Human epithelial cell models are being used to study (1) the biological effects of specific human papillomavirus (HPV) genes in regulating cell growth and differentiation and (2) the ability of normal, HPV- immortalized, and HPV containing cervical tumor lines to secrete and respond to specific lymphokines involved in regulation of inflammation and specific immunity. The HPV E6 and E7 genes are retained in most cervical carcinomas and contribute to maintenance of the malignant phenotype. To examine whether these proteins regulate cell growth and differentiation, normal genital keratinocytes were infected with recombinant retroviruses encoding E6 and E7 alone or in combination. E6 and E7 together stimulated keratinocyte growth, reduced the requirement of cells for exogenous growth factors, and delayed but did not prevent terminal squamous differentiation. Thus, HPV oncoproteins contribute directly to progression of aberrant growth and differentiation associated with genital dysplasia. Epithelial cells secrete a variety of lymphokines which regulate inflammation and specific immune responses. Cultures of normal exo- and endocervical cells also secreted lymphokines including IL-1`, IL- 1~, IL-6, IL-8, GM-CSF, and TNF`. Five cervical cell lines immortalized by HPV-16 or -18 DNAs secreted lymphokines at a level 2- to 10-fold lower than normal cells. Furthermore, immortalized lines expressed much lower levels of lymphokine mRNAs than normal cervical cells. Thus, decreased expression of selected lymphokines by cervical cells harboring HPV DNA may compromise the host's immune response. Leukoregulin (LR) and interferon gamma (IFNgamma), lymphokines secreted by immune cells in regressing HPV infections, inhibited cell proliferation and transcription of E6/E7 RNAs in several human cervical epithelial cell lines immortalized by HPV-16, - 18 or -33 DNAs. HPV-immortalized cells developed partial resistance to these effects after malignant transformation. Thus, LR and IFN selectively inhibit growth and transcription of HPV transforming genes, providing a mechanism by which these lymphokines participate in regression of premalignant cells.
