Induction of Interferon Kappa in Human Papillomavirus 16 Infection by Transforming Growth Factor Beta-Induced Promoter Demethylation

Persistent high-risk human papillomavirus (HPV) infection is the major causal factor in cervical and other anogenital cancers. Because there are currently no therapeutics capable of preventing neoplastic progression of HPV infections, understanding the mechanisms of HPV-mediated persistence, including immune evasion, is a major research priority. The multifunctional growth factor transforming growth factor beta (TGF beta) has been shown to inhibit expression of early viral transcripts from cells harboring integrated HPV genomes or cells infected with retroviruses expressing HPV oncoproteins. However, the mechanism of TGF beta-induced inhibition has not been fully defined. In this study, we have observed a previously uncharacterized ability of TGF beta to repress the differentiation-induced upregulation of late HPV16 gene expression. In addition, interferon kappa (IFN-kappa), a keratinocyte-specific, constitutively expressed cytokine suppressed by differentiation, can be transcriptionally induced by TGF beta 1. TGF beta-mediated IFN-kappa transcription only occurs in cells containing HPV16, and this is due to TGF beta 1-mediated reversal of HPV-induced methylation of the IFN-kappa promoter through active DNA demethylation mediated by thymine DNA glycosylase (TDG). This novel interaction between growth factor and innate immune signaling may shed light on the mechanisms of HPV persistence and how the virus manipulates both immune and growth factor signaling to promote its life cycle. IMPORTANCE Persistent infection by high-risk HPVs is the primary risk factor for development of HPV-induced cancers. Persistence involves viral evasion of the immune response, including the IFN response. HPV is also known to suppress TGF beta signaling, which inhibits viral gene expression. Here, we show that the TGF beta and IFN pathways are interrelated in the context of HPV16 infection through the upregulation of IFN-kappa by TGF beta. The ability of TGF beta to induce IFN-kappa promoter demethylation and transcriptional activation provides a new explanation for why HPV has evolved mechanisms to inhibit TGF beta in infected cells.