Xu JiaLi, Feng YaDong, Song GuoXin, Gong QiXing, Yin Li, Hu YingYing, Luo Dan, Yin ZhiQiang
Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Front Pharmacol. 2018 Feb 22;9:67. doi: 10.3389/fphar.2018.00067. eCollection 2018.
Topical calcineurin inhibitors including tacrolimus and pimecrolimus are used in the treatment of many inflammatory skin diseases mainly via blocking T-cell proliferation. Our previous studies found that pimecrolimus 1% cream could reverse high-dose ultraviolet B (UVB) irradiation-induced epidermal Langerhans cell (LC) reduction via inhibition of LC migration. We conducted this study to investigate the effects of topical tacrolimus 0.03% ointment on high-dose UVB-irradiated human epidermal LCs. Twenty fresh human foreskin tissues were randomly divided into four groups as follows: , (0.03%), (180 mJ/cm), (180 mJ/cm) + (0.03%). Four time points were set as follows: 0, 18, 24, and 48 h. We collected culture medium and tissues at each time point. The percentage of CD1a+ cells in the medium was detected by means of flow cytometry. Each tissue was prepared for immunohistochemistry, real-time quantitative PCR, and western blot. HaCaT cells were cultured and divided into four groups: , (1 μg/ml), (30 mJ/cm), (30 mJ/cm) + (1 μg/ml). The cells were incubated for 24 h and prepared for real-time quantitative PCR and western blot. Topical tacrolimus significantly reversed high-dose UVB irradiation-induced epidermal LC reduction and CD1a+ cell increment in culture medium. Tacrolimus significantly inhibited UVB irradiation-induced tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB)/p65 mRNA and protein expression in HaCaT cells. Tacrolimus also significantly inhibited high-dose UVB irradiation-induced TNF-α expression in cultured tissues. Finally, TNF-α antagonist (recombinant human TNF-α receptor II: IgG Fc fusion protein) could significantly reverse UVB irradiation-induced epidermal LC reduction. Topical tacrolimus 0.03% could reverse UVB irradiation-induced epidermal LC reduction by inhibiting TNF-α secretion in keratinocytes via regulation of NF-κB/p65.
包括他克莫司和吡美莫司在内的外用钙调神经磷酸酶抑制剂主要通过阻断T细胞增殖来治疗多种炎症性皮肤病。我们之前的研究发现，1%吡美莫司乳膏可通过抑制朗格汉斯细胞（LC）迁移来逆转高剂量紫外线B（UVB）照射引起的表皮LC减少。我们进行这项研究以调查0.03%外用他克莫司软膏对高剂量UVB照射的人表皮LC的影响。将20块新鲜人包皮组织随机分为以下四组： ， （0.03%）， （180 mJ/cm）， （180 mJ/cm） + （0.03%）。设置了以下四个时间点：0、18、24和48小时。我们在每个时间点收集培养基和组织。通过流式细胞术检测培养基中CD1a+细胞的百分比。每个组织都准备用于免疫组织化学、实时定量PCR和蛋白质印迹。培养HaCaT细胞并将其分为四组： ， （1 μg/ml）， （30 mJ/cm）， （30 mJ/cm） + （1 μg/ml）。将细胞孵育24小时并准备用于实时定量PCR和蛋白质印迹。外用他克莫司显著逆转了高剂量UVB照射引起的表皮LC减少和培养基中CD1a+细胞增加。他克莫司显著抑制UVB照射诱导的HaCaT细胞中肿瘤坏死因子-α（TNF-α）和核因子κB（NF-κB）/p65 mRNA及蛋白质表达。他克莫司还显著抑制高剂量UVB照射诱导的培养组织中TNF-α表达。最后，TNF-α拮抗剂（重组人TNF-α受体II：IgG Fc融合蛋白）可显著逆转UVB照射引起的表皮LC减少。0.03%外用他克莫司可通过调节NF-κB/p65抑制角质形成细胞中TNF-α分泌，从而逆转UVB照射引起的表皮LC减少。
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