Regulatory roles of c-jun in H5N1 influenza virus replication and host inflammation.
The cytokine storm which is a great burden on humanity in highly pathogenic influenza virus infections requires activation of multiple signaling pathways. These pathways, such as MAPK and JNK, are important for viral replication and host inflammatory response. Here we examined the roles of JNK downstream molecule c-jun in host inflammatory responses and H5N1 virus replication using a c-jun targeted DNAzyme (Dz13). Transfection of Dz13 significantly reduced H5N1 influenza virus replication in human lung epithelial cells. Concomitantly, there was a decreased expression of pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interferon (IFN)-β and interleukin (IL)-6) in c-jun suppressed cells, while the expression of anti-inflammatory cytokines, such as IL-10, was increased. In vivo, compared with control groups, suppression of c-jun improved the survival rate of mice infected with H5N1 virus (55.5% in Dz13 treated mice versus ≤11% of control mice) and decreased the CD8(+) T cell proliferation. Simultaneously, the pulmonary inflammatory response and viral burden also decreased in the Dz13 treated group. Thus, our data demonstrated a critical role for c-jun in the establishment of H5N1 infection and subsequent inflammatory reactions, which suggest that c-jun may be a potential therapeutic target for viral pneumonia.
Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Jingjing
J
Xie
Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Shouping
S
Zhang
Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Yanxin
Y
Hu
Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Dirui
D
Li
Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Jingmin
J
Cui
Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Jia
J
Xue
Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Guozhong
G
Zhang
Centre for Vascular Research, University of New South Wales, Australia; Department of Haematology, The Prince of Wales Hospital, Sydney NSW 2031, Australia.
Levon M
LM
Khachigian
Biotechnology, DRDC, Box 4000, Station Main, Medicine Hat, Alberta T1A 8K6, Canada. Electronic address: Jonathan.Wong@drdc-rddc.gc.ca.
Jonathan
J
Wong
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410078, China. Electronic address: lunquansun@csu.edu.cn.
Lunquan
L
Sun
Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Key Laboratory of Veterinary Bioproduction and Veterinary Medicine of the Ministry of Agriculture, Zhongmu Institute of China Animal Husbandry Industry Co., Ltd, No. 156 Beiqing Road, Haidian District, Beijing 100095, China. Electronic address: vetdean@cau.edu.cn.
Ming
M
Wang
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004285:Dogs; D005260:Female; D055785:Gene Knockdown Techniques; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology* / Q000502:physiology; D061985:Madin Darby Canine Kidney Cells; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014779:Virus Replication / Q000276:immunology*
D000873:Anthracenes; D016207:Cytokines; D016755:Proto-Oncogene Proteins c-jun; C432165:pyrazolanthrone
DNAzyme; H5N1; Inflammation; c-jun