Interleukin-37 suppresses the inflammatory response to protect cardiac function in old endotoxemic mice

• Published in: Cytokine (Philadelphia, Pa.) Vol. 95; pp. 55 - 63
• Main Authors: Li, Jilin, Zhai, Yufeng, Ao, Lihua, Hui, Haipeng, Fullerton, David A., Dinarello, Charles A., Meng, Xianzhong
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-07-2017
• Subjects: Aging; Aging - physiology; Animals; Cardiac function; Cardiac microvascular endothelial cells; Cells, Cultured; Chemokine CCL2 - metabolism; Cytokines - metabolism; Endothelium, Vascular - metabolism; Endotoxemia; Endotoxemia - metabolism; Endotoxemia - pathology; Endotoxemia - physiopathology; IL-37; Intercellular Adhesion Molecule-1 - metabolism; Interleukin-1 - genetics; Interleukin-1 - physiology; Male; Mice, Inbred C57BL; Mice, Transgenic; Myocardium - cytology; Myocardium - metabolism; NF-kappa B - metabolism; Recombinant Proteins - pharmacology; Toll-Like Receptor 4 - metabolism; Ventricular Function, Left; NF-κB; MCP-1; IL; TNF-α; MIP; Cardiac function; Aging; IL-37; TLR; Cardiac microvascular endothelial cells; LPS; Endotoxemia
• DOI: 10.1016/j.cyto.2017.02.008
• EISSN: 1096-0023
• ISSN: 1043-4666

•IL-37 protects against cardiac dysfunction in old mice during endotoxemia.•Endotoxemic old IL-37tg mice have reduced myocardial inflammation.•IL-37 inhibits NF-κB activation in cardiac cells exposed to endotoxin.•IL-37 blocks endotoxin-induced inflammatory responses in cardiac cells.
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.