CL097, a TLR7/8 ligand, inhibits TLR-4--dependent activation of IRAK-M and BCL-3 expression

Shock. 2009 Nov;32(5):484-90. doi: 10.1097/SHK.0b013e3181a5ac8a.

Abstract

Prolonged or repeated stimulation of Toll-like receptor (TLR) 4 leads to hyporesponsiveness of monocyte-derived macrophages, which seems to be a hallmark of immunosuppression related to sepsis and cancer. Two negative regulators of TLR-4 signaling are IL-1 receptor-associated kinase M and B-cell leukemia 3. Here, we demonstrate that the expression of both proteins is inhibited when the TLR-7/TLR-8 agonist CL097 is added to monocyte cultures despite costimulation with the TLR-4 agonist LPS or hyaluronic acid. Reduction of IL-1 receptor-associated kinase M and B-cell leukemia 3 was paralleled by a significant increased cytokine induction of TNF-alpha, IL-10, and IL-12 observed after intracellular and extracellular TLR stimulation. In ex vivo stimulated whole blood of patients who have prolonged sepsis or metastatic cancer, TLR-7/TLR-8 agonists retained their ability of increased stimulation of TNF-alpha. These data might add to the understanding of sepsis and cancer-associated immune suppression in men.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • B-Cell Lymphoma 3 Protein
  • Cells, Cultured
  • Enzyme Activation / drug effects*
  • Gene Expression Regulation / drug effects*
  • Humans
  • Hyaluronic Acid / pharmacology
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Interleukin-10 / metabolism
  • Interleukin-12 / metabolism
  • Ligands
  • Lipopolysaccharides / pharmacology
  • Middle Aged
  • Proto-Oncogene Proteins / metabolism*
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptor 7 / agonists
  • Toll-Like Receptor 8 / agonists
  • Toll-Like Receptors / agonists*
  • Toll-Like Receptors / metabolism
  • Transcription Factors / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • B-Cell Lymphoma 3 Protein
  • BCL3 protein, human
  • CL097 compound
  • Imidazoles
  • Ligands
  • Lipopolysaccharides
  • Proto-Oncogene Proteins
  • Quinolines
  • TLR4 protein, human
  • TLR7 protein, human
  • TLR8 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Toll-Like Receptors
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-12
  • Hyaluronic Acid
  • IRAK3 protein, human
  • Interleukin-1 Receptor-Associated Kinases