Interferon-γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) β2.
Interferon-γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) β2.
复制标题
DOI：
10.1002/jcp.24337
复制
发表时间：
2013-08
影响因子：
5.6
通讯作者：
Trojanowska, Maria
中科院分区：
文献类型：
--
作者：
Chrobak, Izabela;Lenna, Stefania;Stawski, Lukasz;Trojanowska, Maria
系统性硬化症（SSc）是一种以血管改变、免疫系统激活和组织纤维化为特征的复杂疾病。以前的研究表明干扰素通路的激活参与了SSc的发病机制。本研究的目的是确定是否干扰素I型和/或II型可以发挥致病作用的SSc血管病变。人真皮微血管内皮细胞（HDMVEC）和成纤维细胞获得自健康新生儿的包皮。使用RT Profiler PCR阵列系统筛选EndoMT基因。IFN-α或IFN-γ处理下调Fli 1和VE-钙粘蛋白。IFN-α和IFN-γ对α-SMA、CTGF、ET-1和TGFβ2的表达有相反的作用，IFN-α下调而IFN-γ上调。阻断TGFβ信号使IFN-γ介导的Fli 1、VE-钙粘蛋白、CTGF和ET-1水平的变化正常化，而α-SMA和TGFβ2的上调不受影响。波生坦治疗在逆转IFN-γ的作用方面比TGFβ阻断剂更有效，包括α-SMA和TGFβ2的下调，表明ET-1通路的激活在HDMECs中的IFN-γ应答中起主要作用。IFN-γ诱导与内皮-间充质转化（EndoMT）相关的选定基因的表达，包括Snail 1、FN 1、PAI 1、TWIST 1、STAT 3、RGS 2和WNT途径的组分。IFN-γ通过TGFβ2和ET-1信号通路对EndoMT的影响。这项研究表明IFN-α和IFN-γ对血管内皮细胞生物学的不同影响。IFN-γ可能部分通过诱导EndoMT参与SSc的异常血管重塑和纤维化。
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.
登录
查看更多内容
影响因子：
15.9
作者：
LAMAS, S;MICHEL, T;MARSDEN, PA
通讯作者：
MARSDEN, PA
影响因子：
3.4
作者：
Capaldo, Christopher T.;Nusrat, Asma
通讯作者：
Nusrat, Asma
影响因子：
4.8
作者：
Nakerakanti, Sashidhar S.;Kapanadze, Bagrat;Trojanowska, Maria
通讯作者：
Trojanowska, Maria
DOI：
10.1080/10623320390272299
发表时间：
2003-01-01
影响因子：
--
作者：
Minagar, A;Long, A;Alexander, JS
通讯作者：
Alexander, JS
影响因子：
6
作者：
Kubo, M;Czuwara-Ladykowska, J;Trojanowska, M
通讯作者：
Trojanowska, M