TGF-beta1 and IL-4 downregulate human papillomavirus-16 oncogene expression but have differential effects on the malignant phenotype of cervical carcinoma cells.
Host immune response to human papillomavirus (HPV) is a crucial factor in viral clearance and control of persistent infections. The existence of an intercellular control mechanism mediated by cytokines to suppress HPV-gene transcription and to prevent malignant conversion of HPV-infected cells, has been postulated. In a previous study, we demonstrated the inhibitory activity of several cytokines on the HPV-16 long control region (LCR)-driven transcription; among these, IL-4 was reported as a LCR inhibitor for the first time and proposed as a candidate for further studies. Here, we addressed the question of whether IL-4 represses HPV-16 oncogene transcription and exerts antitumor activity in HPV-16 positive cervical carcinoma cell lines. Results indicated that downregulation of E6 and E7 levels by IL-4 in CaSki cells is weaker than that exerted by TGF-beta1, a known LCR inhibitor, although both cytokines are equally active in suppressing LCR-driven transcriptional activity in a reporter cell line. Moreover, only TGF-beta rescued p53 expression, Rb response pathway, and induced cellular senescence. SiHa cells were unresponsive to both cytokines. These findings suggest that the two cytokines may play a role in the control of HPV infections, however, cervical carcinoma cells developed a partial or a total resistance to their inhibitory activity.
Donalisio
Manuela
M
Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy.
Cornaglia
Maura
M
Landolfo
Santo
S
Lembo
David
D
D045744:Cell Line, Tumor; D016922:Cellular Senescence; D015536:Down-Regulation; D005260:Female; D015967:Gene Expression Regulation, Viral; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; D015847:Interleukin-4