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Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):2313-2318. doi: 10.1073/pnas.1619011114. Epub 2017 Feb 13.

Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance.

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Department of Medicine, University of Colorado Denver, Aurora, CO 80045.
Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, 20132 Italy.
Department of Medicine, Radboud University Medical Center, 6525 HP Nijmegen, The Netherlands.
Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309.
Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045.
Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045.
Experimental Immunopathology, Humanitas Research Institute, Rozzano, 20089 Italy.
Department of Medicine, University of Colorado Denver, Aurora, CO 80045;


IL-1 family member interleukin 37 (IL-37) has broad antiinflammatory properties and functions as a natural suppressor of innate inflammation. In this study, we demonstrate that treatment with recombinant human IL-37 reverses the decrease in exercise performance observed during systemic inflammation. This effect was associated with a decrease in the levels of plasma and muscle cytokines, comparable in extent to that obtained upon IL-1 receptor blockade. Exogenous administration of IL-37 to healthy mice, not subjected to an inflammatory challenge, also improved exercise performance by 82% compared with vehicle-treated mice (P = 0.01). Treatment with eight daily doses of IL-37 resulted in a further 326% increase in endurance running time compared with the performance level of mice receiving vehicle (P = 0.001). These properties required the engagement of the IL-1 decoy receptor 8 (IL-1R8) and the activation of AMP-activated protein kinase (AMPK), because both inhibition of AMPK and IL-1R8 deficiency abrogated the positive effects of IL-37 on exercise performance. Mechanistically, treatment with IL-37 induced marked metabolic changes with higher levels of muscle AMPK, greater rates of oxygen consumption, and increased oxidative phosphorylation. Metabolomic analyses of plasma and muscles of mice treated with IL-37 revealed an increase in AMP/ATP ratio, reduced levels of proinflammatory mediator succinate and oxidative stress-related metabolites, as well as changes in amino acid and purine metabolism. These effects of IL-37 to limit the metabolic costs of chronic inflammation and to foster exercise tolerance provide a rationale for therapeutic use of IL-37 in the treatment of inflammation-mediated fatigue.


AMPK; fatigue; inflammation; interleukin 37; metabolism

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