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      Laquinimod Protects Against TNF-α-Induced Attachment of Monocytes to Human Aortic Endothelial Cells (HAECs) by Increasing the Expression of KLF2

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          Abstract

          Introduction

          As a worldwide health issue, the treatment and prevention of atherosclerosis present an important goal. Increased levels of proinflammatory cytokines such as TNF-α-associated chronic inflammatory response cause endothelial cells to lose their ability to regulate vascular function. Lipid-laden immune cells are recruited to the endothelium where they adhere to the endothelial wall and invade the intimal space, thereby leading to the development of atherosclerotic lesions, fatty plaques, and thickening of the arterial wall. In the present study, for the first time, we investigated the effects of laquinimod, an immunomodulatory agent used for the treatment of multiple sclerosis, on human aortic endothelial in a TNF-α-induced atherosclerotic microenvironment. At present, the mechanism of action of laquinimod is not well defined.

          Methods

          The effects of laquinimod on the gene expression of IL-6, MCP-1, VCAM-1, E-selectin, and KLF2 were measured by real-time PCR. ELISA assay was used to determine protein secretion and expression. Phosphorylation of ERK5 and the protein level of KLF2 were measured by Western blot analysis. The attachment of monocytes to endothelial cells was assayed by calcein-AM staining and fluorescent microscopy.

          Results

          Our findings demonstrate that laquinimod reduced the expression of key inflammatory cytokines and chemokines, including IL-6, MCP-1, and HMGB1. We further demonstrate that laquinimod significantly reduced the attachment of monocytes to endothelial cells, which is mediated through reduced expression of the cellular adhesion molecules VCAM-1 and E-selectin. Here, we found that laquinimod could significantly increase the expression of KLF2 through activation of ERK5 signaling. The results of our KLF2 knockdown experiment confirm that the effects of laquinimod observed in vitro are dependent on KLF2 expression.

          Conclusion

          Together, these findings suggest a potential antiatherosclerotic capacity of laquinimod. Further research will elucidate the underlying mechanisms.

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          Most cited references 28

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          Macrophage subsets in atherosclerosis.

          Macrophage accumulation within the vascular wall is a hallmark of atherosclerosis. In atherosclerotic lesions, macrophages respond to various environmental stimuli, such as modified lipids, cytokines, and senescent erythrocytes, which can modify their functional phenotypes. The results of studies on human atherosclerotic plaques demonstrate that the relative proportions of macrophage subsets within a plaque might be a better indicator of plaque phenotype and stability than the total number of macrophages. Understanding the function of specific macrophage subsets and their contribution to the composition and growth of atherosclerotic plaques would aid the identification of novel strategies to delay or halt the development of the disease and its associated pathophysiological consequences. However, most studies aimed at characterizing the phenotypes of human macrophages are performed in vitro and, therefore, their functional relevance to human pathology remains uncertain. In this Review, the diverse range of macrophage phenotypes in atherosclerotic lesions and their potential roles in both plaque progression and stability are discussed, with an emphasis on human pathology.
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            Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis.

            Two key features of atherosclerotic plaques that precipitate acute atherothrombotic vascular occlusion ("vulnerable plaques") are abundant inflammatory mediators and macrophages with excess unesterified, or "free," cholesterol (FC). Herein we show that FC accumulation in macrophages leads to the induction and secretion of two inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). The increases in TNF-alpha and IL-6 mRNA and protein were mediated by FC-induced activation of the IkappaB kinase/NF-kappaB pathway as well as activation of MKK3/p38, Erk1/2, and JNK1/2 mitogen-activated protein kinases (MAPK). Activation of IkappaB kinase and JNK1/2 was needed for the induction of both cytokines. However, MKK3/p38 signaling was specifically involved in TNF-alpha induction, and Erk1/2 signaling was required for IL-6. Most interestingly, activation of all of the signaling pathways and induction of both cytokines required cholesterol trafficking to the endoplasmic reticulum (ER). The CHOP branch of the unfolded protein response, an ER stress pathway, was required for Erk1/2 activation and IL-6 induction. In contrast, one or more other ER-related pathways were responsible for activation of p38, JNK1/2, and IkappaB kinase/NF-kappaB and for the induction of TNF-alpha. These data suggest a novel scenario in which cytokines are induced in macrophages by endogenous cellular events triggered by excess ER cholesterol rather than by exogenous immune cell mediators. Moreover, this model may help explain the relationship between FC accumulation and inflammation in vulnerable plaques.
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              • Article: not found

              Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                30 April 2020
                2020
                : 14
                : 1683-1691
                Affiliations
                [1 ]Department of Cardiovascular Medicine, The Third Hospital of Jilin University , Changchun 130033, People’s Republic of China
                [2 ]Jilin Provincial Precision Medicine Key Laboratory for Cardiovascular Genetic Diagnosis, The Third Hospital of Jilin University , Changchun 130033, People’s Republic of China
                [3 ]Jilin Provincial Engineering Laboratory for Endothelial Function and Genetic Diagnosis of Cardiovascular Disease, The Third Hospital of Jilin University , Changchun 130033, People’s Republic of China
                Author notes
                Correspondence: Zhongyu Wang Department of Cardiovascular Medicine, The Third Hospital of Jilin University , No. 126, Xiantai Street, Changchun130033, People’s Republic of ChinaTel +86-431-84995258 Email jldxwzy@jlu.edu.cn
                Article
                243666
                10.2147/DDDT.S243666
                7222522
                © 2020 Jiang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 8, References: 36, Pages: 9
                Categories
                Original Research

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