Studies have focused on the interaction between human papillomaviruses (HPV) and human cervical epithelial cells. The pathogenesis of cervical HPV infection is influenced by the host's immune response which is regulated by production of specific cytokines. Specifically, (1) expression of specific cytokines and histocompatible genes was measured in cervical cells at different stages of malignant progression; and (2) high- titer retroviruses were developed to examine whether overexpression of wild-type p53 altered cervical cell growth or differentiation. Normal cervical epithelial cell cultures secreted a wide range of immune cytokines, including IL-1alpha, Il-1beta, IL-6, IL-8, GM-CSF, and TNF- alpha. Five cervical cell lines immortalized with HPV-16 or -18 recombinant DNAs and three cervical carcinoma-derived cell lines secreted cytokines at significantly lower levels. Downregulation occurred at the level of RNA expression. IFN-gamma induced major histocompatibility of class 1 and 2 proteins in normal cells, but results with immortal and carcinoma lines were variable. Thus, cervical epithelial cells have the potential to influence inflammation and immunity via cytokine production. Furthermore, decreased cytokine and histocompatibility gene expression by cells containing HPV might compromise the host immune response. The HPV oncogene E6 is believed to contribute to transformation by inactivating the tumor-suppressor gene product p53. To examine whether modulation of p53 influences epithelial differentiation, normal keratinocytes and six cell lines containing HPV were infected with recombinant retroviruses encoding p53. Overexpression of p53 in organotypic cultures of normal cells decreased the growth rate and induced premature cell flattening and expression of involucrin, a marker of differentiation. In contrast, p53 overexpression in six cell lines containing HPV did not alter growth or reverse dysplastic epithelial differentiation. Thus, continued downregulation of p53 by the HPV-16 E6 oncoprotein is not necessary to maintain growth of carcinoma cells containing HPV.
