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      Elevation of serum CXCL16 level correlates well with atherosclerotic ischemic stroke

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          Abstract

          Introduction

          Currently there are no reliable biological markers for ischemic stroke. The novel chemokine CXCL16 is known to be involved in the development of atherosclerosis. Nevertheless, the real role of CXCL16 in atherosclerotic disorders remains uncertain. The goal of our study was to investigate the associations between serum-soluble CXCL16 level and atherosclerotic ischemic stroke, including large artery atherosclerosis (LAA) and small artery occlusion (SAO) subtypes, and to explore whether elevation in CXCL16 levels is correlated with the severity of large arterial stenosis.

          Material and methods

          The study recruited 227 subjects, including 74 controls and 153 consecutive patients with acute ischemic stroke from atherosclerosis of the carotid artery. The etiology of the acute ischemic strokes was classified into LAA ( n = 86) subtype and SAO ( n = 67) subtype according to the TOAST criteria, and the severity of carotid artery stenosis was assessed by the NASCET criteria. Serum-soluble CXCL16 concentration was measured by enzyme-linked immunosorbent assay.

          Results

          Serum CXCL16 concentrations were significantly increased in both LAA (2.36 ng/ml) and SAO subtypes (2.13 ng/ml) when compared to that of the controls (2.04 ng/ml, p < 0.01 and p < 0.05, respectively), and it was significantly elevated in LAA subtype than in SAO subtype ( p < 0.05). However, significant differences in CXCL16 levels between the high-grade stenosis group (2.36 ng/ml) and moderate-grade stenosis group (2.24 ng/ml) of LAA subtype were not found ( p > 0.05). A correlation of serum levels of CXCL16 with serum levels of hs-CRP, fibrinogen and lipid parameters was not observed ( p > 0.05).

          Conclusions

          Increased serum level of soluble CXCL16 was independently associated with atherosclerotic ischemic stroke, particularly LAA subtype.

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          Most cited references21

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          The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10.

          The novel CXC-chemokine ligand 16 (CXCL16) functions as transmembrane adhesion molecule on the surface of APCs and as a soluble chemoattractant for activated T cells. In this study, we elucidate the mechanism responsible for the conversion of the transmembrane molecule into a soluble chemokine and provide evidence for the expression and shedding of CXCL16 by fibroblasts and vascular cells. By transfection of human and murine CXCL16 in different cell lines, we show that soluble CXCL16 is constitutively generated by proteolytic cleavage of transmembrane CXCL16 resulting in reduced surface expression of the transmembrane molecule. Inhibition experiments with selective hydroxamate inhibitors against the disintegrin-like metalloproteinases a disintegrin and metalloproteinase domain (ADAM)10 and ADAM17 suggest that ADAM10, but not ADAM17, is involved in constitutive CXCL16 cleavage. In addition, the constitutive cleavage of transfected human CXCL16 was markedly reduced in embryonic fibroblasts generated from ADAM10-deficient mice. By induction of murine CXCL16 in ADAM10-deficient fibroblasts with IFN-gamma and TNF-alpha, we show that endogenous ADAM10 is indeed involved in the release of endogenous CXCL16. Finally, the shedding of endogenous CXCL16 could be reconstituted by retransfection of ADAM10-deficient cells with ADAM10. Analyzing the expression and release of CXCXL16 by cultured vascular cells, we found that IFN-gamma and TNF-alpha synergize to induce CXCL16 mRNA. The constitutive shedding of CXCL16 from the endothelial cell surface is blocked by inhibitors of ADAM10 and is independent of additional inhibition of ADAM17. Hence, during inflammation in the vasculature, ADAM10 may act as a CXCL16 sheddase and thereby finely control the expression and function of CXCL16 in the inflamed tissue.
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            IL-6: an early marker for outcome in acute ischemic stroke.

            Inflammation plays an important role in the pathophysiology of stroke. We correlated interleukin (IL)-6, IL-10, C-reactive protein (CRP) and T-lymphocyte subtype levels in acute ischemic stroke patients with stroke volume and clinical outcome. Blood samples were obtained from 11 patients at defined intervals during 1 year. Nine healthy age-matched subjects served as controls. IL-6, IL-10 and CRP were quantified by enzyme-linked immunosorbent assay and T lymphocytes by flow cytometry. Volume measurement was carried out by computed tomography or magnetic resonance imaging and clinical outcome was scored by the European stroke scale (ESS) and Barthel index (BI). IL-6 levels were increased in the acute phase of stroke compared with healthy controls (P = 0.002) and correlated with larger stroke volume (P = 0.012) and less favorable prognosis after 1 year, measured by ESS (P = 0.014) and BI (P = 0.006). IL-10, CRP and T-lymphocyte subtypes in the acute phase were not correlated with stroke volume or clinical outcome. IL-6 seems to be a robust early marker for outcome in acute ischemic stroke.
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              Cutting edge: profile of chemokine receptor expression on human plasma cells accounts for their efficient recruitment to target tissues.

              We systematically examined the repertoire of chemokine receptors expressed by human plasma cells. Fresh bone marrow plasma cells and myeloma cells consistently expressed CXCR4, CXCR6, CCR10, and CCR3. Accordingly, plasma cells responded to their respective ligands in chemotaxis and very late Ag-4-dependent cell adhesion to fibronectin. Immobilized CXC chemokine ligand (CXCL)16, a novel transmembrane-type chemokine and CXCR6 ligand, also directly induced adhesion of plasma cells without requiring G(alpha i) signaling or divalent cations. Furthermore, we revealed consistent expression of CXCL12 (CXCR4 ligand), CXCL16 (CXCR6 ligand), and CC chemokine ligand 28 (CCR10 and CCR3 ligand) in tissues enriched with plasma cells including bone marrow, and constitutive expression of CXCL12, CXCL16, and CC chemokine ligand 28 by cultured human bone marrow stromal cells. Collectively, plasma cells are likely to be recruited to bone marrow and other target tissues via CXCR4, CXCR6, CCR10, and CCR3. CXCR6 may also contribute to tissue localization of plasma cells through its direct binding to membrane-anchored CXCL16.
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                Author and article information

                Journal
                Arch Med Sci
                Arch Med Sci
                AMS
                Archives of Medical Science : AMS
                Termedia Publishing House
                1734-1922
                1896-9151
                23 February 2014
                24 February 2014
                : 10
                : 1
                : 47-52
                Affiliations
                [1 ]Department of Neurology, the Affiliated Hospital of the Medical College, Qingdao University, Qingdao, PR China
                [2 ]Department of Neurology, Haiyang Hospital, Haiyang, PR China
                [3 ]Laboratory of Human Micromorphology, The Medical College of Qingdao University, Qingdao, PR China
                Author notes
                Corresponding author: Xudong Pan, Department of Neurology, the Affiliated Hospital of the Medical College, Qingdao University, No. 59 Haier Road, Qingdao, Shandong Province, 266100, PR China, Phone: +86 532 82913033, Fax: +86 532 82911840. E-mail: maaijun.cn@ 123456163.com
                Article
                21871
                10.5114/aoms.2013.39200
                3953970
                24701213
                d63a5263-c97f-4f54-87d1-097c8e2e620b
                Copyright © 2014 Termedia & Banach

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 01 December 2012
                : 11 February 2013
                : 01 March 2013
                Categories
                Clinical Research

                Medicine
                cxcl16,chemokine,atherosclerosis,ischemic stroke,inflammation
                Medicine
                cxcl16, chemokine, atherosclerosis, ischemic stroke, inflammation

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