Low-intensity exercise enhances expression of markers of alternative activation in circulating leukocytes: roles of PPARγ and Th2 cytokines.
OBJECTIVE
Pharmacological activation of the nuclear receptor PPARγ 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 'alternative' anti-inflammatory M2 macrophage phenotype. As we have recently shown that participation in low-intensity exercise increases PPARγ 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 10,000steps/day, three times/week). Changes in expression of PPARs and the PPARγ co-activators PGC-1α and PGC-1β; 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, TNFα, 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-1α and PGC-1β, and with downregulation of M1 markers. Moreover, plasma levels of Th2 cytokines increased after exercise, while those of Th1 cytokines decreased. However, other PPARs (PPARα; PPARβ/δ) 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 PPARγ/PGC-1α/β.


CONCLUSIONS
Given the similarities between these effects and pharmacologically induced M2 polarisation, we propose that exercise-induced PPARγ/PGC-1α/β-mediated M2 polarisation may constitute a novel anti-inflammatory benefit of low-intensity exercise.
Yakeu
G
G
Centre for Biomedical Sciences, Cardiff School of Health Sciences, University of Wales Institute Cardiff, Cardiff CF5 2YB, UK.
Butcher
L
L
Isa
S
S
Webb
R
R
Roberts
A W
AW
Thomas
A W
AW
Backx
K
K
James
P E
PE
Morris
K
K
D000328:Adult; D002454:Cell Differentiation; D015444:Exercise; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000378:metabolism*; D010641:Phenotype; D018418:Th2 Cells / Q000166:cytology*
D047495:PPAR gamma; D016753:Interleukin-10; D015847:Interleukin-4