Rb/E2F1 Regulates the Innate Immune Receptor Toll-Like Receptor 3 in Epithelial Cells

Tumor suppressor genes regulate the antiviral host defense through molecular mechanisms that are not yet well explored. Here, we show that the tumor suppressor retinoblastoma (Rb) protein positively regulates Toll-like receptor 3 (TLR3) expression, the sensing receptor for viral double-stranded RNA and poly(I.C). TLR3 expression was lower in Rb knockout (Rb-/-) mouse embryonic fibroblasts (MEF) and in mammalian epithelial cells transfected with Rb small-interfering RNA (siRNA) than in control cells. Consequently, induction of cytokines interleukin-8 and beta interferon after poly(I.C) stimulation was impaired in Rb-/- MEF and Rb siRNA-transfected cells compared to controls. TLR3 promoter analysis showed that Rb modulates the transcription factor E2F1, which directly binds to the proximal promoter of TLR3. Exogenous addition of E2F1 decreased TLR3 promoter activity, while Rb dose dependently curbed the effect of E2F1. Interestingly, poly(I.C) increased the Rb expression, and the poly(I.C)-induced TLR3 expression was impaired in Rb-depleted cells, suggesting the importance of Rb in TLR3 induction by poly(I.C). Together, these data indicated that E2F1 suppresses TLR3 transcription, but during immune stimulation, Rb is up-regulated to block the inhibitory effect of E2F1 on TLR3, highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells.