Abstract
TLRs sense microbial products and initiate adaptive immune responses by activating dendritic cells (DCs). DCs have been shown to produce leukotrienes and, conversely, leukotrienes are known to modulate several DC functions. In this study, we examined the modulation of expression and function of cysteinyl-leukotriene receptor type 1 (CysLT1) on human monocyte-derived DCs during their differentiation and subsequent maturation with zymosan, a TLR2 agonist. Maturation of DCs with zymosan reduced CysLT1 mRNA levels and protein expression in a time-dependent fashion and was associated with a diminution of functional responsiveness to leukotriene D(4) as assessed by intracellular calcium mobilization, CCL2 and CCL3 production, and chemotaxis. The effect of zymosan was mediated by both TLR2 and dectin-1 activation. Zymosan also induced a rapid expression of cyclooxygenase-2 and the production of PGE(2) and IL-10. Addition of an anti-IL-10 neutralizing Ab or inhibitors of cyclooxygenase greatly reduced the ability of zymosan to down-regulate CysLT1 expression. Down-regulation of CysLT1 expression by zymosan could be reproduced by a combination of IL-10 and PGE(2), and was dependent on MAPK activation. Taken together, our findings indicate that zymosan down-regulates CysLT1 expression in DCs with consequently reduced functional responsiveness of the cells to leukotriene D(4) stimulation. This effect is partially dependent on an endogenous production of PGs and IL-10 by DCs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Cells, Cultured
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Chemokine CCL2 / immunology
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Chemokine CCL2 / metabolism
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Chemokine CCL3 / immunology
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Chemokine CCL3 / metabolism
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Chemotaxis / drug effects
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Chemotaxis / immunology
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Cyclooxygenase 2 / drug effects
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Cyclooxygenase 2 / metabolism
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Cyclooxygenase 2 / physiology
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dinoprostone / agonists
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Dinoprostone / immunology
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Dinoprostone / metabolism
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Down-Regulation / drug effects
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Down-Regulation / immunology
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Humans
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Interleukin-10 / agonists
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Lectins, C-Type
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Leukotriene D4 / antagonists & inhibitors
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Leukotriene D4 / immunology
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Leukotriene D4 / metabolism
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Membrane Proteins / agonists
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / immunology
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Nerve Tissue Proteins / agonists
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Nerve Tissue Proteins / immunology
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Nerve Tissue Proteins / metabolism
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Protein Kinase Inhibitors / pharmacology
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Receptors, Leukotriene / drug effects
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Receptors, Leukotriene / immunology*
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Receptors, Leukotriene / metabolism
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Recombinant Proteins / drug effects
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Recombinant Proteins / immunology
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Recombinant Proteins / metabolism
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Toll-Like Receptor 2 / agonists
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Toll-Like Receptor 2 / immunology*
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Toll-Like Receptor 2 / metabolism
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Zymosan / pharmacology
Substances
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CCL2 protein, human
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CCL3 protein, human
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Chemokine CCL2
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Chemokine CCL3
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IL10 protein, human
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Lectins, C-Type
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Membrane Proteins
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Nerve Tissue Proteins
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Protein Kinase Inhibitors
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Receptors, Leukotriene
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Recombinant Proteins
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TLR2 protein, human
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Toll-Like Receptor 2
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dectin 1
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Interleukin-10
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Leukotriene D4
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Zymosan
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Cyclooxygenase 2
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PTGS2 protein, human
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Mitogen-Activated Protein Kinase Kinases
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Dinoprostone
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leukotriene D4 receptor