Our results demonstrate for the first time that IRF3 and IRF7 are both involved in inducing TLR4-dependent IFN-b expression in response to HSV2 in its primary infected genital epithelial cells. We have shown for the first time that HSV-2 activates TLR4dependent NF-kB activation and TLR4-dependent Mal/MyD88/ NF-kB signaling contributes to the innate immune response in HCE cells. In this study, we confirmed that HSV-2 infection induces TLR4-dependent expression of IFN-b by knockdown experiment. A recent report also indicated the critical role of TLR4 in mediating innate response during primary infection of human lymphatic endothelial 
cells and lytic replication of the latent Kaposi Sarcoma herpesvirus. TLR9 is thought to be the typically sensor of DNA viruses such as HSV. Studies using natural DNA suggest that both CpG content and the level of methylation of the motif strongly affect the ability of DNA to activate TLR9. TLR9 is only important for the host immune response to pathogens that can reach the lymphoid organs or blood. The innate immune response to HSV infection is complex since different virus strains have different cellular tropisms and the host immune response to viral infection is also cell-type specific. Our previous study showed that molecules MyD88 and Mal are required in TLR4-dependent signaling in response to HSV-2. Silenced expression of Mal/MyD88 suppressed the Danshensu production of IL-6, but showed partially reduced effect on the production of IFN-b. Type I IFN is induced only in the intracellular compartments. Induction of the IFNB gene by signaling through TLR4 is mostly TRAM-TRIF dependent in macrophages stimulated with LPS. Our data demonstrate that TRIF and TRAM may play a role in TLR4-dependent induction of IFN-b in response to HSV-2 by ELISA analysis. Interestingly, when knockdown both adaptors and TLR4, the basal level of IFN-b was extremely low. We repeated the Ginsenoside-Ro experiments and observed the similar pa ern of IFN-b. We believe that TLR4 and TRIF/TRAM are involved in IFN-b production by HSV-2, while we could not rule out other factors that decrease basal level of IFN-b but are TLR4-unrelated. Type I IFN is critical for the antiviral activity of the epithelial cells that it is regulated by multiple factors, for example, activation of NF-&B, ATF-2/c-Jun, IRF3, and IRF7 may interact with IFNb promoter or enhancer region, thereby induce its expression, while other signals lead to separately activation of each transcription factors. Our data demonstrated that TLR4 mediates the phosphorylation and activation of IRF3, which thereafter regulates the expression of IFN-b in response to HSV-2. The phosphorylation of IRF3 was observed as early as 4 h p.i. and remained the elevated level at 16 h p.i.. In Figure 1, the secretion of IFN-b peaks at 6 h p.i. and declines at 16 h p.i.. The discrepancy between the different time points of phosphorylation of IRF3 and production of IFN-b may due to the other regulators and/or signaling of IFN-b. It is very important that immune response returns to the sensitive threshold level soon after pathogen stimulation. The frontotemporal dementias are a group of neurodegenerative disorders affecting primarily the frontal and temporal lobes of the brain, leading to various combinations of behavioural.