Abstract
Targeting myeloid differentiation protein 2 (MD-2) or Toll-like receptor 4 (TLR4) with small molecule inhibitor rescues the systemic inflammatory response syndrome (SIRS) in sepsis due to infection with Gram-negative bacteria but not other microbes. Herein, we provided IκB kinase β (IKKβ) in innate immune process as a molecular target of caffeic acid cyclohexylamide (CGA-JK3) in the treatment of polymicrobial TLR agonists-induced lethal inflammation. CGA-JK3 ameliorated E. coli lipopolysaccharide (LPS, MD-2/TLR4 agonist)-induced endotoxic shock, cecal ligation and puncture (CLP)-challenged septic shock or LPS plus D-galactosamine (GalN)-induced acute liver failure (ALF) in C57BL/6J mice. As a molecular basis, CGA-JK3 inhibited IKKβ-catalyzed kinase activity in a competitive mechanism with respect to ATP, displaced fluorescent ATP probe from the complex with IKKβ, and docked at the ATP-binding active site on the crystal structure of human IKKβ. Furthermore, CGA-JK3 inhibited IKKβ-catalyzed IκB phosphorylation, which is an axis leading to IκB degradation in the activating pathway of nuclear factor-κB (NF-κB), in macrophages stimulated with TLR (1/2, 2/6, 4, 5, 7, 9) agonists from Gram-positive/negative bacteria and viruses. CGA-JK3 consequently interrupted IKKβ-inducible NF-κB activation and NF-κB-regulated expression of TNF-α, IL-1α or HMGB-1 gene, thereby improving TLRs-associated redundant inflammatory responses in endotoxemia, polymicrobial sepsis and ALF.
Highlights
Targeting myeloid differentiation protein 2 (MD-2) or Toll-like receptor 4 (TLR4) with small molecule inhibitor rescues the systemic inflammatory response syndrome (SIRS) in sepsis due to infection with Gram-negative bacteria but not other microbes
Eritoran antagonizes LPS binding to the receptor MD-2 associated with TLR4, and TAK-242 interacts with the Cys-747 residue on intracellular domain of TLR4, thereby blocking inflammatory responses in sepsis specially due to Gram-negative bacterial infection but not other microbes[5,6]
Novel therapeutic target responding to TLR pathogens from Gram-positive bacteria and viruses, affecting redundant SIRS pathways other than MD-2 or TLR4, is required in the alternative treatment of sepsis patients
Summary
Targeting myeloid differentiation protein 2 (MD-2) or Toll-like receptor 4 (TLR4) with small molecule inhibitor rescues the systemic inflammatory response syndrome (SIRS) in sepsis due to infection with Gram-negative bacteria but not other microbes. Eritoran antagonizes LPS binding to the receptor MD-2 associated with TLR4, and TAK-242 interacts with the Cys-747 residue on intracellular domain of TLR4, thereby blocking inflammatory responses in sepsis specially due to Gram-negative bacterial infection but not other microbes[5,6]. Mammalian TLRs sense pathogen-associated molecular patterns from microbes and danger-associated molecular pattern molecules from dying host cells They transmit the innate immune responses via intracellular adaptor molecules such as myeloid differentiation factor 88 (MyD88) and toll/ IL-1 receptor-containing adaptor inducing interferon (IFN)-β(TRIF)[7]. Data are mean ±SEM. *P < 0.05 vs. LPS- or CLP alone-challenged group
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