Inhibition of direct and indirect TLR-mediated activation of human NK cells by low molecular weight dextran sulfate.
NK cells express toll-like receptors (TLR) that recognize conserved pathogen or damage associated molecular patterns and play a fundamental role in innate immunity. Low molecular weight dextran sulfate (DXS), known to inhibit the complement system, has recently been reported by us to inhibit TLR4-induced maturation of human monocyte-derived dendritic cells (MoDC). In this study, we investigated the capability of DXS to interfere with human NK cell activation triggered directly by TLR2 agonists or indirectly by supernatants of TLR4-activated MoDC. Both TLR2 agonists and supernatants of TLR4-activated MoDC activated NK cells phenotypically, as demonstrated by the analysis of NK cell activation markers (CD56, CD25, CD69, NKp30, NKp44, NKp46, DNAM-1 and NKG2D), and functionally as shown by increased NK cell degranulation (CD107a surface expression) and IFN-gamma secretion. DXS prevented the up-regulation of NK cell activation markers triggered by TLR2 ligands or supernatants of TLR4-activated MoDC and dose-dependently abrogated NK cell degranulation and IFN-gamma secretion. In summary our results suggest that DXS may be a useful reagent to inhibit the direct and indirect TLR-mediated activation of NK cells.
Millard
Anne-Laure
AL
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
Spirig
Rolf
R
Mueller
Nicolas J
NJ
Seebach
Jörg D
JD
Rieben
Robert
R
D015550:Cell Degranulation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051056:Complement Inactivating Agents / Q000737:chemistry / Q000494:pharmacology; D017077:Culture Media, Conditioned; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D016264:Dextran Sulfate / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008970:Molecular Weight; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000037:antagonists & inhibitors; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000037:antagonists & inhibitors; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors*
D051056:Complement Inactivating Agents; D017077:Culture Media, Conditioned; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D007371:Interferon-gamma; D016264:Dextran Sulfate