title: Regulation of influenza A virus induced CXCL-10 gene expression requires PI3K/Akt pathway and IRF3 transcription factor.
abstract: Influenza A virus infects human airway epithelial cells, and induces the CXC chemokine gamma interferon (IFN-γ)-inducible protein CXCL-10/IP-10 production. To understand the regulation of CXCL-10, we investigated the role of PI3K/AKT pathway in regulating virus induced CXCL-10 production. Previously we have shown that wild type (WT) influenza A virus infection activates PI3K/AKT pathway, whereas PR8-SH3-mf-1 mutant virus is unable to activate this pathway. Here we report that WT influenza A virus infection induced CXCL-10 production in A549 cells. PR8-SH3-mf-1 mutant virus infection led to reduced level of CXCL-10 mRNA transcription and protein expression. To define the transcriptional regulation factors that are important in this process, we performed studies using several mutant CXCL-10 promoter-luciferase constructs. Mutation of either of four Forkhead binding sites and two NF-κB response elements in CXCL-10 promoter did not alter promoter activity induced by WT virus. However, mutation of ISRE binding site markedly reduced luciferase activity. Our data suggested that PI3K/AKT pathway contributes to influenza A virus induced CXCL-10 production. This process is involved in binding of IRF3 to the ISRE binding site in CXCL-10 promoter region.
authors.affiliation: Vaccine and Infectious Disease Organization, University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, S7N 5E3, Canada.
authors.forename: Xinya
authors.initials: X
authors.lastname: Lu
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Masic
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D004285:Dogs; D051858:Forkhead Transcription Factors / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020545:Respiratory Mucosa / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D051858:Forkhead Transcription Factors; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt