Boston University School of Medicine, Arthritis Center, Boston, Massachusetts 02118, USA.
J Cell Physiol. 2013 Aug;228(8):1774-83. doi: 10.1002/jcp.24337.
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.
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。先前的研究表明，干扰素途径的激活与 SSc 的发病机制有关。本研究旨在确定 I 型和/或 II 型干扰素是否在 SSc 血管病变中发挥致病作用。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。利用 RT Profiler PCR 阵列系统筛选 EndoMT 基因。IFN-α或 IFN-γ处理下调 Fli1 和 VE-cadherin。相反，IFN-α和 IFN-γ对α-SMA、CTGF、ET-1 和 TGFβ2 的表达有相反的影响，IFN-α下调，IFN-γ上调这组基因。TGFβ 信号阻断使 IFN-γ介导的 Fli1、VE-cadherin、CTGF 和 ET-1 水平的变化正常化，而α-SMA 和 TGFβ2 的上调不受影响。波生坦治疗比 TGFβ 阻断更有效地逆转 IFN-γ的作用，包括下调α-SMA 和 TGFβ2，这表明 ET-1 途径的激活在 HDMECs 中 IFN-γ反应中起主要作用。IFN-γ诱导内皮-间充质转化（EndoMT）相关基因的表达，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。本研究表明 I 型和 II 型 IFN 对血管内皮细胞生物学有不同的影响。IFN-γ可能通过诱导 EndoMT 导致 SSc 中异常的血管重塑和纤维化。
