Paeonol suppresses solar ultraviolet-induced skin inflammation by targeting T-LAK cell-originated protein kinase.

Peipei Xue,Dan Wu,Yong Wang,Hui Lu,Jinguang Guo,Jingwen Chen,Juanjuan Xiao,Ping Yuan,Huaxiong Pan,Qiuhong Duan,Mingmin Lu,Fanfan Zeng,Fei Shi,Lin Liu,Feng Zhu,Ruijuan Xiu

doi:10.18632/oncotarget.15636

Abstract

Excessive exposure to solar UV (SUV) is related with numerous human skin disorders, such as skin inflammation, photoaging and carcinogenesis. T-LAK cell- originated protein kinase (TOPK), an upstream of p38 mitogen-activated protein kinase (p38) and c-Jun N-terminal kinases (JNKs), plays an important role in SUV -induced skin inflammation, and targeting TOPK has already been a strategy to prevent skin inflammation. In this study, we found that the expression of TOPK, phosphorylation of p38 or JNKs was increased in human solar dermatitis tissues. The level of phosphorylation of p38 or JNKs increased in a dose and time dependent manner in HaCat cells or JB6 Cl41 cells after SUV treatment. Paeonol is an active component isolated from traditional Chinese herbal medicines, and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2H-tetrazdium) assay showed that it has no toxicity to cells. Microscale thermophoresis (MST) assay showed that paeonol can bind TOPK ex vivo. In vitro kinase assay showed paeonol can inhibit TOPK activity. Ex vivo studies further showed paeonol suppressed SUV-induced phosphorylation level of p38, JNKs, MSK1 and histone H2AX by inhibiting TOPK activity in a time and dose dependent manner. Paeonol inhibited the secretion of IL-6 and TNF-α in HaCat and JB6 cells ex vivo. In vivo studies demonstrated that paeonol inhibited SUV-induced increase of TOPK, the phosphorylation of p38, JNKs and H2AX, and the secretion of IL-6 and TNF-α in Babl/c mouse. In summary, our data indicated a protective role of paeonol against SUV-induced inflammation by targeting TOPK, and paeonol could be a promising agent for the treatment of SUV-induced skin inflammation.

Highlights

Exposure to ultraviolet (UV) irradiation causes DNA damage and other cellular responses that contribute to numerous human skin disorders, such as skin inflammation, photoaging, and carcinogenesis [1,2,3]
The data (See Supplementary Figure 1) indicated that solar UV (SUV) could induce elevated T-LAK celloriginated protein kinase (TOPK) and mitogen-activated protein kinases (MAPKs), such as phosphorylated p38 and Jun N-terminal kinases (JNKs) accompanied with skin inflammation
TOPK could be a therapeutic target for SUV; induced skin inflammation

Summary

Introduction

Exposure to ultraviolet (UV) irradiation causes DNA damage and other cellular responses that contribute to numerous human skin disorders, such as skin inflammation, photoaging, and carcinogenesis [1,2,3]. All UVC and most of UVB (95%) can be absorbed by the ozone layer efficiently [5]. Both UVA and UVB are harmful to human skin. T-LAK cell-originated protein kinase (TOPK) was first studied as a novel MAPKK-like protein kinase [6] in 2000. It is highly expressed in a variety of tumors including breast cancer [7], colorectal cancer [8], lung cancer [9] and hepatocellular carcinoma [10]. It has been shown that TOPK is closely related to Solar UV (SUV) -induced skin inflammation and considered to be an effective therapeutic target for SUV-induced skin inflammation [11, 12]

Methods

Results

Conclusion