Pro-pigmentary action of 5-fluorouracil through the stimulated secretion of CXCL12 by dermal fibroblasts  

作　　者：Zhi-Kai Liao Shuang-Hai Hu Bin-Yu Han Xie Qiu Shan Jiang Tie-Chi Lei 

机构地区：[1]Department of Dermatology,Renmin Hospital of Wuhan University,Wuhan,Hubei 430060,China

出　　处：《Chinese Medical Journal》2021年第20期2475-2482,共8页中华医学杂志（英文版）

基　　金：supported by a grant from the National Natural Science Foundation of China(No.81972919)。

摘　　要：Background:There is growing evidence that 5-fluorouracil(5-FU)combined with therapeutic trauma can effectively induce skin repigmentation in vitiligo patients who are unresponsive to conventional treatments.Previous studies have mainly focused on identifying the antimitotic activity of 5-FU for the treatment of skin cancer,but few studies have investigated its extra-genotoxic actions favoring melanocyte recruitment.Methods:We utilized the full thickness excisional skin wound model in Dct-LacZ transgenic mice to dynamically assess the migration of melanocytes in the margins of wounds treated with or without 5-FU.Thein-situ expression of CXCL12 was examined in the wound beds using immunofluorescence staining.Quantitative real-time polymerase chain reaction and Western blotting analyses were performed to detect the expression levels of CXCL12 mRNA and protein in primary mouse dermal fibroblasts treated with or without 5-FU.Transwell assays and fluorescein isothiocyanate(FITC)-phalloidin staining were used to observe cell migration and filamentous actin(F-actin)changes of melan-a murine melanocytes.Results:Whole mount and cryosection X-gal staining showed that the cell numbers of LacZ-positive melanocytes were much higher in the margins of dorsal and tail skin wounds treated with 5-FU compared with the controls.Meanwhile,CXCL12 immunostaining was significantly increased in the dermal compartment of wounds treated with 5-FU(controlvs.5-FU,22.47±8.85vs.44.69±5.97,P<0.05).Moreover,5-FU significantly upregulated the expression levels of CXCL12 mRNA(controlvs.5-FU,1.00±0.08vs.1.54±0.06,P<0.05)and protein(controlvs.5-FU,1.00±0.06vs.2.93±0.10,P<0.05)in cultured fibroblasts.Inhibition of the CXCL12/CXCR4 axis suppressed melanocyte migrationin vitro using a CXCL12 small interfering RNA(siRNA)or a CXCR4 antagonist(AMD3100).Conclusion:5-FU possesses a pro-pigmentary activity through activation of the CXCL12/CXCR4 axis to drive the chemotactic migration of melanocytes.

关 键 词：Fluorouracil MELANOCYTE Migration FIBROBLAST CHEMOKINE VITILIGO 

分 类 号：R739.5[医药卫生—肿瘤]