Interleukin-1 promotes proliferation of vascular smooth muscle cells in coordination with PDGF or a monocyte derived growth factor

doi:10.1016/0014-4827(89)90104-3

Experimental Cell Research

Volume 181, Issue 2, April 1989, Pages 475-482

https://doi.org/10.1016/0014-4827(89)90104-3 Get rights and content

Abstract

We report that interleukin-1 (IL-1) potentiates the proliferation of vascular smooth muscle cells. Growth of early passage smooth muscle cells was not significantly affected by IL-1 alone. Treatment with IL-1 together with the platelet derived growth factor (PDGF) or another polypeptide growth factor derived from mitogen activated human monocytes (MDGF) resulted in a significant enhancement of cell growth over either PDGF or MDGF alone. DNA synthesis was enhanced only marginally (30–40%) in quiescent cultures treated with an optimal concentration of IL-1 alone. In the presence of 5 units/ml of PDGF or MDGF, IL-1 produced about six- to eightfold higher DNA synthesis than the untreated cultures. Induction of DNA synthesis was linear between 0.1 and 1.0 pM IL-1, dependent on PDGF concentration, and was effectively neutralized by monoclonal antibodies against IL-1β. The growth promoting activity of IL-1 was extremely potent producing half-maximum stimulation at a concentration of 0.5 pM. These results suggest that IL-1 may play an important role in the modulation of growth and other activities of vascular smooth muscle cells. These observations are especially important with regard to defining the potential macrophage derived mediators contributing to vascular cell proliferation during inflammation and the pathogenesis of atherosclerosis. It is shown here that elicitation of IL-1 induced growth response requires a coordinated action with another priming growth factor such as PDGF. In this regard, IL-1 mediated proliferation of smooth muscle cells may have analogy with the IL-1 mediated T-cell activation and IL-2 production where concerted actions of antigen/mitogen and IL-1 are required.

