Viral Modulation of TLRs and Cytokines and the Related Immunotherapies for HPV-Associated Cancers

Figure 3

Inhibition of TLR9 expression by HPV16 E7 oncogene takes place via NF-κB canonical pathway, when this oncoprotein recruits the inhibitory complex NF-κB p50–p65 to a new cis element at the TLR9 promoter. This occurs with the additional binding of ERα (estrogen α) to another neighbour cis element, ERE (estrogen-responsive element), within that same promoter, and in the presence of HPV16 E7. ERα is also able to interact with the p65 subunit in the peri- or intranuclear region and contribute to transcription repression. Furthermore, it was also observed that there was a chromatin repressive complex composed by JARID1B demethylase and by HDAC1 deacetylase. These two catalytic units interact with ERα and negatively regulate TLR9 expression. The consequence of preventing TLR9 expression is the establishment of an immunosuppressive status with the inhibition of interferon and immune surveillance by cytokine responses [8]. NF-κB blue circle corresponds to p50 subunit and the purple one to p65. The straight blue arrows indicate an activation process or progress to the next stage; the curved arrows indicate motion; and the progressive arrows indicate the movement of some molecules interacting with the target. IKK: inhibitor of kappa B kinase; P: phosphate group; M: methyl group; A: adenyl group; JARID1B: lysine-specific demethylase 5B; HDAC1: histone deacetylase 1; Site B: 9-10 base pair DNA sites where p50 and p65 subunits bind.