Mechanisms by Which Licochalcone E Exhibits Potent Anti-Inflammatory Properties: Studies with Phorbol Ester-Treated Mouse Skin and Lipopolysaccharide-Stimulated Murine Macrophages

Han Lee,Han Cho,Jung Park,Young-Hee Kang,Ki Lee,Do Lim

doi:10.3390/ijms140610926

Abstract

In this study we found that licochalcone E (LicE), a recently isolated retrochalcone from Glycyrrhiza inflata, exhibits potent anti-inflammatory effects in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema and lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage models. Topical application of LicE (0.5–2 mg) effectively inhibited TPA-induced (1) ear edema formation; (2) phosphorylation of stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK), c-Jun, and extracellular signal regulated kinase 1/2; and (3) expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 proteins in mouse skin. The treatment of RAW 264.7 cells with LicE (2.5–7.5 μmol/L) induced a profound reduction in LPS-induced (1) release of NO and prostaglandin E2; (2) mRNA expression and secretion of interleukin (IL)-6, IL-1β and tumor necrosis factor-α; (3) promoter activity of iNOS and COX-2 and expression of their corresponding mRNAs and proteins; (4) activation of AKT, p38 mitogen activated protein kinase (MAPK), SAPK/JNK and c-Jun; (5) phosphorylation of inhibitor of κB (IκB) kinase-αβ and IκBα, degradation of IκBα, translocation of p65 (RelA) to the nucleus and transcriptional activity of nuclear factor (NF)-κB; and (6) transcriptional activity of activator protein (AP)-1. These results indicate that the LicE inhibition of NF-κB and AP-1 transcriptional activity through the inhibition of AKT and MAPK activation contributes to decreases in the expression of pro-inflammatory cytokines and the inducible enzymes iNOS and COX-2.

Highlights

Inflammation performs an important role as the first line of host defense mechanisms against infection of pathogenic microorganisms and functions to clear injurious materials.over the past decade, it has become widely accepted that improper resolution of inflammatory networks is centrally involved in the pathogenesis of many acute and chronic diseases.inflammation is a driving force behind a wide variety of chronic diseases including cancer, diabetes, obesity and Alzheimer’s disease [4]
Dexamethasone was very effective in inhibiting ear edema formation as well as the expression of inducible nitric oxide synthase (iNOS) and COX-2 (Figure 2A–D)
The activation of mitogen activated protein kinase (MAPK) regulates TPA-induced expression of COX-2 in mouse skin [36]. These results indicate that licochalcone E (LicE) inhibition of these kinases are involved in the inhibition of NF-κB and activator protein (AP)-1 activation, which leads to the reduced transcription of the inflammatory enzymes COX-2 and iNOS

Summary

Introduction

Inflammation performs an important role as the first line of host defense mechanisms against infection of pathogenic microorganisms and functions to clear injurious materials (reviewed in [1,2,3]).over the past decade, it has become widely accepted that improper resolution of inflammatory networks is centrally involved in the pathogenesis of many acute and chronic diseases.inflammation is a driving force behind a wide variety of chronic diseases including cancer, diabetes, obesity and Alzheimer’s disease [4]. Inflammation performs an important role as the first line of host defense mechanisms against infection of pathogenic microorganisms and functions to clear injurious materials (reviewed in [1,2,3]). Over the past decade, it has become widely accepted that improper resolution of inflammatory networks is centrally involved in the pathogenesis of many acute and chronic diseases. Inflammation is a driving force behind a wide variety of chronic diseases including cancer, diabetes, obesity and Alzheimer’s disease [4]. The down-regulation of inflammation-related risk factors could be an excellent strategy to prevent or delay these chronic diseases. Macrophages are the primary pro-inflammatory cells and the activation of macrophages plays a vital role in the initiation and propagation of inflammatory responses by production of cytokines including interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α, nitric oxide (NO), prostaglandin. There are three isoforms of NOS: neuronal NOS, endothelial NOS, and inducible

Results

Discussion

Conclusion