Introduction: Type I and type III interferons (IFN) play a crucial role in coordinating both antiviral and inflammatory responses. While the response to type I IFN is ubiquitous across tissue types, restricted type III IFN receptor expression results in tissue-specific responses to stimulation. This suggests fundamentally distinct roles for these cytokines in coordinating innate and adaptive immune responses. On the other hand, both the type I and III IFN signaling cascades overlap in their utilization of adaptor molecules and transcription factors, resulting in the induction of largely shared downstream effector genes. While previous studies have demonstrated that the kinetics and magnitude of gene expression differs following interferon sensing, the molecular mechanisms for the distinct responses to type I IFN and type III IFN and their functional consequences are not fully understood.
Methods: Here, we provide a detailed investigation on the distinct receptor-ligand interactions between the type I and type III IFN receptor to confirm the temporal recruitment and activation of adaptor molecules and transcription factors that guide ISG expression in epithelial cells. Moreover, we look at the regulation of metabolic responses to address roles of IFN in regulation of cellular growth and proliferation.
Results: Both type I and type III IFNs can induce similar downstream effector genes with unique quantitative and temporal transcriptional and translational signatures. Moreover, these responses are crucial for the regulation of basal metabolic responses in hepatocytes.
Conclusion: This study demonstrates unique roles of type I and type III IFNs in the control of immune responses and cellular proliferation.