Abstract

The immunobiological functions of Rg6, a rare ginsenoside from ginseng, have been largely unreported. In this paper, we demonstrate that Rg6 has a significant immunosuppressive function on Toll-like receptor (TLR) 4-induced systemic inflammatory responses. Rg6 was found to negatively regulate pro-inflammatory responses and severity in vivo, and thus induced recovery in mice with lipopolysaccharide (LPS)-induced septic shock and cecal ligation and puncture (CLP)-induced sepsis. Rg6 treatment also facilitated recovery in mice with LPS-induced lung damage via reduced neutrophil infiltration and tumor necrosis factor-α expression in lung tissues. Rg6 injection also downregulated pro-inflammatory cytokines and increased the levels of interleukin (IL)-10 in the serum of septic mice. Mechanistically, Rg6 did not induce TLR negative regulators, such as A20 and IRAK-M, in bone marrow-derived macrophages (BMDMs). Instead, addition of Rg6 to LPS-activated BMDMs augmented IL-10 expression, whereas it inhibited inflammatory signaling, such as by nuclear factor κB activation and mitogen-activated protein kinases. Furthermore, Rg6 significantly induced miR-146a, an operator miRNA for anti-inflammation, in BMDMs. Collectively, these data indicate that Rg6 inhibits inflammatory responses through the induction of IL-10 and miR-146a.

Highlights

  • Sepsis is the cause of one-third of the deaths of hospital patients[1,2,3]

  • Since the amount of the rare ginsenoside Rg6 in black ginseng (BG) is very low, we developed a new manufacturing method to produce Rg6 from the ginsenoside Re23, which is one of the major ginsenoside component in the fresh or white ginseng (Fig. 1a)

  • After analyzing the purity of newly produced ginsenoside Rg6 by HPLC system (Supplementary Fig. S1), bone marrow-derived macrophages (BMDMs) were treated with either purified or purchased Rg6 to evaluate their anti-inflammatory activity against LPS stimulation

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Summary

Introduction

Sepsis is the cause of one-third of the deaths of hospital patients[1,2,3]. It is a life-threatening condition caused by infection, accompanied by a strong inflammatory response, which is called a cytokine storm, involving tissue and organ damage during the acute phase of sepsis. The induction of IL-10 may reduce the levels of pro-inflammatory cytokines, but has been demonstrated to control innate immunity by clearing bacteria from pathogen-infected lungs and improving the survival of the host[9]. Www.nature.com/scientificreports signaling pathway is another treatment option to downregulate excessive inflammatory responses in patients with LPS-induced septic shock. By targeting TRAF6 and IRAK1, which are downstream molecules in the TLR signaling pathway, miR-146a controls inflammatory cytokine signaling through a negative feedback regulation loop. This miRNA has been established as a potent negative regulator of inflammation[15,16,17]. The characteristics of several rare ginsenosides have not yet been elucidated

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