Inhibition of IRAK-4 activity for rescuing endotoxin LPS-induced septic mortality in mice by lonicerae flos extract

Sun Hong Park, Eunmiri Roh, Hyun Soo Kim, Seung Il Baek, Nam Song Choi, Narae Kim, Bang Yeon Hwang, Sang Bae Han, Youngsoo Kim

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Lonicerae flos extract (HS-23) is a clinical candidate currently undergoing Phase I trial in lipopolysaccharide (LPS)-injected healthy human volunteers, but its molecular basis remains to be defined. Here, we investigated protective effects of HS-23 or its major constituents on Escherichia coli LPS-induced septic mortality in mice. Intravenous treatment with HS-23 rescued LPS-intoxicated C57BL/6J mice under septic conditions, and decreased the levels of cytokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β and high-mobility group box-1 (HMGB-1) in the blood. Chlorogenic acid (CGA) and its isomers were assigned as major constituents of HS-23 in the protection against endotoxemia. As a molecular mechanism, HS-23 or CGA isomers inhibited endotoxin LPS-induced autophosphorylation of the IL-1 receptor-associated kinase 4 (IRAK-4) in mouse peritoneal macrophages as well as the kinase activity of IRAK-4 in cell-free reactions. HS-23 consequently suppressed downstream pathways critical for LPS-induced activation of nuclear factor (NF)-κB or activating protein 1 (AP-1) in the peritoneal macrophages. HS-23 also inhibited various toll-like receptor agonists-induced nitric oxide (NO) production, and down-regulated LPS-induced expression of NF-κB/AP-1-target inflammatory genes in the cells. Taken together, HS-23 or CGA isomers exhibited anti-inflammatory therapy against LPS-induced septic mortality in mice, at least in part, mediated through the inhibition of IRAK-4.

Original languageEnglish (US)
Pages (from-to)183-188
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume442
Issue number3-4
DOIs
StatePublished - Dec 13 2013
Externally publishedYes

Keywords

  • Anti-inflammatory therapy
  • Chlorogenic acid isomers
  • Endotoxin LPS
  • IRAK-4
  • Lonicerae flos extract
  • Septic mortality

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