Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, D-72076 Tübingen, Germany.
Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, D-72076 Tübingen, Germany.
J Dermatol Sci. 2017 Sep;87(3):246-251. doi: 10.1016/j.jdermsci.2017.06.005. Epub 2017 Jun 12.
Chronic inflammatory skin diseases are characterized by controlled proliferation of keratinocytes. Here, activating transcription factor 3 (ATF3) might play a fundamental role. In these inflammatory diseases, proliferation is controlled and only rarely leads to cancer development which can be supported by an inflammatory microenvironment. ATF3 is a dual function protein as it suppresses pro-inflammatory IL-6 and IL-8, but also acts as a pro-oncogenic factor by the suppression of p53. We therefore analyzed ATF3 expression comparing myeloid cells with keratinocytes.
To dissect the bi-modal role of ATF3 we pharmacologically induced ATF3 and analyzed its influence on cytokine expression and secretion in a cell type specific manner.
Since inflammatory skin diseases can be treated systemically with Cyclosporin A or Dimethylfumarate we stimulated myeloid cells and primary human keratinocytes with these drugs and analyzed gene expression by quantitative real-time PCR. Cytokine secretion was measured by ELISA.
In the present study, we could show that ATF3 is induced in PBMCs by DMF and weakly by Ebselen, while CsA is the most prominent inducer of ATF3 in keratinocytes without enhancing HO-1 transcription. Further we could show that induction of stress by LPS treatment elevates IL-1β and IL-6 and weakly ATF3 transcription in PBMCs. While transcription of both cytokines is elevated, LPS treatment mediates IL-6 secretion with only little IL-1β secretion. Treatment with DMF dampens LPS-induced transcription.
Taken together, our results shed light into the different carcinogenic potential of CsA and DMF, which both target ATF3. Collectively our data demonstrate that CsA strongly induces pro-carcinogenic ATF3 in keratinocytes, whereas ATF3 induction by DMF in myeloid cells acts anti-inflammatory.
慢性炎症性皮肤病的特征是角质形成细胞的受控增殖。在这里，激活转录因子 3（ATF3）可能发挥着基本作用。在这些炎症性疾病中，增殖受到控制，很少导致癌症发展，而炎症微环境可以支持癌症发展。ATF3 是一种具有双重功能的蛋白质，因为它可以抑制促炎细胞因子 IL-6 和 IL-8 的表达，但也可以通过抑制 p53 发挥致癌作用。因此，我们分析了髓样细胞与角质形成细胞中 ATF3 的表达情况。
为了剖析 ATF3 的双模态作用，我们通过药理学方法诱导 ATF3 表达，并以细胞类型特异性的方式分析其对细胞因子表达和分泌的影响。
由于炎症性皮肤病可以用环孢素 A 或二甲基富马酸进行系统性治疗，我们用这些药物刺激髓样细胞和原代人角质形成细胞，并通过定量实时 PCR 分析基因表达。通过 ELISA 测量细胞因子的分泌。
在本研究中，我们可以证明 DMF 可诱导 PBMCs 中的 ATF3 表达，而 Ebselen 则较弱诱导，而 CsA 是角质形成细胞中最显著的 ATF3 诱导剂，而不会增强 HO-1 转录。此外，我们还可以证明 LPS 处理诱导的应激会升高 PBMCs 中的 IL-1β 和 IL-6 以及较弱的 ATF3 转录。虽然两种细胞因子的转录都升高，但 LPS 处理介导 IL-6 分泌，而只有少量的 IL-1β 分泌。DMF 处理可抑制 LPS 诱导的转录。
总之，我们的研究结果阐明了 CsA 和 DMF 对 ATF3 的不同致癌潜力，这两种药物都靶向 ATF3。我们的数据表明，CsA 强烈诱导角质形成细胞中的促癌 ATF3，而 DMF 在髓样细胞中诱导 ATF3 则具有抗炎作用。
