TY - JOUR
T1 - Crosstalk between Toll like receptors and C5a receptor in human monocyte derived DCs suppress inflammatory cytokine production
AU - Zaal, Anouk
AU - Lissenberg-Thunnissen, Suzanne N
AU - van Schijndel, Gijs
AU - Wouters, Diana
AU - van Ham, S Marieke
AU - ten Brinke, Anja
N1 - Copyright © 2012 Elsevier GmbH. All rights reserved.
PY - 2013/2
Y1 - 2013/2
N2 - The complement anaphylatoxin, C5a has been implicated in regulation of adaptive immune responses through modulation of APC function as shown mainly in studies in mice. C5a was shown to enhance cytokine production in immature DCs, but the effect of C5a on DC function during DC activation has not been elucidated in human. In this study we investigated the effect of C5a on human monocyte derived DCs when simultaneously stimulated with TLR ligands. While C5a indeed enhanced cytokine production of immature DCs, the addition of C5a inhibited production of IL-12, IL-23 and TNFα induced by various TLR ligands such as LPS, R848 and Pam(3)CSK(4). The inhibitory effect of C5a on LPS induced IL-6 production was less pronounced and LPS induced IL-10 was not affected at all. This indicates that C5aR signaling has a differential effect on human DC differentiation depending on the crosstalk with other receptors. Furthermore we found that C5a affects the LPS induced cytokines in a small time frame, and requires almost concurrent signaling of C5a receptor and TLR4. These data emphasize the complexity of DC regulation by anaphylatoxins. While complement activation may provide proinflammatory signals to immature DCs in the absence of pathogens, the same products may serve to downmodulate or deviate immune responses upon combat against infections. These context depending effects of anaphylatoxins on immune responses may have important implications for the emerging use of complement inhibitors in clinical practice.
AB - The complement anaphylatoxin, C5a has been implicated in regulation of adaptive immune responses through modulation of APC function as shown mainly in studies in mice. C5a was shown to enhance cytokine production in immature DCs, but the effect of C5a on DC function during DC activation has not been elucidated in human. In this study we investigated the effect of C5a on human monocyte derived DCs when simultaneously stimulated with TLR ligands. While C5a indeed enhanced cytokine production of immature DCs, the addition of C5a inhibited production of IL-12, IL-23 and TNFα induced by various TLR ligands such as LPS, R848 and Pam(3)CSK(4). The inhibitory effect of C5a on LPS induced IL-6 production was less pronounced and LPS induced IL-10 was not affected at all. This indicates that C5aR signaling has a differential effect on human DC differentiation depending on the crosstalk with other receptors. Furthermore we found that C5a affects the LPS induced cytokines in a small time frame, and requires almost concurrent signaling of C5a receptor and TLR4. These data emphasize the complexity of DC regulation by anaphylatoxins. While complement activation may provide proinflammatory signals to immature DCs in the absence of pathogens, the same products may serve to downmodulate or deviate immune responses upon combat against infections. These context depending effects of anaphylatoxins on immune responses may have important implications for the emerging use of complement inhibitors in clinical practice.
KW - Cell Differentiation
KW - Cells, Cultured
KW - Cytokines/metabolism
KW - Dendritic Cells/immunology
KW - Humans
KW - Imidazoles/metabolism
KW - Immune Tolerance
KW - Inflammation Mediators/metabolism
KW - Lipopeptides/metabolism
KW - Lipopolysaccharides/metabolism
KW - Monocytes/immunology
KW - Receptor Cross-Talk/immunology
KW - Receptor, Anaphylatoxin C5a
KW - Receptors, Complement/immunology
KW - Signal Transduction/immunology
KW - Toll-Like Receptor 4/immunology
U2 - 10.1016/j.imbio.2012.02.014
DO - 10.1016/j.imbio.2012.02.014
M3 - Article
C2 - 22559913
SN - 0171-2985
VL - 218
SP - 175
EP - 180
JO - Immunobiology
JF - Immunobiology
IS - 2
ER -