Global and distinct targets of IRF-5 and IRF-7 during innate response to viral infection.
The interferon regulatory factors (IRF) are transcriptional mediators of cellular response to viral invasion that play a critical role in the innate antiviral defense. Two of these factors, IRF-5 and IRF-7, play a critical role in the induction of interferon (IFNA) genes in infected cells; they are expressed constitutively in monocytes, B cells, and precursors of dendritic cells (pDC2) that are high producers of interferon alpha, and their expression can be further stimulated by type I interferon. The goal of the present study was to identify and analyze expression of cellular genes that are modulated by IRF-5 and IRF-7 during the innate response to viral infection. The transcription profiles of infected BJAB cells overexpressing IRF-5 or IRF-7 were determined by using oligonucleotide arrays with probe sets representing about 6800 human genes. This analysis shows that IRF-5 and IRF-7 activate a broad profile of heterologous genes encoding not only antiviral, inflammatory, and pro-apoptotic proteins but also proteins of other functional categories. The number of IRF-5- and IRF-7-modulated genes was significantly higher in infected than in uninfected cells, and the transcription signature was predominantly positive. Although IRF-5 and IRF-7 stimulated a large number of common genes, a distinct functional profile was associated with each of these IRFs. The noted difference was a broad antiviral and early inflammatory transcriptional profile in infected BJAB/IRF-5 cells, whereas the IRF-7-induced transcripts were enriched for the group of mitochondrial genes and genes affecting the DNA structure. Taken together, these data indicate that IRF-5 and IRF-7 act primarily as transcriptional activators and that IRF-5-and IRF-7-induced innate antiviral response results in a broad alteration of the transcriptional profile of cellular genes.
The Sidney Kimmel Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109, USA.
Betsy J
BJ
Barnes
John
J
Richards
Margo
M
Mancl
Sam
S
Hanash
Laura
L
Beretta
Paula M
PM
Pitha
D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D016899:Interferon-beta / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D018075:RNA, Complementary / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
C515202:CXCL11 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C431713:IRF5 protein, human; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D018075:RNA, Complementary; D012333:RNA, Messenger; D014157:Transcription Factors; D016899:Interferon-beta; D004247:DNA; D007372:Interferons; D002251:Carbon Tetrachloride