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It has been found that certain cytokines (IL-4, IL-10 and TGF-β1) are highly expressed locally in biopsies from patients with premalignant lesions and cervical cancer, and may induce a local immune-suppression state. In particular, IL-10 is highly expressed in tumor cells and its expression is directly proportional to the development of HPV-positive cervical cancer, suggesting an important role of HPV proteins in the expression of IL-10. In fact, we demonstrated that E6 and E7 HPV proteins regulate TGF-β1 gene expression in cervical cancer cells. Here, we found by band shifting analysis that the HPV E2 protein binds to the regulatory region of the human IL-10 gene (-2054 nt) and induces high promoter activity in epithelial cells. Additionally, cervical cancer cells transfected to express the HPV E2 protein induce elevated levels of IL-10 mRNA in human papillomavirus-infected cells. The elevated expression of IL-10 may allow for virus persistency, the transformation of cervical epithelial cells, and consequently cancer development.

Objective: Our aims were to examine the ability of the human papillomaviruse (HPV) 16 E2 protein to induce apoptosis in a murine HPV-transformed cell line, and to evaluate its antitumor properties on HPV-associated tumors in vivo in immunocompetent mice., Methods: HPV-transformed murine BMK-16/myc cells and human SiHa cells were transfected with the HPV 16 E2 gene to examine the effects of the E2 protein on cell growth and on the E6 and E7 oncogenes as well as DNA fragmentation and activation of the extrinsic pathway of apoptosis. Finally, to test the antitumor effect of the E2 protein on an experimental mouse tumor model, we generated a recombinant adenovirus expressing the E2 protein., Results: The E2 protein inhibited the growth of SiHa and BMK-16/myc cell lines, and repressed the E6 and E7 oncogenes. Moreover, the E2 protein induced DNA fragmentation and apoptosis through activation of caspases 8 and 3 in BMK-16/myc cells. On the other hand, E2 also showed antitumor effects in vivo., Conclusions: Our findings indicate that E2 exerts pro-apoptotic activity in a murine HPV-transformed cell line as well as an antitumor effect in vivo., (Copyright 2009 S. Karger AG, Basel.)