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Act1 is a negative regulator in T and B cells via direct inhibition of STAT3

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机构： [1]Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA. [2]Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300051, China. [3]Center for Neuroinflammation, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China. [4]Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China. [5]Wuhan Institute of Biotechnology, Wuhan 430200, China. [6]Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. [7]National Gnotobiotic Rodent Resource Center, Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599, USA. [8]Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. [9]Department of Rheumatologic and Immunologic Disease, Cleveland Clinic, Cleveland, OH 44106, USA. [10]Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA. [11]Discovery Biology, Bristol-Myers Squibb, Princeton, NJ 08540, USA. [12]Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA. [13]Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212, USA. [14]Type 1 Diabetes Center, Novo Nordisk A/S, S?borg 2860, Denmark. [15]Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

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Although Act1 (adaptor for IL-17 receptors) is necessary for IL-17-mediated inflammatory responses, Act1- (but not ll17ra-, ll17rc-, or ll17rb-) deficient mice develop spontaneous SLE-and Sjogren's-like diseases. Here, we show that Act1 functions as a negative regulator in T and B cells via direct inhibition of STAT3. Mass spectrometry analysis detected an Act1-STAT3 complex, deficiency of Act1 (but not ll17ra-, ll17rc-, or II17rb) results in hyper IL23- and IL-21-induced STAT3 activation in T and B cells, respectively. IL-23R deletion or blockade of IL-21 ameliorates SLE- and Sjogren's-like diseases in Act1(-/-) mice. Act1 deficiency results in hyperactivated follicular Th17 cells with elevated IL-21 expression, which promotes T-B cell interaction for B cell expansion and antibody production. Moreover, antiIL-21 ameliorates the SLE- and Sjogren's-like diseases in Act1-deficient mice. Thus, IL-21 blocking antibody might be an effective therapy for treating SLE- and Sjogren's-like syndrome in patients containing Act1 mutation.

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出版当年[2017]版：

大类 | 1 区

综合性期刊

小类 | 1 区综合性期刊

最新[2025]版：

大类 | 1 区

综合性期刊

小类 | 1 区综合性期刊

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出版当年[2016]版：

Q1 MULTIDISCIPLINARY SCIENCES

最新[2024]版：

Q1 MULTIDISCIPLINARY SCIENCES

影响因子： 15.7 最新[2024版] 17.2 最新五年平均 12.124 出版当年[2016版] 13.092 出版当年五年平均 11.329 出版前一年[2015版] 12.353 出版后一年[2017版]

第一作者：

第一作者机构： [1]Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA. [2]Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300051, China. [3]Center for Neuroinflammation, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.

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通讯作者：

通讯机构： [1]Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA.

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