Schmidt K N, Podda M, Packer L, Baeuerle P A
Institute of Biochemistry, Albert Ludwigs University, Freiburg, Germany.
J Immunol. 1996 Jun 1;156(11):4514-9.
Anthralin is one of the most effective and safest therapeutic agents for the treatment of psoriasis, a skin disease characterized by epidermal hyperproliferation and hyperkeratosis. The drug induces and inflammatory response in the skin involving the expression of cytokine and cell adhesion molecule genes that is thought to be essential for its therapeutic efficacy. Reactive oxygen intermediates (ROIs) generated in vivo during the auto-oxidation of anthralin were discussed as mediators of the inflammatory response, but it is not yet understood how this is translated into novel inflammatory gene expression. In this study, we show that at little as 10 microM anthralin can activate a prototypic form of transcription factor NF-(kappa)B, a central transcriptional regulator of inflammatory and immune responses. Two different lines of evidence show that ROIs, in particular H2O2, are second messengers for the anthralin-induced NF-(kappa)B activation. Firstly, the activation could be inhibited by the structurally unrelated antioxidants N-acetyl-L-cysteine and pyrrolidinedithiocarbamate. Secondly, keratinocytes stably overexpressing catalase showed a significant reduction of NF-(kappa)B activation, while stable overexpression of Cu/Zn-superoxide dismutase augmented the anthralin effect. Our data suggest that ROI-induced NF-(kappa)B plays a role in the anti-psoriatic activity of the drug anthralin.
蒽林是治疗银屑病最有效且最安全的治疗药物之一，银屑病是一种以表皮过度增殖和角化过度为特征的皮肤病。该药物可在皮肤中诱导炎症反应，涉及细胞因子和细胞黏附分子基因的表达，这被认为对其治疗效果至关重要。蒽林自氧化过程中在体内产生的活性氧中间体（ROIs）被认为是炎症反应的介质，但目前尚不清楚这是如何转化为新的炎症基因表达的。在本研究中，我们发现低至10微摩尔的蒽林就能激活转录因子NF-κB的原型形式，NF-κB是炎症和免疫反应的核心转录调节因子。两条不同的证据表明，ROIs，尤其是H2O2，是蒽林诱导的NF-κB激活的第二信使。首先，结构不相关的抗氧化剂N-乙酰-L-半胱氨酸和吡咯烷二硫代氨基甲酸盐可抑制这种激活。其次，稳定过表达过氧化氢酶的角质形成细胞显示NF-κB激活显著降低，而稳定过表达铜/锌超氧化物歧化酶则增强了蒽林的作用。我们的数据表明，ROI诱导的NF-κB在蒽林的抗银屑病活性中起作用。
