title: IRAK4 as a molecular target in the amelioration of innate immunity-related endotoxic shock and acute liver injury by chlorogenic acid.
abstract: Mice lacking the IL-1R-associated kinase 4 (IRAK4) are completely resistant to LPS-induced endotoxic disorder or the TLR9 agonist CpG DNA plus d-galactosamine-induced acute liver injury (ALI), whereas wild-type strains succumb. However, translational drugs against sepsis or ALI remain elusive. Lonicerae flos extract is undergoing the clinical trial phase I in LPS-injected healthy human volunteers for sepsis treatment. In the current study, chlorogenic acid (CGA), a major anti-inflammatory constituent of lonicerae flos extract, rescued endotoxic mortality of LPS-intoxicated C57BL/6 mice, as well as ameliorated ALI of LPS/d-galactosamine-challenged C57BL/6 mice. As a mechanism, CGA inhibited various TLR agonist-, IL-1α-, or high-mobility group box-1-stimulated autophosphorylation (activation) of IRAK4 in peritoneal macrophages from C57BL/6 or C3H/HeJ mice via directly affecting the kinase activity of IRAK4, a proximal signal transducer in the MyD88-mediated innate immunity that enhances transcriptional activity of NF-κB or AP-1. CGA consequently attenuated protein or mRNA levels of NF-κB/AP-1 target genes encoding TNF-α, IL-1α, IL-6, and high-mobility group box-1 in vivo under endotoxemia or ALI. Finally, this study suggests IRAK4 as a molecular target of CGA in the treatment of innate immunity-related shock and organ dysfunction following insult of various TLR pathogens from bacteria and viruses.
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: Seung-Il
authors.initials: SI
authors.lastname: Baek
authors.affiliation: Bio-evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Korea; and.
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea;
authors.forename: Seungmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea;
authors.forename: Da Young
authors.initials: DY
authors.lastname: Yoon
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, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Jung
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea;
authors.forename: Bang Yeon
authors.initials: BY
authors.lastname: Hwang
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; youngsoo@chungbuk.ac.kr.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002726:Chlorogenic Acid / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007113:Immunity, Innate / Q000235:genetics*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D002726:Chlorogenic Acid; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; C507774:Irak4 protein, mouse