as the prevailing cytokine milieu [5]. In summary, although further research is required to fully clarify this area, there is much evi- dence that distinct subpopulations of macrophage can arise in different circumstances [6], or in response to different stimuli [7]. For example, microbial stimuli such as LPS and Th1 cytokines such as Interferon- and Interleukin (IL-1) direct differentiation towards the ‘classical’ pro-inflammatory M1 macrophage pheno- type that secretes pro-inflammatory cytokines including TNF- and IL-6, whereas Th2 cytokines such as IL-4, IL-10 or IL-13 induce differentiation into ‘alternative’ M2 macrophages that gen- erate anti-inflammatory mediators such as IL-10, TGF- and IL-1 receptor antagonist [8,9]. Both M1 and M2 macrophages have been demonstrated within human atherosclerotic lesions, with immunohistochemical analysis showing that M2 macrophages are 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.07.002