1. Academic Validation
  2. IRAK4 as a molecular target in the amelioration of innate immunity-related endotoxic shock and acute liver injury by chlorogenic acid

IRAK4 as a molecular target in the amelioration of innate immunity-related endotoxic shock and acute liver injury by chlorogenic acid

  • J Immunol. 2015 Feb 1;194(3):1122-30. doi: 10.4049/jimmunol.1402101.
Sun Hong Park 1 Seung-Il Baek 1 Jieun Yun 2 Seungmin Lee 1 Da Young Yoon 1 Jae-Kyung Jung 1 Sang-Hun Jung 3 Bang Yeon Hwang 1 Jin Tae Hong 1 Sang-Bae Han 1 Youngsoo Kim 4
Affiliations

Affiliations

  • 1 College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea;
  • 2 Bio-evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Korea; and.
  • 3 College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea.
  • 4 College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea; youngsoo@chungbuk.ac.kr.
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.

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