Alpha Interferon and Gamma Interferon Stimulate Transcription of a Single Gene through Different Signal Transduction Pathways

Abstract

Interferons (IFNs) play a key role in the defense against virus infection and the regulation of cell growth and differentiation, in part through changes in specific gene transcription in target cells. We describe several differences between the signal transduction events that result in transcriptional activation of the human gene coding for a guanylate-binding protein (GBP) by alpha interferon (IFN-α) and gamma interferon (IFN-γ). Activation by IFN-α was rapid, transient, and cycloheximide resistant. Activation by IFN-γ was slower, sustained, and delayed by cycloheximide. IFN-γ led to the formation of a stable intracellular signal which led to continued GBP transcription even if the ligand was withdrawn, whereas IFN-a-induced GBP transcription decayed rapidly if IFN-α was withdrawn. Perturbations of signaling pathways involving classical second messengers (cyclic AMP, Ca²⁺, protein kinase C) did not induce GBP transcription. However, various kinase inhibitors blocked the transcriptional response to IFN-γ but not IFN-α, suggesting that a specific and possibly novel kinase is involved in gene activation by IFN-γ.