7,7″-Dimethoxyagastisflavone Inhibits Proinflammatory Cytokine Release and Inflammatory Cell Recruitment through Modulating ERα Signaling.

Yi-Shin Wu,Han-Huei Lin,Yin-Hsuan Peng,Chian-Ruei Chen,Yun-Ting Yeh,Yu-Ling Lin

doi:10.3390/biomedicines9121778

Yi-Shin Wu, Han-Huei Lin + Show 4 more

Open Access

https://doi.org/10.3390/biomedicines9121778

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Abstract

Acute systemic inflammatory diseases, including sepsis, usually result in cytokine disorder and multiple-organ failure. 7,7″-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from the needles of Taxus x media var. Hicksii, has previously been evaluated for its antiproliferative and antineoplastic effects in cancer cells. In this study, the effects of DMGF on the cytokine production and cell migration of inflammatory macrophages were investigated. The inhibition of cytokine and chemokine production by DMGF in LPS-treated macrophages was analyzed by a multiplex cytokine assay. Then, the integrin molecules used for cell adhesion and regulators of actin polymerization were observed by RT-PCR and recorded using confocal imaging. The DMGF interaction with estrogen receptor α (ERα) was modeled structurally by molecular docking and validated by an ERα reporter assay. DMGF inhibited TNF-α, IL-1β, and IL-6 production in LPS-induced macrophages. DMGF also inhibited inflammatory macrophage migration by downregulating the gene and protein expression of adhesion molecules (LFA-1 and VLA4) and regulators of actin assembly (Cdc42-Rac1 pathway). DMGF might interact with the ligand-binding domain of ERα and downregulate its transcriptional activity. These results indicated that DMGF effectively inhibited the production of proinflammatory cytokines and the recruitment of inflammatory cells through downregulating ERα signaling.

Highlights

Acute systemic inflammatory diseases, including sepsis, usually result in cytokine disorder and multiple-organ failure. 7,7”-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from the needles of Taxus x media var
In addition to adhesion molecules, DMGF decreased filopodia and lamellipodia production and led to a round cell morphology (Figure 2C,D). These results suggest that the inhibition of macrophage migration in response to DMGF depends on a mechanism relying on F-actin polymerization
In vitro and in vivo studies showed that DMGF effectively inhibited inflammation and protected the endotoxin shock mice from hyperinflammation and organ damage caused by inflammatory macrophage infiltration (Figures 1A and 6)

Summary

Introduction

Acute systemic inflammatory diseases, including sepsis, usually result in cytokine disorder and multiple-organ failure. 7,7”-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from the needles of Taxus x media var. DMGF inhibited inflammatory macrophage migration by downregulating the gene and protein expression of adhesion molecules (LFA-1 and VLA4) and regulators of actin assembly (Cdc42-Rac pathway). DMGF might interact with the ligand-binding domain of ERα and downregulate its transcriptional activity These results indicated that DMGF effectively inhibited the production of proinflammatory cytokines and the recruitment of inflammatory cells through downregulating ERα signaling. DMGF can downregulate the levels of key modulators of the Cdc42/Rac pathway to interfere in F-actin polymerization and suppress the formation of lamellipodia by reducing the phosphorylation of CREB [3] These findings suggest that DMGF may be further developed as a chemotherapeutic drug for patients with metastatic melanoma; the anti-inflammatory activity of DMGF has hitherto not been investigated. The clinical treatment of sepsis focuses on treating the primary triggering condition to disrupt the progression of the continuum of septic shock and multi-organ dys-

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