title: Distinct Patterns of Expression of Transcription Factors in Response to Interferonβ and Interferonλ1.
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 IFNβ or IFNλ1 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 IFNβ and IFNλ1, many ISGs were expressed in a pattern that we modeled with a cubic equation that mathematically defines this threshold effect. Uniquely, IFNβ alone induced early and transient IRF1 transcript and protein expression, while IFNλ1 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 IFNβ and IFNλ1 and that IRF1 may mediate nonredundancy of type I or III IFN in RECs.
authors.affiliation: 1 Center for Biologics Evaluation and Research , US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Hilary
authors.initials: H
authors.lastname: Novatt
authors.affiliation: 1 Center for Biologics Evaluation and Research , US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Terence C
authors.initials: TC
authors.lastname: Theisen
authors.affiliation: 1 Center for Biologics Evaluation and Research , US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Tammy
authors.initials: T
authors.lastname: Massie
authors.affiliation: 2 Drugs Evaluation and Research, USFDA, Silver Spring, Maryland.
authors.forename: Tristan
authors.initials: T
authors.lastname: Massie
authors.affiliation: 1 Center for Biologics Evaluation and Research , US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Vahan
authors.initials: V
authors.lastname: Simonyan
authors.affiliation: 1 Center for Biologics Evaluation and Research , US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Alin
authors.initials: A
authors.lastname: Voskanian-Kordi
authors.affiliation: 1 Center for Biologics Evaluation and Research , US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Lynnsey A
authors.initials: LA
authors.lastname: Renn
authors.affiliation: 1 Center for Biologics Evaluation and Research , US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Rabin
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; D014157:Transcription Factors; D016899:Interferon-beta
keywords: interferon regulatory factor-1 (IRF1); interferon stimulated genes (ISG); interferon-beta; interferon-lambda; respiratory epithelial cells; transcription factors