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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.

Author information

1
Department of Medicine, University of Colorado Denver, Aurora, CO 80045.
2
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.
3
Department of Medicine, Radboud University Medical Center, 6525 HP Nijmegen, The Netherlands.
4
Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309.
5
Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045.
6
Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045.
7
Experimental Immunopathology, Humanitas Research Institute, Rozzano, 20089 Italy.
8
Department of Medicine, University of Colorado Denver, Aurora, CO 80045; cdinare333@aol.com.

Abstract

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.

KEYWORDS:

AMPK; fatigue; inflammation; interleukin 37; metabolism

PMID:
28193888
PMCID:
PMC5338542
DOI:
10.1073/pnas.1619011114
[Indexed for MEDLINE]
Free PMC Article

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