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      Interleukin-2 is Present in Human Blood Vessels and Released in Biologically Active Form by Heparanase

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          Abstract

          Interleukin-2 is a multifaceted cytokine with both immunostimulatory and immunosuppressive properties. Our laboratory recently demonstrated that the availability of IL-2 is regulated, in part, by association with perlecan, a heparan sulfate proteoglycan. Given the abundance of perlecan in blood vessels, we asked whether IL-2 is present in vessel walls. Our results indicate that IL-2 is associated with endothelial and smooth muscle cells within the human arterial wall. This IL-2 is released by heparanase, and promotes the proliferation of an IL-2 dependent cell line. Given the presence of IL-2 in human arteries, we asked whether the large vessels of IL-2 deficient mice were normal. The aortas of IL-2 deficient mice exhibited a loss of smooth muscle cells, suggesting that IL-2 may contribute to their survival. In their entirety, these results suggest a here-to-fore unrecognized role of IL-2 in vascular biology, and have significant implications for both the immune and cardiovascular systems.

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          Most cited references44

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          Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization

          Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic self-tolerance. Neutralization of circulating IL-2 by anti–IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabetes and produces a wide spectrum of T cell–mediated autoimmune diseases, including gastritis, thyroiditis, sialadenitis, and notably, severe neuropathy. Such treatment selectively reduces the number of Foxp3-expressing CD25+ CD4+ T cells, but not CD25− CD4+ T cells, in the thymus and periphery of normal and thymectomized mice. IL-2 neutralization inhibits physiological proliferation of peripheral CD25+ CD4+ T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia-induced homeostatic expansion in a T cell–deficient environment. In normal naive mice, CD25low CD4+ nonregulatory T cells actively transcribe the IL-2 gene and secrete IL-2 protein in the physiological state. IL-2 is thus indispensable for the peripheral maintenance of natural CD25+ CD4+ regulatory T cells (T reg cells). The principal physiological source of IL-2 for the maintenance of T reg cells appears to be other T cells, especially CD25low CD4+ activated T cells, which include self-reactive T cells. Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease.
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            Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity.

            Peptide:MHC II complexes derived from a fluorescent antigen were detected in vivo to identify the cells that present subcutaneously injected antigen to CD4 T cells. Skin-derived dendritic cells (DCs) that acquired the antigen while in the draining lymph nodes were the first cells to display peptide:MHC II complexes. Presentation by these cells induced CD69, IL-2 production, and maximal proliferation by the T cells. Later, DCs displaying peptide:MHC II complexes migrated from the injection site via a G protein-dependent mechanism. Presentation by these migrants sustained expression of the IL-2 receptor and promoted delayed type hypersensitivity. Therefore, presentation of peptide:MHC II complexes derived from a subcutaneous antigen occurs in two temporally distinct waves with different functional consequences.
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              The role of heparan sulphate in inflammation.

              The polysaccharide heparan sulphate is ubiquitously expressed as a proteoglycan in extracellular matrices and on cell surfaces. Heparan sulphate has marked sequence diversity that allows it to specifically interact with many proteins. This Review focuses on the multiple roles of heparan sulphate in inflammatory responses and, in particular, on its participation in almost every stage of leukocyte transmigration through the blood-vessel wall. Heparan sulphate is involved in the initial adhesion of leukocytes to the inflamed endothelium, the subsequent chemokine-mediated transmigration through the vessel wall and the establishment of both acute and chronic inflammatory reactions.
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                Author and article information

                Journal
                8706300
                4179
                Immunol Cell Biol
                Immunology and Cell Biology
                0818-9641
                1440-1711
                19 April 2011
                24 May 2011
                February 2012
                1 August 2012
                : 90
                : 2
                : 159-167
                Affiliations
                Division of Transplantation, University of Nebraska Medical Center, Omaha, Nebraska 68198-3285, United States of America
                Author notes
                Corresponding author: Dr. Lucile E. Wrenshall 983285 Nebraska Medical Center Omaha, NE 68198-3285 Phone: 402-559-6707 Fax: 402-559-3434 lwrenshall@ 123456unmc.edu

                Author contributions J.D.M. designed experiments, performed experiments, and analyzed data. S.E.C. and D.R.S. performed experiments and analyzed data. R.B.S. performed the morphometric analysis. L.E.W. designed experiments, analyzed data, and wrote the manuscript.

                Article
                NIHMS286516
                10.1038/icb.2011.45
                3162067
                21606942
                f007e83b-843a-49ff-93f3-70b32d14a622

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                Cell biology
                Cell biology

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