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

Autor:	Cavalli G; 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., Justice JN; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309., Boyle KE; Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045., D'Alessandro A; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045., Eisenmesser EZ; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045., Herrera JJ; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309., Hansen KC; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045., Nemkov T; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045., Stienstra R; Department of Medicine, Radboud University Medical Center, 6525 HP Nijmegen, The Netherlands., Garlanda C; Experimental Immunopathology, Humanitas Research Institute, Rozzano, 20089 Italy., Mantovani A; Experimental Immunopathology, Humanitas Research Institute, Rozzano, 20089 Italy., Seals DR; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309., Dagna L; 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., Joosten LA; Department of Medicine, Radboud University Medical Center, 6525 HP Nijmegen, The Netherlands., Ballak DB; Department of Medicine, University of Colorado Denver, Aurora, CO 80045.; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309., Dinarello CA; Department of Medicine, University of Colorado Denver, Aurora, CO 80045; cdinare333@aol.com.; Department of Medicine, Radboud University Medical Center, 6525 HP Nijmegen, The Netherlands.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Feb 28; Vol. 114 (9), pp. 2313-2318. Date of Electronic Publication: 2017 Feb 13.
DOI:	10.1073/pnas.1619011114
Abstrakt:	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.
Databáze:	MEDLINE
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