title: Interleukin-37 suppresses the inflammatory response to protect cardiac function in old endotoxemic mice.
abstract: Myocardial inflammatory responses to endotoxemia are enhanced in old mice, which results in worse cardiac dysfunction. Anti-inflammatory cytokine interleukin (IL)-37 has a broad effect on innate immunoresponses. We hypothesized that IL-37 suppresses myocardial inflammatory responses to protect cardiac function during endotoxemia in old mice. Old (20-24month) wild-type (WT), and IL-37 transgenic (IL-37tg) mice were treated with lipopolysaccharide (LPS, 0.5mg/kg, iv) or normal saline (0.1ml/mouse, iv). Six hours later, left ventricle (LV) function was assessed using a pressure-volume microcatheter. Levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in plasma and myocardial tissue, as well as mononuclear cell density in the myocardium, were examined. Cardiac microvascular endothelial cells isolated from WT and IL-37tg mice were treated with LPS (0.2µg/ml) for 0.5-24h. Nuclear factor-kappa B (NF-κB) p65 phosphorylation was examined by immunoblotting, and MCP-1 levels in cell culture supernatant was determined using enzyme-linked immunosorbent assay. LV dysfunction in old WT endotoxemic mice was accompanied by up-regulated MCP-1, myocardial accumulation of mononuclear cells and production of TNF-α, IL-1β and IL-6. Expression of IL-37 suppressed myocardial inflammatory responses to endotoxemia in old mice, resulting in improved LV function. Treatment of old WT endotoxemic mice with recombinant IL-37 also improved LV function. In vitro experiments revealed that cardiac microvascular endothelial cells from IL-37tg mice had attenuated NF-κB activation and MCP-1 production following LPS stimulation. In conclusion, IL-37 is potent to suppress myocardial inflammation and protects against cardiac dysfunction during endotoxemia in old mice.
authors.affiliation: Departments of Surgery, University of Colorado Denver, Aurora, CO 80045, USA; Division of Cardiology, the First Affiliated Hospital, Shantou University Medical College, Shantou 515041, China.
authors.forename: Jilin
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Surgery, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Departments of Surgery, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.affiliation: Departments of Surgery, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Hui
authors.affiliation: Departments of Surgery, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.affiliation: Departments of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Departments of Surgery, University of Colorado Denver, Aurora, CO 80045, USA; Division of Cardiology, the First Affiliated Hospital, Shantou University Medical College, Shantou 515041, China. Electronic address: Xianzhong.meng@ucdenver.edu.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D016277:Ventricular Function, Left
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; C508587:IL37 protein, human; D007375:Interleukin-1; D016328:NF-kappa B; D011994:Recombinant Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018799:Intercellular Adhesion Molecule-1
keywords: Aging; Cardiac function; Cardiac microvascular endothelial cells; Endotoxemia; IL-37