Transcriptional activation induced in macrophages by Toll-like receptor (TLR) ligands: from expression profiling to a model of TLR signaling

Eur J Immunol. 2004 Oct;34(10):2863-73. doi: 10.1002/eji.200425228.

Abstract

Toll-like receptors (TLR) sense microbial compounds and bridge innate and adaptive immunity by activation of antigen-presenting cells. TLR-induced signaling via intracellular adaptor molecules, including MyD88 and TRIF, drives transcriptional activation of genes including pro-inflammatory cytokines and cell activation markers. To globally assess the activation programs triggered by individual TLR in macrophages, we used microarray-based gene expression profiling of the murine macrophage cell line RAW264.7. Here we describe that the TLR4 ligand LPS more strongly modulates gene expression compared to ligands for TLR 2, 3, 7, and 9. Taking advantage of the known dependency of TLR on given adaptor molecules, we operationally define sets of MyD88 and TRIF "private" genes. We conclude with a TLR signaling model that incorporates both negative and synergistic interactions of MyD88- and TRIF-controlled signaling pathways as deduced from the microarray data presented.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport / immunology
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Antigens, Differentiation / immunology
  • Antigens, Differentiation / metabolism
  • Blotting, Northern
  • Cell Line
  • Cytokines / analysis
  • Cytokines / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Profiling
  • Ligands
  • Lipopolysaccharides / immunology
  • Macrophage Activation / immunology*
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism
  • Mice
  • Models, Immunological
  • Myeloid Differentiation Factor 88
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Oligonucleotide Array Sequence Analysis
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / immunology
  • Receptors, Cell Surface / metabolism
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism
  • Signal Transduction / immunology*
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Transcriptional Activation / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Antigens, Differentiation
  • Cytokines
  • Ligands
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • TICAM-1 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors