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* Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom;
Department of Cell Biology, Erasmus Medical Centre, Rotterdam, The Netherlands;
Novartis Institute for Biomedical Research, Vienna, Austria; and
King’s College London School of Medicine, London, United Kingdom
D6 scavenges inflammatory chemokines and is essential for the regulation of inflammatory and immune responses. Mechanisms explaining the cellular basis for D6 function have been based on D6 expression by lymphatic endothelial cells. In this study, we demonstrate that functional D6 is also expressed by murine and human hemopoietic cells and that this expression can be regulated by pro- and anti-inflammatory agents. D6 expression was highest in B cells and dendritic cells (DCs). In myeloid cells, LPS down-regulated expression, while TGF-β up-regulated expression. Activation of T cells with anti-CD3 and soluble CD28 up-regulated mRNA expression 20-fold, while maturation of human macrophage and megakaryocyte precursors also up-regulated D6 expression. Competition assays demonstrated that chemokine uptake was D6 dependent in human leukocytes, whereas mouse D6-null cells failed to uptake and clear inflammatory chemokines. Furthermore, we present evidence indicating that D6 expression is GATA1 dependent, thus explaining D6 expression in myeloid progenitor cells, mast cells, megakaryocytes, and DCs. We propose a model for D6 function in which leukocytes, within inflamed sites, activate D6 expression and thus trigger resolution of inflammatory responses. Our data on D6 expression by circulating DCs and B cells also suggest alternative roles for D6, perhaps in the coordination of innate and adaptive immune responses. These data therefore alter our models of in vivo D6 function and suggest possible discrete, and novel, roles for D6 on lymphatic endothelial cells and leukocytes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by research funding from the Novartis Institute for Biomedical Research (Vienna) (to G.J.G. and R.J.N.) and from INNOCHEM (to G.J.G. and A.R.). S.P. and L.G. are supported by Netherlands Organization for Scientific Research-Earth and Life Sciences Grant 815-02-008.
2 Address correspondence and reprint requests to Dr. Gerard J. Graham, Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, United Kingdom. E-mail address: graham{at}clinmed.gla.ac.uk
3 Abbreviations used in this paper: LEC, lymphatic endothelial cell; PB, peripheral blood; DC, dendritic cell; pDC, plasmacytoid DC; mDC, monocytoid DC; MFI, mean fluorescence intensity; WT, wild type; QPCR, quantitative PCR; Tx, tamoxifen; TPA, 12-O-tetradecanoyl phorbol-13-acetate.
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