Lipopolysaccharide Stimulates the MyD88-independent Pathway and Results in Activation of IFN-regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes

J Immunol. 2001 Nov 15;167(10):5887-94. doi: 10.4049/jimmunol.167.10.5887.

Abstract

Bacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4, a member of the TLR family that participates in pathogen recognition. TLRs recruit a cytoplasmic protein, MyD88, upon pathogen recognition, mediating its function for immune responses. Two major pathways for LPS have been suggested in recent studies, which are referred to as MyD88-dependent and -independent pathways. We report in this study the characterization of the MyD88-independent pathway via TLR4. MyD88-deficient cells failed to produce inflammatory cytokines in response to LPS, whereas they responded to LPS by activating IFN-regulatory factor 3 as well as inducing the genes containing IFN-stimulated regulatory elements such as IP-10. In contrast, a lipopeptide that activates TLR2 had no ability to activate IFN-regulatory factor 3. The MyD88-independent pathway was also activated in cells lacking both MyD88 and TNFR-associated factor 6. Thus, TLR4 signaling is composed of at least two distinct pathways, a MyD88-dependent pathway that is critical to the induction of inflammatory cytokines and a MyD88/TNFR-associated factor 6-independent pathway that regulates induction of IP-10.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / physiology*
  • Cells, Cultured
  • Chemokine CXCL10
  • Chemokines, CXC / biosynthesis
  • Chemokines, CXC / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology
  • Drosophila Proteins*
  • Gene Deletion
  • Interferon Regulatory Factor-3
  • Interferons / physiology
  • Lipid A / pharmacology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Membrane Glycoproteins / metabolism
  • Mice
  • Models, Biological
  • Myeloid Differentiation Factor 88
  • NF-kappa B / metabolism
  • Proteins / physiology
  • RNA, Messenger / biosynthesis
  • Receptors, Cell Surface / metabolism
  • Receptors, Immunologic*
  • Response Elements
  • Signal Transduction*
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology
  • Transcriptional Activation*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Chemokine CXCL10
  • Chemokines, CXC
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Lipid A
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Proteins
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Transcription Factors
  • Interferons