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Identification of a tlr4- and trif-dependent activation program of dendritic cells

Academic Article
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Overview

authors

  • Weighardt, H.
  • Jusek, G.
  • Mages, J.
  • Lang, R.
  • Hoebe, K.
  • Beutler, Bruce
  • Holzmann, B.

publication date

  • February 2004

journal

  • European Journal of Immunology  Journal

abstract

  • 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.

subject areas

  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Cytokines
  • Dendritic Cells
  • Female
  • Gene Expression Regulation
  • Lipid A
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • RNA
  • Receptors, Cell Surface
  • Signal Transduction
  • Toll-Like Receptor 4
  • Toll-Like Receptors
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Research

keywords

  • dendritic cell
  • signal transduction
  • toll-like receptor
  • transcriptome analysis
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Identity

International Standard Serial Number (ISSN)

  • 0014-2980

Digital Object Identifier (DOI)

  • 10.1002/eji.200324714

PubMed ID

  • 14768061
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Additional Document Info

start page

  • 558

end page

  • 564

volume

  • 34

issue

  • 2

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