title: Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance.
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.
authors.affiliation: 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.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cavalli
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309.
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Justice
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Boyle
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Angelo
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Elan Z
authors.initials: EZ
authors.lastname: Eisenmesser
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Herrera
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Kirk C
authors.initials: KC
authors.lastname: Hansen
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Travis
authors.initials: T
authors.lastname: Nemkov
authors.affiliation: Department of Medicine, Radboud University Medical Center, 6525 HP Nijmegen, The Netherlands.
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.affiliation: Experimental Immunopathology, Humanitas Research Institute, Rozzano, 20089 Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.affiliation: Experimental Immunopathology, Humanitas Research Institute, Rozzano, 20089 Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
authors.affiliation: 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.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Dagna
authors.affiliation: Department of Medicine, Radboud University Medical Center, 6525 HP Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045.|Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309.
authors.forename: Dov B
authors.initials: DB
authors.lastname: Ballak
authors.affiliation: 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.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010805:Physical Conditioning, Animal / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D045442:Rotarod Performance Test; D012420:Running / Q000502:physiology
chemical_list: C508587:IL37 protein, human; D007375:Interleukin-1; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; C484529:SIGIRR protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: AMPK; fatigue; inflammation; interleukin 37; metabolism