We observed a remarkable synergism of adenoviruses and LPS in triggering the production of TNF in intact animals. We found that in mice pre-exposed to adenoviruses, LPS injections generated extremely high levels of TNF with altered kinetics. The elevated TNF synthesis stemmed mostly from posttranscriptional up-regulation of TNF production, although transcription of the TNF gene was also induced. Adenoviruses and LPS exhibited a significant but less dramatic synergism in the induction of IL-6, IFN-γ, and NO. Only marginal changes were detected in the synthesis of a panel of other cytokines. Different serotypes of the virus showed practically identical effects. As deletion mutants lacking indispensable viral genes or UV inactivated virions exhibited similar activities as the infectious, wild-type virus, it seems unlikely that the viral genome plays any significant role in the phenomenon. Published data indicate that other viruses also show some kind of synergism with LPS, although by different cellular mechanisms. T cells and their IFN-γ production—crucial in the synergism of influenza viruses and LPS—were dispensable in our experiments. We suggest that the phenomenon is probably a general one: an overlap between different molecular mechanisms detecting bacterial and viral pathogens and inducing mediators of nonspecific cell-mediated host defense. The synergism of viruses and LPS (bacteria) could be a concern in medical practice as well as in gene therapy experiments with high doses of recombinant adenoviruses.

Papillomaviruses cause certain forms of human cancers, most notably carcinomas of the uterine cervix. In contrast to the well-established involvement of papillomavirus infection in the etiology of cervical carcinomas and in carcinomas of a rare hereditary condition, epidermodysplasia verruciformis, a causative role for cutaneous human papillomavirus types in the development of nonmelanoma skin cancer has not been proven. In order to better understand the functions of individual genes of cutaneous papillomavirus types, we generated transgenic mice carrying oncogene E6 of the Mastomys natalensis papillomavirus (MnPV), which causes keratoacanthomas of the skin in its natural host. In the present study, we demonstrate that under conditions of experimental two-stage skin carcinogenesis, fast-paced squamous cell carcinomas develop in nearly 100% of MnPV E6 transgenic mice in comparison to 10% in their nontransgenic littermates (log rank test; P < 0.0001). Therefore, we conclude that the MnPV E6 transgene favors the malignant progression of chemically induced tumors. Whereas an activating H-ras mutation is a consistent feature in benign and malignant tumors in wild-type mice, the majority of papillomas and keratoacanthomas and all squamous cell carcinomas obtained in MnPV E6 transgenic mice contain nonmutated ras alleles. These results indicate that the development of squamous cell carcinomas in MnPV E6 transgenic mice does not depend on an activated H-ras oncogene.Papillomaviruses are widely known to play a causative role in the development of tumors in humans. Certain genotypes cause mostly benign epidermal tumors in humans and animals. Another subgroup of genotypes, the so-called "high-risk" anogenital human papillomavirus (HPV) types, are causally involved in the development of malignant tumors, such as carcinoma of the cervix (17, 47, 49). The carcinogenic potential was first detected in 1935, when Rous and Bernard showed that inoculation into domestic rabbits of the filterable extracts from warts of cottontail rabbits was able to induce skin carcinomas (37). A direct involvement of cutaneous HPV types in the development of squamous cell carcinomas, one of the most frequent malignancies in humans of Caucasian origin, is suspected but still not proven (7, 34). The earliest hints of an involvement of specific HPV types in human skin cancer originated from studies of patients suffering from the very rare hereditary disease epidermodysplasia verruciformis (EV) (32,21). Only a limited number of HPV types, commonly referred to as EV-HPV types, such as HPV5, -8, and -14, are frequently detected in squamous cell carcinomas that develop in ϳ30% of cases within multiple flat warts in sun-exposed areas of the skin in such patients (25). More recent data suggested a role for EV-related papillomaviruses in the origin of skin cancer in immunosuppressed patients (39) and those with renal transplants (28). Thus, specific high-risk cutaneous HPV types comparable to carcinogenic anogenital HPV types have not been identified (48,49)...