The complement inhibitor low molecular weight dextran sulfate prevents TLR4-induced phenotypic and functional maturation of human dendritic cells.
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-1beta, IL-6, IL-12p70, and TNF-alpha. 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 IkappaB-alpha and activation of NF-kappaB. 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.
Spirig
Rolf
R
Departmentof Clinical Research, Laboratory of Cardiovascular Surgery, University of Bern, Bern, Switzerland.
van Kooten
Cees
C
Obregon
Carolina
C
Nicod
Laurent
L
Daha
Mohamed
M
Rieben
Robert
R
D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016264:Dextran Sulfate / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis; D011956:Receptors, Cell Surface / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D003165:Complement System Proteins; D016207:Cytokines; D016264:Dextran Sulfate; D051550:I-kappa B Kinase; D018836:Inflammation Mediators; D016753:Interleukin-10; D037181:Lectins, C-Type; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C495345:TLR4 protein, human