Influenza virus-induced AP-1-dependent gene expression requires activationof the JNK signaling pathway

Influenza A virus infection of cells results in the induction of a variety of antiviral cytokines, including those that are regulated by transcription factors of the activating protein-1 (AP-1) family. Here we show that influ enza virus infection induces AP-1-dependent gene expression in productively infected cells but not in cells that do not support viral replication. Amo ng the AP-1 factors identified to bind to their cognate DNA element during viral infections of Madin-Darby canine kidney and U937 cells are those that are regulated via phosphorylation by JNKs. Accordingly, we observed that i nduction of AP-1-dependent gene expression correlates with a strong activat ion of JNK in permissive cells, which appears to be caused by viral RNA acc umulation during replication. Blockade of JNK signaling at several levels o f the cascade by transient expression of dominant negative kinase mutants a nd inhibitory proteins resulted in inhibition of virus-induced JNK activati on, reduced AP-1 activity, and impaired transactivation of the IFN-beta pro moter. Virus yields from transfected and infected cells in which JNK signal ing was inhibited were higher compared with the levels from control cells. Therefore, we conclude that virus-induced activation of JNK and AP-1 is par t of the innate antiviral response of the cell.