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

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.

• Authors: Sun Hong Park, Eunmiri Roh, Hyun Soo Kim, Seung-Il Baek, Nam Song Choi, Narae Kim, Bang Yeon Hwang, Sang-Bae Han, Youngsoo Kim
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 442 Issue 3-4 Pg. 183-8 (Dec 13 2013) ISSN: 1090-2104 [Electronic] United States
• PMID: 24269819 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Endotoxins
• Lipopolysaccharides
• NF-kappa B
• Plant Extracts
• Transcription Factor AP-1
• Chlorogenic Acid
• lonicerae flos
• Interleukin-1 Receptor-Associated Kinases
• Irak4 protein, mouse

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Chlorogenic Acid (analysis, chemistry, therapeutic use)
• Endotoxins
• Interleukin-1 Receptor-Associated Kinases (antagonists & inhibitors)
• Lipopolysaccharides
• Lonicera (chemistry)
• Metabolic Networks and Pathways (drug effects)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Plant Extracts (chemistry, therapeutic use)
• Sepsis (drug therapy, mortality)
• Transcription Factor AP-1 (metabolism)