Identification of a TLR4- and TRIF-dependent activation program of dendritic cells.
Dendritic cell activation by Toll-like receptors (TLR) is crucial for the generation of protective immune responses. In addition to the common myeloid differentiation factor 88 (MyD88)-dependent signaling pathway, TLR4 engages the adaptor protein Toll/IL-1 receptor (TIR)-domain-containing adaptor inducing IFN-beta (TRIF), leading to interferon regulatory factor 3 (IRF-3) activation and type I interferon production. Using microarray expression profiling we now identify TRIF as a major regulator of the TLR4-triggered activation program of dendritic cells. We show that the expression of 47% of the genes that are responsive to TLR4 stimulation in wild-type dendritic cells is significantly altered in cells carrying a loss-of-function mutation of TRIF. Specifically, expression of IL-12, IL-18, and IL-23 was impaired in the absence of functional TRIF, suggesting that TLR4-promoted Th1 responses are TRIF-dependent. Furthermore, we provide evidence that TRIF regulates TLR4-mediated gene expression both by type I IFN-dependent and -independent mechanisms. Whereas dendritic cell production of CXCL10 and CCL12 was dependent on both TRIF and the type I interferon receptor, expression of IL-6 required TRIF but not type I interferon activity. Functional TRIF was also required for the normal induction of numerous genes considered important for host defense against diverse pathogens.Together, these data therefore identify TRIF as a crucial regulator of TLR4-dependent dendritic cell responses.
Weighardt
Heike
H
Department of Surgery, Technical University Munich, Munich, Germany.
Jusek
Gabriela
G
Mages
Jörg
J
Lang
Roland
R
Hoebe
Kasper
K
Beutler
Bruce
B
Holzmann
Bernhard
B
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D008050:Lipid A / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011956:Receptors, Cell Surface / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D008050:Lipid A; D008562:Membrane Glycoproteins; D012313:RNA; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C476286:Ticam1 protein, mouse