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J Interferon Cytokine Res 2016 Oct;36(10):589-98

Distinct patterns of expression of transcription factors in response to interferon beta and interferon lambda1.

Novatt H, Theisen TC, Massie T, Massie T, Simonyan V, Voskanian-Kordi A, Renn LA, Rabin RL

Abstract

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 IFNß or IFN¿1 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 IFNß and IFN¿1, many ISGs were expressed in a pattern that we modeled with a cubic equation that mathematically defines this threshold effect. Uniquely, IFNß alone induced early and transient IRF1 transcript and protein expression, while IFN¿1 alone induced IRF1 protein expression at low levels that were sustained through 24¿h. In combination, saturating doses of these 2 IFNs together enhanced and sustained IRF1 expression. We conclude that the cubic model quantitates combinatorial effects of IFNß and IFN¿1 and that IRF1 may mediate nonredundancy of type I or III IFN in RECs.


Category: Journal Article
PubMed ID: #27447339 DOI: 10.1089/jir.2016.0031
Includes FDA Authors from Scientific Area(s): Biologics Drugs
Entry Created: 2016-03-08 Entry Last Modified: 2019-06-09
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