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

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.

• Authors: Peipei Xue, Yong Wang, Fanfan Zeng, Ruijuan Xiu, Jingwen Chen, Jinguang Guo, Ping Yuan, Lin Liu, Juanjuan Xiao, Hui Lu, Dan Wu, Huaxiong Pan, Mingmin Lu, Feng Zhu, Fei Shi, Qiuhong Duan
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 16 Pg. 27093-27104 (Apr 18 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28404919 (Publication Type: Journal Article)

Chemical References

• Acetophenones
• Anti-Inflammatory Agents, Non-Steroidal
• Cytokines
• Protein Kinase Inhibitors
• paeonol
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase Kinases
• PDZ-binding kinase

Topics

• Acetophenones (pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Cell Line
• Cytokines (biosynthesis)
• Dermatitis (drug therapy, etiology, metabolism, pathology)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Male
• Mice
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Phosphorylation
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Sunlight (adverse effects)
• Ultraviolet Rays
• p38 Mitogen-Activated Protein Kinases (metabolism)