A novel c-Jun-dependent signal transduction pathway necessary for the transcriptional activation of interferon γ response genes

The biological effects of interferon gamma(IFN gamma) are mediated by interferon-stimulated genes (ISGs), many of which are activated downstream of Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling. Herein we have shown that IFN gamma rapidly activated AP-1 DNA binding that required c-Jun but was independent of JAK1 and STAT1. IFN gamma-induced c-Jun phosphorylation and AP-1 DNA binding required the MEK1/2 and ERK1/2 signaling pathways, whereas the JNK1/2 and p38 mitogen-activated protein kinase pathways were dispensable. The induction of several ISGs, including ifi-205 and iNOS, was impaired in IFN gamma-treated c-Jun(-/-) cells, but others, such as IP-10 and SOCS3, were unaffected, and chromatin immunoprecipitation demonstrated that c-Jun binds to the iNOS promoter following treatment with IFN gamma. Thus, IFN gamma induced JAK1- and STAT1-independent activation of the ERK mitogen-activated protein kinase pathway, phosphorylation of c-Jun, and activation of AP-1 DNA binding, which are important for the induction of a subset of ISGs. This represents a novel signal transduction pathway induced by IFN gamma that proceeds in parallel with conventional JAK/STAT signaling to activate ISGs.