Abstract
Skin inflammation, and skin cancer induced by excessive solar ultraviolet (SUV) is a great threat to human health. SUV induced skin inflammation through activating p38 mitogen-activated protein kinase (p38) and c-Jun N-termeinal kinases (JNKs). T-LAK cell-originated protein kinase (TOPK) plays an important role in this process. Herein, the clinical data showed TOPK, phospho-p38, phospho-JNKs were highly expressed in human solar dermatitis. Ex vivo studies showed that SUV induced the phosphorylation of p38 and JNKs in HaCat and JB6 cells in a dose and time dependent manner. Molecule docking model indicated cefradine, an FDA-approved cephalosporin antibiotic, directly binds with TOPK. The result of in vitro binding assay verified cefradine can directly bind with TOPK. In vitro kinase results showed cefradine can inhibit TOPK activity. Ex vivo studies further showed cefradine inhibited SUV-induced the phosphorylation level of p38, JNKs and H2AX through inhibiting TOPK activity in a dose and time dependent manner, and cefradine inhibited the secretion of IL6 and TNF-α in HaCat and JB6 cells. In vivo studies showed that cefradine down-regulated SUV-induced the phosphorylation of p38, JNKs and H2AX and inhibited the secretion of IL6 and TNF-α in Babl/c mice. These results indicated that cefradine can inhibit SUV-induced skin inflammation by blocking TOPK signaling pathway, and TOPK is an effective target for suppressing inflammation induced by SUV irradiation.
Highlights
Solar ultraviolet (SUV) radiation includes UVA (315-400 nm), UVB (280-315 nm) and UVC (200-280 nm)
The hematoxylin and eosin (H&E) results showed that the hyperkeratosis, thickness of epidermis, and infiltration of inflammatory cells in solar dermatitis were higher compared with the normal skin
Most skin diseases are related to UV irradiation, such as solar dermatitis, ichthyosis, psoriasis, actinic keratosis, and skin cancers
Summary
Solar ultraviolet (SUV) radiation includes UVA (315-400 nm), UVB (280-315 nm) and UVC (200-280 nm). All of UVC, 90% UVB and 10% UVA irradiation are absorbed by the ozone layer [1]. UVA and UVB are considered to be a major contributor to skin inflammation and cancer. Many pathways have been studied using pure UVA and UVB irradiation, the pathological change induced by SUV has not been well understood sufficient for the disease of prevention and treatment. SUV-induced oxidative stress is associated with some chronic inflammation diseases of skin, such as solar dermatitis, psoriasis and skin cancer [3]. Suppression of the signaling pathway of inflammation was an effective strategy to manage SUVinduced skin diseases. P38α and JNKs can be activated strongly in SUV radiation induced inflammation [7]
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