Tacrolimus Inhibits TNF-α/IL-17A-Produced pro-Inflammatory Effect on Human Keratinocytes by Regulating IκBζ
Tacrolimus Inhibits TNF-α/IL-17A-Produced pro-Inflammatory Effect on Human Keratinocytes by Regulating IκBζ
复制标题
他克莫司通过调节 IκBγ 抑制 TNF-α/IL-17A 对人类角质形成细胞产生的促炎作用
DOI：
10.1007/s10753-019-01151-6
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发表时间：
2020-04-01
期刊：
影响因子：
5.1
通讯作者：
Yin, ZhiQiang
中科院分区：
文献类型：
--
作者：
Hu, YingYing;Guo, Jing;Yin, ZhiQiang
银屑病是一种主要由T淋巴细胞和角质形成细胞介导的慢性自身免疫性疾病。他克莫司是T细胞靶向免疫抑制药物，已广泛用于银屑病的局部治疗;然而，他克莫司对人角质形成细胞的药理学作用尚未完全阐明。本研究旨在研究他克莫司对模拟银屑病微环境中TNF-α/ IL-17 A共刺激的人角质形成细胞的潜在调节作用。将培养的正常人角质形成细胞（NHK）分为以下组：对照组、TNF-α/IL-17 A组、他克莫司组和TNF-α/IL-17 A+他克莫司组。24 h后收集培养细胞和上清液，然后进行实时定量PCR、蛋白质印迹和ELISA分析。用TNF-α、IL-17 A和他克莫司0.03%软膏处理包皮组织，然后培养24 h，并进行免疫组织化学。在TNF-α/IL-17 A处理后，NHK表达显著的IL-36 γ、CCL-20、IL-1 β、S100-A9和CXCL-1 mRNA。他克莫司在基因水平显著抑制TNF-α/IL-17 A诱导的IL-36 γ、CCL-20、IL-1 β和S100-A9表达，在蛋白水平显著抑制IL-36 γ和CCL-20表达。我们进一步发现TNF-α/IL-17 A可诱导NHK中I κ B zeta mRNA和蛋白的表达，这可被他克莫司抑制。他克莫司可通过调节I κ B ζ表达抑制TNF-α/IL-17 A对人角质形成细胞的促炎协同作用。
Abstract Psoriasis is a chronic autoimmune disease that is predominantly mediated by T-lymphocytes and keratinocytes. Tacrolimus is T cell-targeted immunosuppression drug that has been widely used in topical therapy of psoriasis; however, the pharmacologic effect of tacrolimus on human keratinocytes has not been fully clarified. This study aimed to investigate the potential regulatory effect of tacrolimus on TNF-alpha/ IL-17A-costimulated human keratinocytes in the mimic psoriatic microenvironment. The cultured normal human keratinocytes (NHKs) were divided into the following groups: control, TNF-alpha/IL-17A, tacrolimus, and TNF-alpha/IL-17A + tacrolimus. Cultured cells and supernatant were collected after 24 h, and then real-time quantitative PCR, western blot, and ELISA analysis were performed. Foreskin tissues were treated by using TNF-alpha, IL-17A, and tacrolimus 0.03% ointment and then cultured for 24 h, and immunohistochemistry was performed. NHKs expressed significant IL-36 gamma, CCL-20, IL-1 beta, S100-A9, and CXCL-1 mRNA after TNF-alpha/IL-17A treatment. Tacrolimus significantly inhibited TNF-alpha/IL-17A-induced IL-36 gamma, CCL-20, IL-1 beta, and S100-A9 expression at gene level and IL-36 gamma and CCL-20 expression at protein level. We further discovered TNF-alpha/IL-17A induced significant I kappa B zeta mRNA and protein expression in NHKs, which could be inhibited by tacrolimus. Tacrolimus can inhibit pro-inflammatory synergistic action of TNF-alpha/IL-17A on human keratinocytes by regulating I kappa B zeta expression.