Regulatory roles of c-jun in H5N1 influenza virus replication and host inflammation

• Published in: Biochimica et biophysica acta 2014-12, Vol.1842 (12), p.2479-2488
• Main Authors: Xie, Jingjing, Zhang, Shouping, Hu, Yanxin, Li, Dirui, Cui, Jingmin, Xue, Jia, Zhang, Guozhong, Khachigian, Levon M., Wong, Jonathan, Sun, Lunquan, Wang, Ming
• Format: Article
• Language: English
• Subjects: Animals; Anthracenes - pharmacology; Blotting, Western; c-jun; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cell Proliferation; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; DNAzyme; Dogs; Female; Gene Knockdown Techniques; H5N1; Host-Pathogen Interactions - immunology; Humans; Inflammation; Inflammation - genetics; Inflammation - immunology; Influenza A Virus, H5N1 Subtype - immunology; Influenza A Virus, H5N1 Subtype - physiology; Madin Darby Canine Kidney Cells; Mice, Inbred BALB C; Orthomyxoviridae Infections - genetics; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - virology; Phosphorylation - drug effects; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - immunology; Proto-Oncogene Proteins c-jun - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Survival Analysis; Virus Replication - immunology
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2014.04.017

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. •c-jun activation was critically involved in IAV replication.•c-jun phosphorylation could globally affect cytokine expression.•Down-regulation of c-jun could lessen the H5N1virus-induced pathological damages.•Suppression of c-jun could improve overall survival of the H5N1-infected animals.