Caffeic Acid Cyclohexylamide Rescues Lethal Inflammation in Septic Mice through Inhibition of IκB Kinase in Innate Immune Process

• Published in: Scientific reports 2017-02, Vol.7 (1), p.41180-41180, Article 41180
• Main Authors: Choi, Jun Hyeon, Park, Sun Hong, Jung, Jae-Kyung, Cho, Won-Jea, Ahn, Byeongwoo, Yun, Cheong-Yong, Choi, Yong Pyo, Yeo, Jong Hun, Lee, Heesoon, Hong, Jin Tae, Han, Sang-Bae, Kim, Youngsoo
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 14/19; 38/77; 42/109; 631/154/436; 631/250/256/2516; 64/60; 692/308/1426; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep41180

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.