TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain

Eur J Pharmacol. 2008 Apr 14;584(1):40-8. doi: 10.1016/j.ejphar.2008.01.026. Epub 2008 Feb 5.


TAK-242, a small-molecule antisepsis agent, has shown to suppress lipopolysaccharide (LPS)-induced inflammation. In this study, we demonstrate that TAK-242 is a selective inhibitor of Toll-like receptor (TLR)-4 signaling. TAK-242 almost completely suppressed production of nitric oxide (NO) or tumor necrosis factor (TNF)-alpha induced by a TLR4-specific ligand, ultra-pure LPS, in mouse RAW264.7, human U-937 and P31/FUJ cells, whereas this agent showed little effect on other TLR ligands, Pam(3)CSK(4) (TLR1/2), peptidoglycan (TLR2/6), double strand RNA (TLR3), R-848 (TLR7) and CpG oligonucleotide (TLR9). Furthermore, TAK-242 potently inhibited nuclear factor (NF)-kappaB activation induced by ultra-pure LPS in HEK293 cells transiently expressing TLR4 and co-receptors, myeloid differentiation protein-2 (MD2) and CD14, whereas this agent showed little effect on other TLRs, TLR1/2, TLR2/6, TLR3, TLR5, TLR7 and TLR9. TAK-242 also inhibited ligand-independent NF-kappaB activation resulting from over-expression of TLR4. Although chimera receptors, which are consist of the extracellular domain of CD4 and the intracellular domain of human or mouse TLR4, showed constitutive NF-kappaB activation, TAK-242 potently inhibited the signaling from CD4-TLR4 chimera receptors. In contrast, the NF-kappaB activation mediated by TLR4 adaptors, myeloid differentiation factor 88 (MyD88), TIR-associated protein (TIRAP), Toll/IL-1R homology (TIR)-domain-containing adaptor protein-inducing interferon-beta (TRIF) or TRIF-related adaptor molecule (TRAM) was not affected by TAK-242. TAK-242 is therefore a selective inhibitor of signaling from the intracellular domain of TLR4 and represents a novel therapeutic approach to the treatment of TLR4-mediated diseases.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • CD4 Antigens / drug effects
  • CD4 Antigens / metabolism
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Humans
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / drug effects
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / drug effects*
  • Sulfonamides / pharmacology*
  • Toll-Like Receptor 4 / chemistry
  • Toll-Like Receptor 4 / drug effects*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism
  • U937 Cells


  • Adaptor Proteins, Signal Transducing
  • Anti-Inflammatory Agents
  • CD4 Antigens
  • Lipopolysaccharides
  • NF-kappa B
  • Recombinant Fusion Proteins
  • Sulfonamides
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
  • lipopolysaccharide, Escherichia coli O111 B4
  • Nitric Oxide