Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 599, Issue 23, Pages 5163-5177Publisher
WILEY
DOI: 10.1113/JP281356
Keywords
inflammation; interleukin-6; immune function; macrophages; monocytes; myokines; physical activity; SHIP1; STAT3
Categories
Funding
- Michael Smith Foundation for Health Research [16890]
- Killam Accelerator Research Fellowship [AWD-018101]
- Canadian Institutes of Health Research [MOP-84539]
- Natural Sciences and Engineering Council (NSERC)
- NSERC [RGPIN-2019-05204]
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Interpreting changes in circulating cytokine concentrations as evidence for altered inflammation may overlook important functional changes in cytokine action at the tissue/cellular level, due to factors influencing cytokine function. Therefore, relying solely on changes in cytokine concentrations may miss significant alterations in inflammatory processes.
Circulating concentrations of canonically pro- and anti-inflammatory cytokines are commonly measured when evaluating the anti-inflammatory effects of exercise. An important caveat to interpreting systemic cytokine concentrations as evidence for the anti-inflammatory effects of exercise is the observed dissociation between circulating cytokine concentrations and cytokine function at the tissue/cellular level. The dichotomization of cytokines as pro- or anti-inflammatory also overlooks the context dependence of cytokine function, which can vary depending on the physiological state being studied, the cytokine's cellular source/target, and magnitude of cytokine responses. We re-evaluate our current understanding of anti-inflammatory cytokine responses to exercise by highlighting nuances surrounding the interpretation of altered systemic cytokine concentrations as evidence for changes in inflammatory processes occurring at the tissue/cellular level. We highlight the lesser known pro-inflammatory and immunostimulatory actions of the prototypical anti-inflammatory cytokine, interleukin (IL)-10, including the potentiation of interferon gamma production during endotoxaemia, CD8(+) T cell activation in tumour bearing rodents and cancer patients in vivo, and CD8(+) T lymphocyte and natural killer cell activation in vitro. IL-10's more well-established anti-inflammatory actions can also be blunted following exercise training and under chronic inflammatory states such as type 2 diabetes (T2D) independently of circulating IL-10 concentrations. The resistance to IL-10's anti-inflammatory action in T2D coincides with blunted STAT3 phosphorylation and can be restored with small-molecule activators of IL-10 signalling, highlighting potential therapeutic avenues for restoring IL-10 action. We posit that inferences based on altered circulating cytokine concentrations alone can miss important functional changes in cytokine action occurring at the tissue/cellular level.
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