A TGF-β- and p63-Responsive Enhancer Regulates IFN-κ Expression in Human Keratinocytes

Type I IFNs have antiviral and immune-modulating activities. IFN-α/-β have very low basal expression levels but are strongly induced upon activation of pattern recognition receptors. In contrast, IFN-κ is constitutively expressed in uninfected keratinocytes and responds only weakly to pattern recognition receptor activation. IFN-κ expression has been implicated in the pathogenesis of inflammatory skin diseases and in limiting human papillomavirus replication in human keratinocytes. We have identified an enhancer ∼5 kb upstream of the IFNK gene driving its expression in keratinocytes. The enhancer consists of binding sites for the transcription factors jun-B, SMAD3/4, AP-2α/γ, and p63, of which the latter two are key regulators of keratinocyte biology. The jun-B and SMAD3/4 elements confer activation by the TGF-β pathway. Furthermore, inhibition of ERK1/2 kinases activates IFN-κ expression. Our study provides a framework for the cell type-specific, constitutive expression of IFN-κ and its modulation by signal transduction pathways in human keratinocytes.