Distinct Patterns of Expression of Transcription Factors in Response to Interferon and Interferon1

After viral infection, type I and III interferons (IFNs) are coexpressed by respiratory epithelial cells (RECs) and activate the ISGF3 transcription factor (TF) complex to induce expression of a cell-specific set of interferon-stimulated genes (ISGs). Type I and III IFNs share a canonical signaling pathway, suggesting that they are redundant. Animal and in vitro models, however, have shown that they are not redundant. Because TFs dictate cellular phenotype and function, we hypothesized that focusing on TF-ISG will reveal critical combinatorial and nonredundant functions of type I or III IFN. We treated BEAS-2B human RECs with increasing doses of IFN or IFN1 and measured expression of TF-ISG. ISGs were expressed in a dose-dependent manner with a nonlinear jump at intermediate doses. At subsaturating combinations of IFN and IFN1, many ISGs were expressed in a pattern that we modeled with a cubic equation that mathematically defines this threshold effect. Uniquely, IFN alone induced early and transient IRF1 transcript and protein expression, while IFN1 alone induced IRF1 protein expression at low levels that were sustained through 24h. In combination, saturating doses of these 2 IFNs together enhanced and sustained IRF1 expression. We conclude that the cubic model quantitates combinatorial effects of IFN and IFN1 and that IRF1 may mediate nonredundancy of type I or III IFN in RECs.