The Inhibitory Effect of IFN-γ on Protease HTRA1 Expression in Rheumatoid Arthritis
The Inhibitory Effect of IFN-γ on Protease HTRA1 Expression in Rheumatoid Arthritis
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DOI：
10.4049/jimmunol.1302700
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发表时间：
2014-07-01
影响因子：
4.4
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
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作者：
Hou, Yuzhu;Lin, Haijiang;Zhao, Yong
高温要求A1（HTRA 1）是一种强效蛋白酶，参与许多疾病，包括类风湿性关节炎（RA）。然而，控制HTRA 1表达的调节机制需要确定。在这项研究中，我们证明，IFN-γ显着抑制基础和LPS诱导的HTRA 1在成纤维细胞和巨噬细胞，这是两个主要的细胞HTRA 1生产RA的表达。重要的是，IFN-γ对HTRA 1表达的抑制作用在胶原诱导的关节炎（CIA）小鼠模型和人RA滑膜细胞中得到证实。与增强的CIA发病率和IFN-γ缺陷小鼠的病理变化平行，HTRA 1在关节组织中的表达也增加，如通过实时PCR和Western印迹所确定的。IFN-γ缺乏可增加CIA的发病率和病理严重程度。通过Ab中和HTRA 1显著逆转IFN-γ缺陷小鼠中CIA频率和严重程度的增加。IFN-γ通过激活p38 MAPK/STAT 1通路负性控制HTRA 1表达。双荧光素酶报告基因分析和染色质免疫沉淀分析表明，STAT 1可以直接结合HTRA 1启动子后，IFN-γ刺激。这项研究为HTRA 1表达的分子调控及其在RA发病机制中的作用提供了新的见解，这可能对RA和其他可能与HTRA 1相关的疾病（包括骨关节炎，年龄相关性黄斑变性和癌症）的临床治疗产生重大影响。
The high temperature requirement A1 (HTRA1) is a potent protease involved in many diseases, including rheumatoid arthritis (RA). However, the regulatory mechanisms that control HTRA1 expression need to be determined. In this study, we demonstrated that IFN-gamma significantly inhibited the basal and LPS-induced HTRA1 expression in fibroblasts and macrophages, which are two major cells for HTRA1 production in RA. Importantly, the inhibitory effect of IFN-gamma on HTRA1 expression was evidenced in collagen-induced arthritis (CIA) mouse models and in human RA synovial cells. In parallel with the enhanced CIA incidence and pathological changes in IFN-gamma-deficient mice, HTRA1 expression in the joint tissues was also increased as determined by real-time PCR and Western blots. IFN-gamma deficiency increased the incidence of CIA and the pathological severity in mice. Neutralization of HTRA1 by Ab significantly reversed the enhanced CIA frequency and severity in IFN-gamma-deficient mice. Mechanistically, IFN-gamma negatively controls HTRA1 expression through activation of p38 MAPK/STAT1 pathway. Dual luciferase reporter assay and chromatin immunoprecipitation analysis showed that STAT1 could directly bind to HTRA1 promoter after IFN-gamma stimulation. This study offers new insights into the molecular regulation of HTRA1 expression and its role in RA pathogenesis, which may have significant impact on clinical therapy for RA and possibly other HTRA1-related diseases, including osteoarthritis, age-related macular degeneration, and cancer.