Ginsenoside Rg1 attenuates ultraviolet B-induced glucocortisides resistance in keratinocytes via Nrf2/HDAC2 signalling.

Jun Li,Daniel Zhang,Dong Liu,Yuan Wang,Juan Du,Changquan Ling,Zifei Yin,Binbin Cheng,Yani Zhang,Jinfeng Wu

doi:10.1038/srep39336

Abstract

Oxidative stress, which occurs after ultraviolet (UV) radiation, usually results in Glucocorticoid (GC) resistance and the subsequent development of skin inflammation. One approach to protecting the skin against UV radiation is the use of antioxidants. The ginsenoside Rg1 is a novel natural antioxidant isolated from the medicinal plant Panax ginseng C.A. Mey. We demonstrated that UVB exposure exacerbated inflammation and reduced both the level of the glucocorticoid receptor (GR) and the efficacy of dexamethasone (Dex) in human keratinocytes (HaCaT cells). Pretreatment with Rg1 increased the expression of GR and restored Dex responsiveness to inflammation in UVB-irradiated HaCaT cells. Mechanistically, Rg1 rescued UVB-induced HDAC2 degradation. HDAC2 knockdown partially abolished the Rg1-induced up-regulation of GR and the enhancement of GC sensitivity. In addition, Rg1 reduced the production of reactive oxygen species (ROS), which preceded the up-regulation of HDAC2, and consequent sensitization of cells to Dex. Moreover, Rg1 treatment promoted the translocation and activation of Nrf2. Nrf2 knockdown partially abolished the Rg1-induced decrease of ROS production and increase of HDAC2. Rg1 also potentiated the anti-inflammatory effects of Dex in UVB-irradiated mouse skin. In conclusion, we demonstrated that Rg1 attenuated UVB-induced GC insensitivity. Notably, these effects were partially mediated by the Nrf2/HDAC2 pathway.

Highlights

Topical glucocorticoids (GCs) are widely used to treat chronic inflammatory and autoimmune diseases of the skin[1]
We evaluated the effects of the ginsenoside Rg1 on Ultraviolet B (UVB)-induced steroid resistance in human keratinocytes and determined that the mechanism occurs via the Nuclear factor erythroid 2-related factor 2 (Nrf2)/histone deacetylase 2 (HDAC2) pathway
After UVB exposure, TNF-α-induced inflammation was enhanced, and limited inhibitory effects of Dex on IL-6 and IL-8 was observed in UVB+TNF-α+Dex group as compared with TNF-α+Dex group

Summary

Introduction

Topical glucocorticoids (GCs) are widely used to treat chronic inflammatory and autoimmune diseases of the skin[1]. A number of reports have demonstrated that oxidative stress plays an important role in glucocorticoid insensitivity by inhibiting the expression and activity of histone deacetylase 2 (HDAC2)[3,4]. Some reports have suggested that enhanced cortisol production[10,11,12,13] and reduced epidermal glucocorticoid receptor (GR) expression caused by UVB exposure might contribute to decreased GCs efficacy in chronic inflammatory diseases of the skin[13]. HDAC2 is a critical component of the GR-corepressor complex that mediates the transrepression of NF-κB transcriptional activity by deacetylating histones in the promoters of pro-inflammatory genes[17] and by deacetylating GR18. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in regulating steroid sensitivity via HDAC2 in response to inflammation in the mouse lung[19]. We evaluated the effects of the ginsenoside Rg1 on UVB-induced steroid resistance in human keratinocytes and determined that the mechanism occurs via the Nrf2/HDAC2 pathway

Methods

Results

Conclusion