Irritant activation of epithelial cells is mediated via protease-dependent EGFR activation.
Irritant activation of epithelial cells is mediated via protease-dependent EGFR activation.
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上皮细胞的刺激性激活是通过蛋白酶依赖性 EGFR 激活介导的。
DOI：
10.1038/jid.2010.308
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Swerlick,RobertA
中科院分区：
文献类型：
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作者：
White,KellieJ;Maffei,VincentJ;Newton-West,Marvin;Swerlick,RobertA
虽然许多研究已经检查了刺激物的活体和体外效应，但大多数研究集中在暴露几个小时到几天后发生的事件。皮肤接触后立即发生的分子事件仍然没有完全定义。早期事件的特征可以导致确定产生炎症介质所需的关键分子信号，这些介质是刺激性接触性皮炎(ICD)的症状和体征的罪魁祸首。用模型刺激物十二烷基硫酸钠(SLS)处理HaCaT细胞，检测ICD的早期分子事件。Western分析显示，SLS介导的早期生长反应-1(EGR-1)是一种转录因子，能够调节ICD的特征，如血管生成、过度增殖和炎症。此外，de novoegr-1的表达与EGR-1mRNA和异核RNA的转录激活成正比。药物抑制剂的使用表明，SLS诱导的EGR-1依赖于MEK1/p44/42 ERK，而不依赖于p38或JNK信号。EGFR抑制剂PD168393和金属蛋白酶抑制剂TAPI-2均可抑制SLS诱导的EGR-1。最后，对EGFR的小干扰RNA沉默可减弱SLS诱导的EGR-1mRNA。这些研究表明EGFR在SLS信号转导中的作用，以及，据我们所知，ICD和EGFR诱导的EGR-1之间存在以前未见报道的关联。
Although numerous studies have examinedin vivoandin vitroeffects of irritants, most focused on events developing hours to days after exposure. Molecular events occurring immediately after skin contact remain incompletely defined. Characterization of early events could lead to the identification of key molecular signals necessary for the production of inflammatory mediators responsible for the signs and symptoms of irritant contact dermatitis (ICD). HaCaT cells treated with sodium lauryl sulfate (SLS), a model irritant, were used to examine early molecular events of ICD. Western analysis showed SLS-mediated induction of early growth response-1 (egr-1), a transcription factor capable of regulating hallmarks of ICD such as angiogenesis, hyperproliferation, and inflammation. Additionally,de novoegr-1 expression was commensurate with transcriptional activation of egr-1 mRNA and heteronuclear RNA. Use of pharmacological inhibitors demonstrated that SLS-induced egr-1 was dependent on MEK1/p44/42 ERK, but not on p38 or JNK signaling. The EGFR inhibitor PD168393 and the metalloprotease inhibitor TAPI-2 both inhibited SLS-induced egr-1. Finally, small interfering RNA silencing of the EGFR diminished SLS-induced egr-1 mRNA. These studies suggest a role of the EGFR in SLS signaling as well as a, to our knowledge, previously unreported association between ICD and EGFR induction of egr-1.