title: The inhibitory effect of IFN-γ on protease HTRA1 expression in rheumatoid arthritis.
abstract: 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-γ 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-γ 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-γ-deficient mice, HTRA1 expression in the joint tissues was also increased as determined by real-time PCR and Western blots. IFN-γ 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-γ-deficient mice. Mechanistically, IFN-γ 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-γ 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.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Yuzhu
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
authors.forename: Haijiang
authors.initials: H
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Linnan
authors.initials: L
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Zhaoting
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Rheumatology and Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing 100044, China;
authors.forename: Fanlei
authors.initials: F
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; General Hospital of Chinese People's Armed Police Forces, Beijing 100039, China;
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Rheumatology, Second Hospital of Hebei Medical University, Shijiazhuang 050000, China; and.
authors.forename: Huifang
authors.initials: H
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Tan
authors.affiliation: Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, and Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; zhaoy@ioz.ac.cn qiangwang@ioz.ac.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Rheumatology and Immunology, Clinical Immunology Center, Peking University People's Hospital, Beijing 100044, China; zhaoy@ioz.ac.cn qiangwang@ioz.ac.cn.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; zhaoy@ioz.ac.cn qiangwang@ioz.ac.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D003094:Collagen / Q000633:toxicity; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007596:Joints / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C573415:IFNG protein, human; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; C492073:HtrA1 protein, mouse; D012697:Serine Endopeptidases