Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Zeng, Qingchun; Song, Rui; Fullerton, David A.; Ao, Lihua; Zhai, Yufeng; Li, S.; Ballak, Dov B.; Cleveland, Joseph C.; Reece, T. Brett; McKinsey, Timothy A.; Xu, Dingli; Dinarello, Charles A.; Meng, Xianzhong

doi:10.1073/pnas.1619667114

Cited by 93 publications

(93 citation statements)

References 43 publications

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“…In a recent study, we observed that recombinant IL-37 inhibits the production of pro-osteogenic mediators (bone morphogenic protein 2 and alkaline phosphatase) in human AVICs exposed to TLR2 and TLR4 agonists, and that the antiosteogenic effect of IL-37 is due to inhibition of ERK1/2 and NF-κB (23). The antiinflammatory effect of IL-37 observed in the present study is correlated with its inhibitory effect on NF-κB activation.…”

Section: Disclosuresupporting

confidence: 78%

“…IL-37 mRNA and protein are present in tissues of patients with inflammatory and autoimmune diseases, such as rheumatoid arthritis, atherosclerosis, Crohn's disease and lupus (21). In cells that overexpress IL-37, the inflammatory responses to a variety of proinflammatory stimuli are markedly attenuated (21,23). More important, mice carrying the human IL-37 gene (IL-37 transgenic mice) are protected against aortic valve lesions induced by proinflammatory stimuli (23).…”

Section: Introductionmentioning

confidence: 99%

“…In cells that overexpress IL-37, the inflammatory responses to a variety of proinflammatory stimuli are markedly attenuated (21,23). More important, mice carrying the human IL-37 gene (IL-37 transgenic mice) are protected against aortic valve lesions induced by proinflammatory stimuli (23). However, it remains unclear whether IL-37 has an effect on the inflammatory responses to TLRs in human AVICs.…”

Section: Introductionmentioning

confidence: 99%

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IL-37 Suppresses MyD88-mediated Inflammatory Responses in Human Aortic Valve Interstitial Cells

Zhan¹,

Zeng²,

Song³

et al. 2017

Mol Med

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Calcific aortic valve disease (CAVD) is common among the elderly, and aortic valve interstitial cells (AVICs) exhibit unique inflammatory and osteogenic responses to proinflammatory stimulation, which plays an important role in valvular fibrosis and calcification. Thus, suppression of AVIC proinflammatory response may have therapeutic utility for the prevention of CAVD progression. Interleukin (IL)-37, an antiinflammatory cytokine, reduces tissue inflammation. This study aimed to test the hypothesis that IL-37 suppresses human AVIC inflammatory responses to Toll-like receptor (TLR) agonists. Human AVICs were exposed to Pam3CSK4, poly(I:C) and lipopolysaccharide in the presence and absence of recombinant human IL-37. Stimulation of TLR4 increased the production of intercellular adhesion molecule-1, IL-6, IL-8 and monocyte chemoattractant protein-1. Knockdown of myeloid differentiation factor 88 (MyD88) or TIR-domain-containing adaptor-inducing interferon-β differentially affected inflammatory mediator production following TLR4 stimulation. IL-37 reduced production of these inflammatory mediators induced by TLR4. Moreover, knockdown of IL-37 enhanced induction of these mediators by TLR4. IL-37 also suppressed inflammatory mediator production induced by the MyD88-dependent TLR2, but had no effect on the inflammatory responses to the TRIF-dependent TLR3. Furthermore, IL-37 inhibited NF-κB activation induced by TLR2 or TLR4 through a mechanism dependent of IL-18 receptor α-chain. Activation of TLR2, TLR3 or TLR4 upregulates the production of inflammatory mediators in human AVICs. IL-37 suppresses MyD88-mediated responses to reduce inflammatory mediator production following stimulation of TLR2 and TLR4. This antiinflammatory cytokine may be useful for suppression of aortic valve inflammation elicited by MyD88-dependent TLR signaling.

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Section: Disclosuresupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IL-37 Suppresses MyD88-mediated Inflammatory Responses in Human Aortic Valve Interstitial Cells

Zhan¹,

Zeng²,

Song³

et al. 2017

Mol Med

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“…Moreover, IL-1b induces BMP2 and BMP4 that have been shown to reduce beta-cell function. By reducing levels of IL-1b and therefore BMP2, IL-37 may therefore improve betacell function (48). Together, this suggests that administration of IL-37 can reverse HFD-induced metabolic stress upon the islets, probably via a reduction of infiltrating macrophages and thereby production of beta-cell cytotoxic IL-1 and induction of BMP2 resulting in improved insulin homeostasis.…”

Section: Discussionmentioning

confidence: 91%

Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue

Ballak

Cavalli

et al. 2018

Journal of Biological Chemistry

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Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control. Transgenic mice expressing human interleukin 37 (IL-37), an anti-inflammatory cytokine of the IL-1 family, are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. Wildtype mice were fed a HFD for 22 weeks and then treated daily with IL-37 (1 µg/mouse) during the last 2 weeks. Compared with vehicle only-treated mice, IL-37-treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance, and insulin content of the islets. The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1β, tumor necrosis factor α (TNFα), and C-X-C motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1β, TNFα, and IL-6 and reduced intracellular levels of IL-1α in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37-treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pM IL-37 reduced spontaneous release of TNFα and 50% of lipopolysaccharide-induced TNFα. These findings indicate that IL-37's antiinflammatory effects can ameliorate established metabolic disturbances during obesity.

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“…Many studies show that inhibition of NF-κB reduces the release of inflammatory cytokines and inducible nitric oxide synthase (iNOS), and protects mice against lethal endotoxemia [12]. Our recent study demonstrates that IL-37 inhibits NF-κB activation induced by oxidized low-density lipoprotein in human aortic valve cells [40]. The in vitro data in the present study indicate that IL-37 represses the NF-κB response to TLR4 stimulation to modulate MCP-1 production in cardiac microvascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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

Zhai

et al. 2017

Cytokine

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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.

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Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Cited by 93 publications

References 43 publications

IL-37 Suppresses MyD88-mediated Inflammatory Responses in Human Aortic Valve Interstitial Cells

IL-37 Suppresses MyD88-mediated Inflammatory Responses in Human Aortic Valve Interstitial Cells

Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue

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

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