Interpreting ‘anti‐inflammatory’ cytokine responses to exercise: focus on interleukin‐10

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. figure legend Chronic inflammation is linked to the development and progression of various cardiometabolic diseases. Increased circulating concentrations of classical ‘anti‐inflammatory’ cytokines such interleukin‐10 (IL‐10) are frequently interpreted as evidence for the ability of exercise to reduce inflammation. However, there are several scenarios where circulating IL‐10 concentrations may not reflect a reduction in inflammation at the cellular level, including: (1) the ability of IL‐10 to act as an immunostimula