title: 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) 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Duan
authors.affiliation: Department of Pathology, Tongji hospital, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
authors.forename: Changshu
authors.initials: C
authors.lastname: Ke
authors.affiliation: Shanghai Biyi Chemical Science and Technology Co., Shanghai, 201203, PR China.
authors.forename: Guiping
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Dermatology of the General Hospital of Air Force, Beijing, 100142, PR China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Dermatology of the General Hospital of Air Force, Beijing, 100142, PR China.
authors.forename: Jinguang
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Dermatology of the General Hospital of Air Force, Beijing, 100142, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002460:Cell Line; D002515:Cephradine / Q000494:pharmacology*; D003872:Dermatitis / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase; C000616811:TOPK protein, mouse; D002515:Cephradine
keywords: TOPK; cefradine; signal transduction pathway; skin inflammation; solar UV