STAT3 Negatively Regulates Type I IFN-Mediated Antiviral Response

被引:140
作者
Wang, Wei-Bei [1 ]
Levy, David E. [2 ]
Lee, Chien-Kuo [1 ]
机构
[1] Natl Taiwan Univ, Coll Med, Grad Inst Immunol, Taipei 100, Taiwan
[2] NYU, Dept Pathol, Sch Med, New York, NY 10016 USA
关键词
SIGNAL TRANSDUCER; TARGETED DISRUPTION; CELL-DEVELOPMENT; INNATE IMMUNITY; VIRAL DISEASE; RIG-I; INTERFERON; ACTIVATION; VIRUS; GENE;
D O I
10.4049/jimmunol.1004128
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Type I IFNs are crucial cytokines of innate immunity for combating viral infections. Signaling through type I IFN receptors triggers the activation of STAT proteins, including STAT1, STAT2, and STAT3. Although an essential role of STAT1 and STAT2 for type I IFN-induced antiviral response has been well established by studies of gene-targeted mice and human mutations, the role of STAT3 for this response remains unclear. Using gain-of-function and loss-of-function approaches, we demonstrated that STAT3 negatively regulates type I IFN-mediated response. STAT3 knockdown or knockout cells displayed enhanced gene expression and antiviral activity in response to IFN-alpha/beta. Restoration of STAT3 to STAT3KO cells resulted in attenuation of the response. Upon viral infection, increased type I IFN production in STAT3KO cells resulted in enhanced STAT activation and ISG expression. One mechanism for the enhanced IFN production and response in the absence of STAT3 might operate through an MDA5-dependent manner. STAT3 also appeared to suppress IFN response directly in a manner dependent on its N-terminal domain and independent of its function as a transcriptional factor. Taken together, these results define STAT3 as a negative regulator of type I IFN response and provide a therapeutic target for viral infections. The Journal of Immunology, 2011, 187: 2578-2585.
引用
收藏
页码:2578 / 2585
页数:8
相关论文
共 38 条
[1]   Signal Transducer and Activator of Transcription-3, Inflammation, and Cancer How Intimate Is the Relationship? [J].
Aggarwal, Bharat B. ;
Kunnumakkara, Ajaikurnar B. ;
Harikumar, Kuzhuvelil B. ;
Gupta, Shan R. ;
Tharakan, Sheeja T. ;
Koca, Cemile ;
Dey, Sanjit ;
Sung, Bokyung .
NATURAL COMPOUNDS AND THEIR ROLE IN APOPTOTIC CELL SIGNALING PATHWAYS, 2009, 1171 :59-76
[2]   Hematopoietic cytokine receptor signaling [J].
Baker, S. J. ;
Rane, S. G. ;
Reddy, E. P. .
ONCOGENE, 2007, 26 (47) :6724-6737
[3]   The interferon-inducible RNA helicase, mda-5, is involved in measles virus-induced expression of antiviral cytokines [J].
Berghall, Heidi ;
Siren, Jukka ;
Sarkar, Devanand ;
Julkunen, Ilkka ;
Fisher, Paul B. ;
Vainionpaa, Raija ;
Matikainen, Sampsa .
MICROBES AND INFECTION, 2006, 8 (08) :2138-2144
[4]   Stat3 as an oncogene [J].
Bromberg, JF ;
Wrzeszczynska, MH ;
Devgan, G ;
Zhao, YX ;
Pestell, RG ;
Albanese, C ;
Darnell, JE .
CELL, 1999, 98 (03) :295-303
[5]   STAT2 hypomorphic mutant mice display impaired dendritic cell development and antiviral response [J].
Chen, Lan-Sun ;
Wei, Pei-Chi ;
Liu, Taming ;
Kao, Chung-Hsuan ;
Pai, Li-Mei ;
Lee, Chien-Kuo .
JOURNAL OF BIOMEDICAL SCIENCE, 2009, 16
[6]   STAT3 positively regulates an early step in B-cell development [J].
Chou, Wei-Chun ;
Levy, David E. ;
Lee, Chien-Kuo .
BLOOD, 2006, 108 (09) :3005-3011
[7]   SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis [J].
Croker, BA ;
Metcalf, D ;
Robb, L ;
Wei, W ;
Mifsud, S ;
DiRago, L ;
Cluse, LA ;
Sutherland, KD ;
Hartley, L ;
Williams, E ;
Zhang, JG ;
Hilton, DJ ;
Nicola, NA ;
Alexander, WS ;
Roberts, AW .
IMMUNITY, 2004, 20 (02) :153-165
[8]   Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency [J].
Dupuis, S ;
Jouanguy, E ;
Al-Hajjar, S ;
Fieschi, C ;
Al-Mohsen, IZ ;
Al-Jumaah, S ;
Yang, K ;
Chapgier, A ;
Eidenschenk, C ;
Eid, P ;
Al Ghonaium, A ;
Tufenkeji, H ;
Frayha, H ;
Al-Gazlan, S ;
Al-Rayes, HA ;
Schreiber, RD ;
Gresser, I ;
Casanova, JL .
NATURE GENETICS, 2003, 33 (03) :388-391
[9]   Targeted disruption of the mouse STAT1 results in compromised innate immunity to viral disease [J].
Durbin, JE ;
Hackenmiller, R ;
Simon, MC ;
Levy, DE .
CELL, 1996, 84 (03) :443-450
[10]   Mitochondrial STAT3 Supports Ras-Dependent Oncogenic Transformation [J].
Gough, Daniel J. ;
Corlett, Alicia ;
Schlessinger, Karni ;
Wegrzyn, Joanna ;
Larner, Andrew C. ;
Levy, David E. .
SCIENCE, 2009, 324 (5935) :1713-1716