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
Summary
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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