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      Toll-Like Receptor 4 Mediates Inflammatory Cytokine Secretion in Smooth Muscle Cells Induced by Oxidized Low-Density Lipoprotein

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          Abstract

          Oxidized low-density lipoprotein (oxLDL)-regulated secretion of inflammatory cytokines in smooth muscle cells (SMCs) is regarded as an important step in the progression of atherosclerosis; however, its underlying mechanism remains unclear. This study investigated the role of toll-like receptor 4 (TLR4) in oxLDL-induced expression of inflammatory cytokines in SMCs both in vivo and in vitro. We found that the levels of TLR4, interleukin 1-β (IL1-β), tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and matrix metalloproteinase-2 (MMP-2) expression were increased in the SMCs of atherosclerotic plaques in patients with femoral artery stenosis. In cultured primary arterial SMCs from wild type mice, oxLDL caused dose- and time-dependent increase in the expression levels of TLR4 and cytokines. These effects were significantly weakened in arterial SMCs derived from TLR4 knockout mice (TLR4−/−). Moreover, the secretion of inflammatory cytokines was blocked by TLR4-specific antibodies in primary SMCs. Ox-LDL induced activation of p38 and NFκB was also inhibited in TLR4−/− primary SMCs or when treated with TLR4-specific antibodies. These results demonstrated that TLR4 is a crucial mediator in oxLDL-induced inflammatory cytokine expression and secretion, and p38 and NFκB activation.

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          Most cited references23

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          Atherosclerosis. the road ahead.

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            Cytokines and atherosclerosis: a comprehensive review of studies in mice

            In the past few years, inflammation has emerged as a major driving force of atherosclerotic lesion development. It is now well-established that from early lesion to vulnerable plaque formation, numerous cellular and molecular inflammatory components participate in the disease process. The most prominent cells that invade in evolving lesions are monocyte-derived macrophages and T-lymphocytes. Both cell types produce a wide array of soluble inflammatory mediators (cytokines, chemokines) which are critically important in the initiation and perpetuation of the disease. This review summarizes the currently available information from mouse studies on the contribution of a specified group of cytokines expressed in atherosclerotic lesions, viz. interleukins (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, IL-20) and macrophage-associated cytokines [tumour necrosis factor-α (TNF-α); macrophage migration inhibitory factor (MIF); interferon-γ (IFN-γ); colony stimulating factors G-CSF,-M-CSF,-GM-CSF) to atherogenesis. Emphasis is put on the consistency of the effects of these cytokines, i.e. inasmuch an effect depends on the experimental approach applied (overexpression/deletion, strain, gender, dietary conditions, and disease stage). An important outcome of this survey is (i) that only for a few cytokines there is sufficient consistent data allowing classifying them as typically proatherogenic (IL-1, IL-12, IL-18, MIF, IFN-γ, TNF-α, and M-CSF) or antiatherogenic (IL-10) and (ii) that some cytokines (IL-4, IL-6 and GM-CSF) can exert pro- or anti-atherogenic effects depending on the experimental conditions. This knowledge can be used for improved early detection, prevention and treatment of atherosclerosis.
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              Toll-like receptor 4 polymorphisms and atherogenesis.

              The ability to mount a prominent inflammatory response to bacterial pathogens confers an advantage in innate immune defense but may signal an increased risk of atherosclerosis. We determined whether recently discovered genetic variants of toll-like receptor 4 (TLR4) that confer differences in the inflammatory response elicited by bacterial lipopolysaccharide are related to the development of atherosclerosis. As part of the five-year follow-up in the Bruneck (Italy) Study, we screened 810 persons in the study cohort for the TLR4 polymorphisms Asp299Gly and Thr399Ile. The extent and progression of carotid atherosclerosis were assessed by high-resolution duplex ultrasonography. As compared with subjects with wild-type TLR4, the 55 subjects with the Asp299Gly TLR4 allele had lower levels of certain proinflammatory cytokines, acute-phase reactants, and soluble adhesion molecules, such as interleukin-6 and fibrinogen. Although these subjects were found to be more susceptible to severe bacterial infections, they had a lower risk of carotid atherosclerosis (odds ratio, 0.54; 95 percent confidence interval, 0.32 to 0.98; P=0.05) and a smaller intima-media thickness in the common carotid artery (regression coefficient, -0.07; 95 percent confidence interval, -0.12 to -0.02; P=0.01). The Asp299Gly TLR4 polymorphism, which attenuates receptor signaling and diminishes the inflammatory response to gram-negative pathogens, is associated with a decreased risk of atherosclerosis. This finding is consistent with the hypothesis that innate immunity may play a part in atherogenesis. Copyright 2002 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                22 April 2014
                : 9
                : 4
                : e95935
                Affiliations
                [1 ]Department of Cardiology, Rui Jin Hospital, Medical School of Jiaotong University, Shanghai, People’s Republic of China
                [2 ]Institute of Cardiovascular Diseases, Medical School of Jiaotong University, Shanghai, People’s Republic of China
                Scuola Superiore Sant’Anna, Italy
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YL WFS. Performed the experiments: KY XJZ LJC XHL ZHL XQW. Analyzed the data: QJC LL. Wrote the paper: KY YL WFS.

                Article
                PONE-D-13-54240
                10.1371/journal.pone.0095935
                3995878
                24755612
                acb38e9d-d579-446a-98a3-1b5d70c93209
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 December 2013
                : 1 April 2014
                Page count
                Pages: 10
                Funding
                This work was supported by grants from the National Natural Science Foundation of China (30900521/H0206 and 81200204/H0215) and a grant from municipal government (10JC1410501). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Muscle Tissue
                Muscle Cells
                Cardiovascular Anatomy
                Cell Biology
                Cellular Types
                Molecular Cell Biology
                Developmental Biology
                Molecular Development
                Cytokines
                Immunology
                Clinical Immunology
                Immune System
                Physiology
                Immune Physiology
                Medicine and Health Sciences
                Cardiology
                Cardiovascular Diseases
                Valvular Diseases
                Vascular Medicine
                Atherosclerosis
                Coronary Artery Disease

                Uncategorized
                Uncategorized

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