Regulation of type-III interferons in airway epithelial cells. (51.13)

• Published in: The Journal of immunology (1950) 2010-04, Vol.184 (1_Supplement), p.51-51.13
• Main Authors: Gallagher, Grant, Siegel, Rachael, Eskdale, Joyce
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.184.Supp.51.13

The type-III interferons (IFNs) are the most recently discovered IFN family, comprising three protein ligands: IFN-λ1, IFN-λ2 and IFN-λ3. Their expression is induced by viruses and they share many anti-viral characteristics with the type-I IFNs (IFN-α and IFN-β), but type-III IFNs have an important specific functional niche at the immune-epithelial interface. However, their expression is diminished in bronchial epithelial cells of rhinovirus-infected asthmatic individuals. We set out to understand type-III IFN regulation. Here, we identify critical elements for IFN-λ1 promoter regulation in bronchial epithelial cells and define key activators (c-REL/p65 NF-κB heterodimer and IRF-1) and repressors (p50 NF-κB homodimer, BLIMP-1 and ZEB1). We show that IRF-1 and BLIMP-1 may occupy an overlapping promoter element. Following poly I:C stimulation, IFN-λ1 expression peaks at 3 hours. This is accompanied by loss of repression by p50 NF-κB homodimers at the promoter. Two important activators are recruited to the promoter: the c-REL/p65 NF-κB heterodimer and IRF-1. Post-induction repression is mediated by p50 NF-κB homodimers, ZEB1 and BLIMP-1. We show that ZEB1 does not regulate type-I IFN expression; thus, it is the first specific regulator of the type-III IFNs. This study represents the first characterization of any type-III IFN promoter in its native context and conformation, and can now be applied to understanding pathogenic dysregulation of IFN-λ1.