TNF-α and IFN-γ Are Potential Inducers of Fas-Mediated Keratinocyte Apoptosis through Activation of Inducible Nitric Oxide Synthase in Toxic Epidermal Necrolysis
TNF-α and IFN-γ Are Potential Inducers of Fas-Mediated Keratinocyte Apoptosis through Activation of Inducible Nitric Oxide Synthase in Toxic Epidermal Necrolysis
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DOI：
10.1038/jid.2012.330
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发表时间：
2013-02-01
影响因子：
6.5
通讯作者：
French, Lars E.
中科院分区：
文献类型：
--
作者：
Viard-Leveugle, Isabelle;Gaide, Olivier;French, Lars E.
中毒性表皮坏死松解(TEN)是一种严重的免疫介导的不良皮肤药疹，其特征是表皮和粘膜中的上皮细胞迅速而广泛的死亡。导致这种通常是致命的疾病的分子事件只被部分了解，但有证据表明，一种双重机制牵涉到一边是“药物”特异性免疫反应，另一边是包括FasL在内的促凋亡分子启动的靶细胞死亡。在这里，我们描述了这两个事件之间的潜在分子桥，涉及诱导型一氧化氮合酶(INOS)，它在10名患者的皮肤中高度上调。我们发现激活的T细胞分泌大量的肿瘤坏死因子-α和干扰素-γ，并且这两种细胞因子都导致角质形成细胞iNOS的表达和活性增加。同样的观察也来自于一名接触过这种药物的10名患者的药物特异性T淋巴细胞。由此产生的一氧化氮增加显著上调角质形成细胞FasL的表达，导致Fas和caspase-8介导的角质形成细胞死亡。综上所述，我们的数据提示，10名患者的T淋巴细胞被药物激活可能通过涉及肿瘤坏死因子-α、干扰素-γ和诱导型一氧化氮合酶的分子桥梁间接导致FasL介导的角质形成细胞的凋亡。《皮肤病研究杂志》(2013年)133489-498；doi：10.1038/jid.2012.330；2012年9月20日在线发布
Toxic epidermal necrolysis (TEN) is a severe immune-mediated adverse cutaneous drug eruption characterized by rapid and extensive epithelial cell death in the epidermis and mucosae. The molecular events leading to this often fatal condition are only partially understood, but evidence suggests a dual mechanism implicating a "drug"-specific immune response on one side and the onset of target cell death by proapoptotic molecules including FasL on the other side. Herein, we describe a potential molecular bridge between these two events that involves inducible nitric oxide synthase (iNOS), which is highly upregulated in the skin of TEN patients. We show that activated T cells secrete high amounts of tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma, and that both cytokines lead to increased expression and activity of keratinocyte iNOS. A similar observation has been made with drug-specific T lymphocytes from a TEN patient exposed to the culprit drug. The resulting increase in nitric oxide significantly upregulates keratinocyte FasL expression, resulting in Fas- and caspase-8-mediated keratinocyte cell death. Taken together, our data suggest that T-lymphocyte activation by drugs in TEN patients may indirectly lead to FasL-mediated keratinocyte apoptosis, via a molecular bridge involving TNF-alpha, IFN-gamma, and iNOS. Journal of Investigative Dermatology (2013) 133, 489-498; doi:10.1038/jid.2012.330; published online 20 September 2012