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Mendelian randomization studies are consistent with the thesis that IL-6 does indeed play a mediating role in cardiovascular (CV) disease [10,11]. With respect to IL-1β, this cytokine promotes pro-inflammatory behavior in vascular endothelium, and stimulates vascular smooth muscle proliferation [12–17]. In vivo, exogenous IL-1β promotes coronary intimal lesions, whereas ApoE-deficient mice in which IL-1β is also knocked out, or in which monoclonal antibodies are administered to target this cytokine, are less prone to atherogenesis [18–21].
The results of multi-center trials of B vitamin supplementation reveal that, whereas moderately elevated homocysteine predicts increased risk for coronary disease, it does not play a mediating role in this regard. This essay proposes that interleukin-1beta can act on hepatocytes to suppress expression of the hepatocyte-specific forms of methionine adenosyltransferase; this in turn can be expected to decrease hepatic activity of cystathionine-β-synthase, leading to an increase in plasma homocysteine. It is further proposed that interleukin-1beta (IL-1β) is a true mediating risk factor for cardiovascular disease, and that elevated homocysteine predicts coronary disease because it can serve as a marker for increased IL-1β activity. Potent statin therapy may decrease IL-1β production by suppressing inflammasome activation – thereby accounting for the marked protection from cardiovascular events observed in the classic JUPITER study, in which the enrolled subjects had low-normal Low Density Lipoprotein cholesterol but elevated C-reactive protein.
Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial)
2016, Contemporary Clinical Trials
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IL-1α also plays a critical role in chronic inflammation, and recent studies suggest that IL-1α may regulate IL-1β secretion [6–8,14]. It is intriguing that, IL-1 signaling drives proliferation of smooth muscle cells (SMC) and myofibroblast formation [2,3,44], a pathologic hallmark of subacute arteriopathy seen in KD. Recent genome wide association studies have identified several risk loci and polymorphisms in patients with KD.
Although Kawasaki disease (KD) is the most common cause of acquired heart disease in children and may result in coronary artery aneurysms (CAA) with an attendant risk of myocardial infarction, there is no recommended therapy to halt progression of arterial wall damage and prevent aneurysm formation in the acute phase of the vasculitis. While intravenous immunoglobulin (IVIG) reduces the risk of CAA, up to 20% of KD patients are IVIG resistant and have a higher risk for developing CAA. The IL-1 pro-inflammatory pathway is upregulated in children with acute KD and plays a critical role in the experimental animal model of KD. Thus, IL-1 is a logical therapeutic target.
The goal of this study is to determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of anakinra, a recombinant human IL-1 receptor antagonist, in acute KD patients with coronary artery abnormalities on the baseline echocardiogram.
This is a two-center dose-escalation Phase I/IIa trial in 30 acute KD patients ≥ 8 months old with a coronary artery Z score ≥ 3.0 in the right coronary artery and/or left anterior descending artery or an aneurysm. Subjects will receive a 2- to 6-week course of anakinra by daily subcutaneous injection and will be assessed for resolution of inflammation and dose limiting toxicities (leukopenia, anaphylactoid reaction, or severe infection).
The safety and tolerability of blocking both IL-1α and Il-1β by anakinra will be evaluated as a strategy to prevent or attenuate coronary artery damage in infants and children with acute KD.
Trial registration: Clinical Trials.gov # NCT02179853, registered June 28, 2014
Monocyte/macrophage cytokine activity regulates vascular smooth muscle cell function within a degradable polyurethane scaffold
2014, Acta Biomaterialia
Citation Excerpt :
This increase in DNA was not the result of residual monocytes remaining in the MCM, as the MCM was acellular (Fig. 1B), but was hypothesized to be due to an increase in VSMC growth supported by the presence of predominantly monocyte/MDM-released factors. Monocyte co-culture with VSMCs has previously been shown to support VSMC proliferation [37,38]. However, since other studies have contrastingly shown that monocyte co-culture can also inhibit VSMC proliferation [19,21], this effect could be dependent on the differential activation state of the macrophage within the M1 to M2 spectrum when cultured on different biomaterial substrates or in different microenvironments [23].
Tissue engineering strategies rely on the ability to promote cell proliferation and migration into porous biomaterial constructs, as well as to support specific phenotypic states of the cells in vitro. The present study investigated the use of released factors from monocytes and their derived macrophages (MDM) and the mechanism by which they regulate vascular smooth muscle cell (VSMC) response in a VSMC–monocyte co-culture system within a porous degradable polyurethane (D-PHI) scaffold. VSMCs cultured in monocyte/MDM-conditioned medium (MCM), generated from the culture of monocytes/MDM on D-PHI scaffolds for up to 28 days, similarly affected VSMC contractile marker expression, growth and three-dimensional migration when compared to direct VSMC–monocyte co-culture. Monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) were identified as two cytokines present in MCM, at concentrations that have previously been shown to influence VSMC phenotype. VSMCs cultured alone on D-PHI scaffolds and exposed to MCP-1 (5 ng ml⁻¹) or IL-6 (1 ng ml⁻¹) for 7 days experienced a suppression in contractile marker expression (with MCP-1 or IL-6) and increased growth (with MCP-1) compared to no cytokine medium supplementation. These effects were also observed in VSMC–monocyte co-culture on D-PHI. Neutralization of IL-6, but not MCP-1, was subsequently shown to decrease VSMC growth and enhance calponin expression for VSMC–monocyte co-cultures on D-PHI scaffolds for 7 days, implying that IL-6 mediates VSMC response in monocyte–VSMC co-cultures. This study highlights the use of monocytes and their derived macrophages in conjunction with immunomodulatory biomaterials, such as D-PHI, as agents for regulating VSMC response, and demonstrates the importance of monocyte/MDM-released factors, such as IL-6 in particular, in this process.
Reduced systemic inflammatory response to implantation of sirolimus-eluting stents in patients with stable coronary artery disease
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Citation Excerpt :
An early increase in IL-6 has been observed after stenting [19] and has been shown to play a crucial role in late restenosis [5,20] by inducing other cytokines, growth factors and mitogens [21,22]. IL-1β has a distinct role in neointimal formation and smooth muscle cell proliferation [23]. Serum levels of this substance are reported to be increased in patients who develop restenosis, while patients without restenosis show a decrease 48 h after PCI and intracoronary stent implantation [6].
