Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed using global transcriptional profiling.
Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed using global transcriptional profiling.
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发表时间：
2004
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通讯作者：
T. Banno;Alix Gazel;M. Blumenberg
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作者：
T. Banno;Alix Gazel;M. Blumenberg
肿瘤坏死因子- α (TNF - α)作为炎性疾病（如类风湿关节炎、克罗恩病和牛皮癣）的关键因子的鉴定，导致TNF - α靶向治疗，尽管避免了以前药物的许多副作用，但仍会引起其他副作用，包括继发性感染和癌症。通过控制基因表达，TNF α协调皮肤对环境损伤和炎症的反应。为了确定TNF α在表皮中的作用，我们使用寡核苷酸微阵列比较了未经TNF α处理和TNF α处理1、4、24和48小时的正常人角质形成细胞的转录谱。我们发现TNF α不仅调节免疫和炎症反应，还调节组织重塑、细胞运动、细胞周期和细胞凋亡。具体来说，TNF - α通过诱导一组特征性的趋化因子来调节先天免疫和炎症，包括新发现的TNF - α靶点，吸引中性粒细胞、巨噬细胞和皮肤特异性记忆t细胞。这提示TNF α参与银屑病、固定药疹、特应性和过敏性接触性皮炎的发病机制。TNF α通过诱导基底膜组分和胶原降解蛋白酶促进组织修复。出乎意料的是，TNF α诱导肌动蛋白细胞骨架调节因子和整合素，增强角化细胞的运动性和附着性，这些作用以前与TNF α无关。同样出乎意料的是TNF α通过调节细胞周期和凋亡相关基因对角质形成细胞命运的影响。因此，TNF α不仅启动炎症和损伤反应，还启动随后的表皮修复。这些结果提供了对TNF α有害和有益作用的新见解，并定义了实现这些结果的机制和基因，这两者对于TNF α靶向治疗都很重要。
Identification of tumor necrosis factor-alpha (TNF alpha) as the key agent in inflammatory disorders, e.g. rheumatoid arthritis, Crohn's disease, and psoriasis, led to TNF alpha-targeting therapies, which, although avoiding many of the side-effects of previous drugs, nonetheless causes other side-effects, including secondary infections and cancer. By controlling gene expression, TNF alpha orchestrates the cutaneous responses to environmental damage and inflammation. To define TNF alpha action in epidermis, we compared the transcriptional profiles of normal human keratinocytes untreated and treated with TNF alpha for 1, 4, 24, and 48 h by using oligonucleotide microarrays. We found that TNF alpha regulates not only immune and inflammatory responses but also tissue remodeling, cell motility, cell cycle, and apoptosis. Specifically, TNF alpha regulates innate immunity and inflammation by inducing a characteristic large set of chemokines, including newly identified TNF alpha targets, that attract neutrophils, macrophages, and skin-specific memory T-cells. This implicates TNF alpha in the pathogenesis of psoriasis, fixed drug eruption, atopic and allergic contact dermatitis. TNF alpha promotes tissue repair by inducing basement membrane components and collagen-degrading proteases. Unexpectedly, TNF alpha induces actin cytoskeleton regulators and integrins, enhancing keratinocyte motility and attachment, effects not previously associated with TNF alpha. Also unanticipated was the influence of TNF alpha upon keratinocyte cell fate by regulating cell-cycle and apoptosis-associated genes. Therefore, TNF alpha initiates not only the initiation of inflammation and responses to injury, but also the subsequent epidermal repair. The results provide new insights into the harmful and beneficial TNF alpha effects and define the mechanisms and genes that achieve these outcomes, both of which are important for TNF alpha-targeted therapies.