Pervanadate mimics IFN gamma-mediated induction of ICAM-1 expression via activation of STAT proteins
Pervanadate mimics IFN gamma-mediated induction of ICAM-1 expression via activation of STAT proteins
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DOI：
10.1111/1523-1747.ep12286465
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发表时间：
1997-03-01
影响因子：
6.5
通讯作者：
Caughman, SW
中科院分区：
文献类型：
--
作者：
Duff, JL;Quinlan, KL;Caughman, SW
细胞间粘附分子-1（ICAM-1）在表皮中的差异表达在皮肤炎症、免疫反应和组织修复的调节中起关键作用。ICAM-1响应于干扰素-γ（IFN-γ）的转录上调通过回文反应元件pI γ RE发生。pI γ RE与IFN γ激活序列同源，其与转录因子家族的酪氨酸磷酸化成员（称为信号转导和转录激活因子（STAT））结合。STAT途径中酪氨酸磷酸化事件的重要性促使我们研究蛋白酪氨酸磷酸酶抑制剂过钒酸盐对ICAM-1表达的影响。我们表明，治疗A431细胞和人角质形成细胞与过钒酸刺激蛋白复合物的形成pI γ RE在时间和浓度依赖性的方式，如流动性supershift测定所示，过钒酸刺激的复合物是类似的IFN γ刺激的复合物，并包含Stat 1。过钒酸盐处理还导致总体蛋白酪氨酸磷酸化和Stat 1磷酸化的增加，以及随后ICAM-1 mRNA和细胞表面蛋白水平的增加。这些数据表明过钒酸盐可以模拟IFN γ介导的导致ICAM-1表达的途径中的每个步骤，证明药理学试剂能够绕过增加ICAM-1表达所需的标准精氨酸-受体相互作用，并强调蛋白酪氨酸磷酸酶和蛋白酪氨酸激酶在介导皮肤炎症反应中的重要性。
Differential expression of intercellular adhesion molecule-1 (ICAM-1) in the epidermis plays a critical role in the regulation of cutaneous inflammation, immunologic reactions, and tissue repair, Transcriptional upregulation of ICAM-1 in response to interferon-gamma (IFN gamma) occurs through a palindromic response element pI gamma RE. pI gamma RE is homologous to IFN gamma-activated sequences, which bind to tyrosine phosphorylated members of the transcription factor family known as signal transducers and activators of transcription (STAT). The importance of tyrosine phosphorylation events in the STAT pathway led us to investigate the effect of the protein tyrosine phosphatase inhibitor, pervanadate, on ICAM-1, expression. We show that treatment of A431 cells and human keratinocytes with pervanadate stimulates protein complex formation on pI gamma RE in a time- and concentration-dependent manner, As demonstrated by mobility supershift assays, the pervanadate-stimulated complex is similar to the IFN gamma-stimulated complex and contains Stat1. Pervanadate treatment also led to an increase in overall protein tyrosine phosphorylation and phosphorylation of Stat1, as well as the subsequent increase in ICAM-1 mRNA and cell surface protein levels, These data show that pervanadate can mimic each step in the IFN gamma-mediated pathway leading to ICAM-1 expression, demonstrate the ability of a pharmacologic agent to bypass the standard cytokine-receptor interaction required for increased ICAM-1 expression, and emphasize the importance of protein tyrosine phosphatases and protein tyrosine kinases in mediating inflammatory responses in the skin.