TLR4-mediated pro-inflammatory dendritic cell differentiation in humans requires the combined action of MyD88 and TRIF.
TLR4 ligation can activate both the MyD88 and the Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) signaling route. Whereas MyD88 is generally recognized as a universal adaptor for pro-inflammatory responses, TRIF is mainly thought to contribute to specific type I IFN responses. Here, we investigated the contribution of both MyD88 and TRIF to TLR4-mediated pro-inflammatory dendritic cell (DC) differentiation in human. Pro-inflammatory cytokine induction was strongly decreased in monophosphoryl lipid A- and LPS-matured monocyte-derived DCs when either MyD88 or TRIF were down-regulated by small interfering RNA electroporation. Induction of co-stimulatory molecule expression was entirely dependent on the TRIF pathway. Our results demonstrate that in human DCs the TRIF pathway is important for overall pro-inflammatory DC differentiation via TLR4 by mediating co-stimulation and playing a non-redundant role in pro-inflammatory cytokine induction.
Department of Immunopathology, Sanquin Blood Supply, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, the Netherlands.
Sonja T H M
ST
Kolanowski
Miranda C
MC
Dieker
Suzanne N
SN
Lissenberg-Thunnissen
Gijs M W
GM
van Schijndel
S Marieke
SM
van Ham
Anja
A
ten Brinke
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism*; D008050:Lipid A / Q000031:analogs & derivatives / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk; D015398:Signal Transduction / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000276:immunology*
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D018836:Inflammation Mediators; D008050:Lipid A; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C470409:TICAM1 protein, human; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; C048436:monophosphoryl lipid A
LPS; MPLA; TLR4; maturation; siRNA