Caffeic Acid Cyclohexylamide Rescues Lethal Inflammation in Septic Mice through Inhibition of I?B Kinase in Innate Immune Process.

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 I?B kinase ? (IKK?) 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 IKK?-catalyzed kinase activity in a competitive mechanism with respect to ATP, displaced fluorescent ATP probe from the complex with IKK?, and docked at the ATP-binding active site on the crystal structure of human IKK?. Furthermore, CGA-JK3 inhibited IKK?-catalyzed I?B phosphorylation, which is an axis leading to I?B degradation in the activating pathway of nuclear factor-?B (NF-?B), 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 IKK?-inducible NF-?B activation and NF-?B-regulated expression of TNF-?, IL-1? or HMGB-1 gene, thereby improving TLRs-associated redundant inflammatory responses in endotoxemia, polymicrobial sepsis and ALF.

SUBMITTER: Choi JH 

PROVIDER: S-EPMC5286524 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature