Influenza Virus-induced NF-κB-dependent Gene Expression Is Mediated by Overexpression of Viral Proteins and Involves Oxidative Radicals and Activation of IκB Kinase

Influenza A viruses are capable of inducing the expression of a variety of cytokine and proapoptotic genes in infected cells. The promoter regions of most of these genes harbor binding sites for the transcription factor NF-κB which is an important mediator of immune and inflammatory responses. Our present study is based on an observation that influenza A virus infection of cells stimulates transcriptional activation of the HIV-1 long terminal repeat (LTR) which harbors two regulatory NF-κB elements, and is aimed at identifying the molecular mechanisms involved in this process. We found that the expression of influenza virus hemagglutinin (HA), matrix protein (M), and nucleoprotein (NP), as single factors is sufficient to transcriptionally activate the HIV-1 LTR. This process is mediated by oxidative radicals because treatment of cells with pyrrolidine dithiocarbamate, a scavenger of such radicals, abolished the transactivating ability. Expression of different influenza proteins induces activation of NF-κB-dependent gene expression but not transcriptional activation of an AP-1/Ets-dependent promoter, indicating a selectivity for NF-κB transactivation. Furthermore, influenza protein expression induces activation of IκB kinase (IKK). Accordingly coexpression of a catalytically inactive mutant of IKK abolishes influenza protein induced activation of NF-κB as well as HIV-1 LTR-dependent reporter gene expression, suggesting that IKK is an important intermediate within this signaling process. Taken together, our results show that various influenza virus proteins act as viral transactivators to modulate transcriptional activity of κB-element harboring promoters such as the HIV-LTR.