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* Laboratory of Cardiovascular Surgery and
Laboratory of Pneumology, Department of Clinical Research, University of Bern, Bern, Switzerland; and
Laboratory of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
Low molecular weight dextran sulfate (DXS) has been reported to inhibit the classical, alternative pathway as well as the mannan-binding lectin pathway of the complement system. Furthermore, it acts as an endothelial cell protectant inhibiting complement-mediated endothelial cell damage. Endothelial cells are covered with a layer of heparan sulfate (HS), which is rapidly released under conditions of inflammation and tissue injury. Soluble HS induces maturation of dendritic cells (DC) via TLR4. In this study, we show the inhibitory effect of DXS on human DC maturation. DXS significantly prevents phenotypic maturation of monocyte-derived DC and peripheral myeloid DC by inhibiting the up-regulation of CD40, CD80, CD83, CD86, ICAM-1, and HLA-DR and down-regulates DC-SIGN in response to HS or exogenous TLR ligands. DXS also inhibits the functional maturation of DC as demonstrated by reduced T cell proliferation, and strongly impairs secretion of the proinflammatory mediators IL-1β, IL-6, IL-12p70, and TNF-
. Exposure to DXS leads to a reduced production of the complement component C1q and a decreased phagocytic activity, whereas C3 secretion is increased. Moreover, DXS was found to inhibit phosphorylation of I
B- and activation of NF-B. These findings suggest that DXS prevents TLR-induced maturation of human DC and may therefore be a useful reagent to impede the link between innate and adaptive immunity.
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 work was supported by the European Union Sixth Framework Integrated Research Project "Reprogramming the Immune System for the Establishment of Tolerance" and Grant 3200B0-104228 from the Swiss National Science Foundation.
2 Address correspondence and reprint requests to Dr. Robert Rieben, Department of Clinical Research, University of Bern, Murtenstrasse 31, P.O. Box 33, CH-3010 Bern, Switzerland. E-mail address: robert.rieben{at}dkf.unibe.ch
3 Abbreviations used in this paper: DXS, dextran sulfate; DC, dendritic cell; MoDC, monocyte-derived DC; HS, heparan sulfate; LTA, lipoteichoic acid.
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