Stent implantation causes significant injury to the vascular wall, resulting in inflammatory activation. Although sirolimus-eluting stents (SES) have anti-inflammatory properties, their effect on periprocedural systemic inflammatory response has not been sufficiently investigated. Eighty-one patients with stable coronary artery disease involving severe stenosis of one major epicardial coronary artery underwent coronary angioplasty with stent implantation and randomly received either SES or bare metal stents (BMS). Blood samples were taken 24 h before, at 24 h, 48 h and 1 month after the angioplasty and levels of high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) were determined. HsCRP after BMS implantation increased over 24 h (p < 0.001) and then remained steady, as did IL-6 and IL-1β similarly. In contrast, their levels in SES patients decreased to below baseline by the end of the month. MCP-1 levels increased by the end of 1 month (p < 0.001) in the BMS group, whereas in SES they steadily decreased, becoming significantly lower than baseline from 48 h (p = 0.015). In conclusion, patients with SES exhibit an attenuation of the postprocedural systemic inflammatory activation during a 1-month follow-up after stent implantation. This might partially explain the reduced restenosis rate associated with SES.
Chapter 11 Disruption of CREB regulated of gene expression in diabetes
2006, Advances in Molecular and Cellular Endocrinology
Citation Excerpt :
Thus, increase PPARγ expression is thought to limit excessive vascular remodeling in atherosclerosis [63–67]. One of the actions of IL-1β is to increase the expression of PDGFRα and enhance the release of PDGF-AA from SMC [68–71]. Thus, cytokines augment PDGF action in the vasculature by increasing both PDGFRα ligand and receptor.
Cardiovascular disease it is the leading cause of death in diabetes. In light of this, diabetes has recently been named and a cardiovascular disease equivalent. The molecular mechanisms that place persons with diabetes at excess vascular risk are numerous, including dyslipidemia, hypertension, hyperglycemia chronic inflammation and oxidative stress. These different factors place the diabetic vasculature in a state of chronic metabolic stress and this stress leads to vascular dysfunction. Our laboratory has focused on gaining a better understanding of the impact of diabetes and insulin resistance (IR) upon vascular smooth muscle cell gene regulation. Specifically, we have observed that the transcription factor CREB (cAMP response element binding protein) is critical for the maintenance of healthy quiescent (contractile and non-proliferative) vascular smooth muscle cell (SMC) function. In rodent models of diabetes and IR there is decreased expression of CREB protein in the vasculature. Loss of vascular CREB expression is associated with simultaneous increased expression of pro-atherogenic transcriptional regulators, such as NF-kB and C/EBP delta (CCAAT enhancer binding protein). This imbalance promotes SMC activation (proliferation, migration, matrix production and apoptosis) and may be important for excess vascular disease in diabetes. The evidence for CREB regulation of SMC function and its disruption in models of diabetes and atherosclerosis will be discussed in this chapter.
In addition to macrovascular disease, many other target organs are injured by the metabolic stress of diabetes including pancreatic beta cells (which contribute to disease progression) and cardiac and neuronal cells (which contribute to complications). We have identified a pattern of changes in gene regulation, loss of CREB function and augmentation of stress induced gene expression, that may contribute to the multi-organ dysfunction observed in diabetes.
Peroxisome Proliferator-activated Receptor-γ Activation Inhibits Interleukin-1β-mediated Platelet-derived Growth Factor-α Receptor Gene Expression via CCAAT/Enhancer-binding Protein-δ in Vascular Smooth Muscle Cells
2001, Journal of Biological Chemistry
Citation Excerpt :
These results reveal a new role of PPARγ activators on VSMC growth and proliferation and also provide us with important information to understand the underlying mechanism in the pathogenesis and progression of atherosclerosis and restenosis. Previous studies (9-11) have shown that the mitogenic response of IL-1β for fibroblasts and VSMCs is mediated by an indirect pathway, causing the release of endogenous PDGFs, especially PDGF-AA, via an autocrine or paracrine loop. Because the action of PDGF-AA is mediated by its specific receptor, PDGFαR, there is a possibility that it becomes a therapeutic target to control PDGFαR expression in the proliferative VSMCs of atherosclerotic lesions.
CCAAT/enhancer-binding protein (C/EBP)-binding motifs have been identified in the promoter regions of interleukin (IL)-6, tumor necrosis factor-α, and platelet-derived growth factor-α receptor (PDGFαR). Recently, peroxisome proliferator-activated receptors (PPARs) have been suggested to be important immunomodulatory mediators. Although many studies have demonstrated that the interaction between C/EBPs and PPARs plays a central role in lipid metabolism, expression and function of these factors are unknown in vascular smooth muscle cells (VSMCs). In the present study, we clarified a functional relationship between C/EBPs and PPARγ in the regulation of IL-1β-induced PDGFαR expression in VSMCs. PPARγ activators, troglitazone and 15-deoxy-Δ^12,14-prostaglandin J₂, inhibited IL-1β-induced PDGFαR expression and suppressed PDGF-induced proliferation activity of VSMCs. Electromobility shift and supershift assays for a C/EBP motif in the PDGFαR promoter region revealed that PPARγ activators suppressed IL-1β-induced DNA binding activity of C/EBPδ and β. PPARγ activators also suppressed IL-1β-induced C/EBPδ expression. In contrast, overexpression of C/EBPδ reversed the suppressive effect of PPARγ activators on PDGFαR expression almost completely. From these results, we conclude that the inhibitory effect of PPARγ activators on PDGFαR expression is mainly mediated by C/EBPδ suppression. Regulation of C/EBPδ by PPARγ activators probably plays critical roles in modulating inflammatory responses in the arterial wall.

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Regular articleInterleukin-1 promotes proliferation of vascular smooth muscle cells in coordination with PDGF or a monocyte derived growth factor

Abstract

J. Clin. Invest

J. Immunol

J. Exp. Med

J. Exp. Med

Science

J. Immunol

J. Immunol

J. Exp. Med

New Engl. J. Med

Lymphokine Res

Regular article
Interleukin-1 promotes proliferation of vascular smooth muscle cells in coordination with PDGF or a monocyte derived growth factor