Dectin-1 synergizes with TLR2 and TLR4 for cytokine production in human primary monocytes and macrophages.
The beta-glucan receptor dectin-1 and Toll-like receptors TLR2 and TLR4 are the main receptors for recognition of Candida albicans by the innate immune system. It has been reported that dectin-1 amplifies TLR2-dependent induction of cytokines in mouse models. In the present study we hypothesized that dectin-1 has potent synergistic effects with both TLR2 and TLR4 in human PBMCs and macrophages. Human PBMCs and monocyte-derived macrophages were stimulated with curdlan, a linear beta-1,3-glucan-polymer derived from Alcaligenes faecalis with specific ligand affinity for dectin-1, in combination with the synthetic TLR2 ligand Pam3Cys and the ultrapure TLR4 ligand LPS. TNF-alpha and IL-10 production was measured in the supernatants with ELISA. Curdlan is a specific dectin-1 ligand without TLR2- or TLR4-stimulating properties. Human primary monocytes and macrophages express dectin-1 on the cell membrane. Stimulation of human PBMCs with curdlan in combination with Pam3Cys or LPS leads to synergistic increase in TNF-alpha production that was inhibited by GE2, a neutralizing dectin-1 antibody. Dectin-1-dependent synergy between curdlan and TLR agonists was also apparent in human monocyte-derived macrophages. Conclusively, dectin-1 synergizes with both TLR2 and TLR4 pathways for the production of TNF-alpha in human primary PBMCs and in monocyte-derived macrophages.
Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Gerben
G
Ferwerda
Friederike
F
Meyer-Wentrup
Bart-Jan
BJ
Kullberg
Mihai G
MG
Netea
Gosse J
GJ
Adema
D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D037181:Lectins, C-Type; D008070:Lipopolysaccharides / Q000276:immunology; D008074:Lipoproteins / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D009419:Nerve Tissue Proteins / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D047071:beta-Glucans / Q000276:immunology; D000099181:Dectin-1
D003545:Cysteine; D016753:Interleukin-10; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D008074:Lipoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D047071:beta-Glucans; D000099181:Dectin-1; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C082161:lipopolysaccharide A; C038459:curdlan; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine