title: Caffeic Acid Cyclohexylamide Rescues Lethal Inflammation in Septic Mice through Inhibition of IκB 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 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.
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Jun Hyeon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Sun Hong
authors.initials: SH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Jung
authors.affiliation: College of Pharmacy, Chonnam National University, Gwangju 500-757, Korea.
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
authors.affiliation: College of Veterinary Medicine, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Byeongwoo
authors.initials: B
authors.lastname: Ahn
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Cheong-Yong
authors.initials: CY
authors.lastname: Yun
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Yong Pyo
authors.initials: YP
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Jong Hun
authors.initials: JH
authors.lastname: Yeo
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Heesoon
authors.initials: H
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002109:Caffeic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D003514:Cyclohexylamines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D005688:Galactosamine / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D051550:I-kappa B Kinase / Q000737:chemistry / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D000067996:RAW 264.7 Cells; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D002109:Caffeic Acids; D003514:Cyclohexylamines; D008070:Lipopolysaccharides; D005688:Galactosamine; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse