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 (20–24 month) wild-type (WT), and IL-37 transgenic (IL-37tg) mice were treated with lipopolysaccharide (LPS, 0.5 mg/kg, iv) or normal saline (0.1 ml/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 (0.2 μg/ml) for 0.5–24 hours. 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.

The Effects of Selective Hematopoietic Expression of Human IL-37 on Systemic Inflammation and Atherosclerosis in LDLr-Deficient Mice

“…Despite dampening the inflammatory state of the mice, hematopoietic IL-37 expression neither reduced the atherosclerotic lesion size nor the macrophage content of the lesions in the present study. This is in seeming contrast to other recent studies where treatment with recombinant IL-37 reduced atherosclerosis development in streptozotocin-induced diabetic apolipoprotein E-deficient ( Apoe −/− ) mice [ 25 ], and protected WT mice from endotoxemia-induced cardiac dysfunction [ 26 ] and damage-induced myocardial ischaemia/reperfusion injury via a reduction in inflammatory state [ 27 ]. Two reasons may account for the lack of effect of hematopoietic IL-37 on atherosclerosis development.…”

Activation of mast cells mediates inflammatory response in psoriasis: Potential new therapeutic approach with IL‐37

“…Interleukin‐37 can protect transgenic mice against LPS treatment and stimulate the production of anti‐inflammatory cytokine IL‐10 as well as generating a greater resistance to infections, autoimmune diseases, and atherosclerosis (Li et al, ).…”

“…Interleukin-37 can protect transgenic mice against LPS treatment and stimulate the production of anti-inflammatory cytokine IL-10 as well as generating a greater resistance to infections, autoimmune diseases, and atherosclerosis (Li et al, 2017). Activated MCs generate IL-1, IL-33, and TNF which are correlated with cartilage destruction in vivo and in vitro and could be inhibited by IL-37 (Siebert, Tsoukas, & Robertson, 2015).…”

Interleukin-37: A crucial cytokine with multiple roles in disease and potentially clinical therapy (Review)

“…Expression of IL-37 suppresses LPS-induced MCP-1 and ICAM-1 production and NF-κB activation in cardiac microvascular endothelial cells (80). In addition, Xu et al found that IL-37 suppresses MPO expression and recombinant IL-37 effectively suppresses activation of the NF-κB signaling pathway, and finally results in an anti-inflammatory effect in AMI mice (77).…”