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首页> 美国卫生研究院文献>other >Interferon-γ Promotes Vascular Remodeling in Human Microvascular Endothelial Cells by Upregulating Endothelin (ET)-1 and Transforming Growth Factor (TGF) β2
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Interferon-γ Promotes Vascular Remodeling in Human Microvascular Endothelial Cells by Upregulating Endothelin (ET)-1 and Transforming Growth Factor (TGF) β2

机译：γ-干扰素通过上调内皮素（ET）-1和转化生长因子（TGF）β2促进人微血管内皮细胞的血管重塑

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Systemic sclerosis (SSc) is a complex disease characterized by vascular alterations, activation of the immune system and tissue fibrosis. Previous studies have implicated activation of the interferon pathways in the pathogenesis of SSc. The goal of this study was to determine whether interferon type I and/or type II could play a pathogenic role in SSc vasculopathy. Human dermal microvascular endothelial cells (HDMVECs) and fibroblasts were obtained from foreskins of healthy newborns. The RT Profiler PCR Array System was utilized to screen for EndoMT genes. Treatment with IFN-α or IFN-γ downregulated Fli1 and VE-cadherin. In contrast, IFN-α and IFN-γ exerted opposite effects on the expression of α-SMA, CTGF, ET-1, and TGFβ2, with IFN-α downregulating and IFN-γ upregulating this set of genes. Blockade of TGFβ signaling normalized IFN-γ-mediated changes in Fli1, VE-cadherin, CTGF, and ET-1 levels, whereas upregulation of α-SMA and TGFβ2 was not affected. Bosentan treatment was more effective than TGFβ blockade in reversing the actions of IFN-γ, including downregulation of α-SMA and TGFβ2, suggesting that activation of the ET-1 pathway plays a main role in the IFN-γ responses in HDMECs. IFN-γ induced expression of selected genes related to endothelial-to-mesenchymal transition (EndoMT), including Snail1, FN1, PAI1, TWIST1, STAT3, RGS2, and components of the WNT pathway. The effect of IFN-γ on EndoMT was mediated via TGFβ2 and ET-1 signaling pathways. This study demonstrates distinct effects of IFN-α and IFN-γ on the biology of vascular endothelial cells. IFN-γ may contribute to abnormal vascular remodeling and fibrogenesis in SSc, partially via induction of EndoMT.
机译：系统性硬化症（SSc）是一种复杂的疾病，其特征在于血管改变，免疫系统激活和组织纤维化。先前的研究暗示SSc的发病机理中干扰素途径的激活。这项研究的目的是确定I型和/或II型干扰素是否可以在SSc血管病中发挥致病作用。从健康新生儿的包皮中获得人真皮微血管内皮细胞（HDMVEC）和成纤维细胞。 RT Profiler PCR阵列系统用于筛选EndoMT基因。 IFN-α或IFN-γ的治疗下调了Fli1和VE-钙黏着蛋白。相反，IFN-α和IFN-γ对α-SMA，CTGF，ET-1和TGFβ2的表达产生相反的作用，其中IFN-α下调而IFN-γ上调这组基因。阻断TGFβ信号可正常化IFN-γ介导的Fli1，VE-钙粘蛋白，CTGF和ET-1水平的变化，而α-SMA和TGFβ2的上调则不受影响。在逆转IFN-γ的作用（包括下调α-SMA和TGFβ2的作用）方面，波生坦治疗比TGFβ阻断更有效，这表明ET-1途径的激活在HDMECs的IFN-γ反应中起主要作用。 IFN-γ诱导了与内皮到间充质转化（EndoMT）相关的选定基因的表达，包括Snail1，FN1，PAI1，TWIST1，STAT3，RGS2和WNT途径的组成部分。 IFN-γ对EndoMT的影响是通过TGFβ2和ET-1信号通路介导的。这项研究证明了IFN-α和IFN-γ对血管内皮细胞生物学的独特影响。 IFN-γ可能部分通过诱导EndoMT促成SSc中异常的血管重塑和纤维生成。

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