Cefradine blocks solar-ultraviolet induced skin inflammation through direct inhibition of T-LAK cell-originated protein kinase

Abstract

Skin inflammation, and skin cancer induced by excessive solar ultraviolet (SUV) isa great threat to human health. SUV induced skin inflammation through activating p38mitogen-activated protein kinase (p38) and c-Jun N-termeinal kinases (JNKs). T-LAKcell-originated protein kinase (TOPK) plays an important role in this process. Herein,the clinical data showed TOPK, phospho-p38, phospho-JNKs were highly expressed inhuman solar dermatitis. Ex vivo studies showed that SUV induced the phosphorylationof p38 and JNKs in HaCat and JB6 cells in a dose and time dependent manner. Moleculedocking model indicated cefradine, an FDA-approved cephalosporin antibiotic, directlybinds with TOPK. The result of in vitro binding assay verified cefradine can directlybind with TOPK. In vitro kinase results showed cefradine can inhibit TOPK activity.Ex vivo studies further showed cefradine inhibited SUV-induced the phosphorylationlevel of p38, JNKs and H2AX through inhibiting TOPK activity in a dose and timedependent manner, and cefradine inhibited the secretion of IL6 and TNF-a in HaCatand JB6 cells. In vivo studies showed that cefradine down-regulated SUV-induced thephosphorylation of p38, JNKs and H2AX and inhibited the secretion of IL6 and TNF-ain Babl/c mice. These results indicated that cefradine can inhibit SUV-induced skininflammation by blocking TOPK signaling pathway, and TOPK is an effective targetfor suppressing inflammation induced by SUV irradiation.