DIFFERENTIAL REGULATION OF THE JE GENE ENCODING THE MONOCYTE CHEMOATTRACTANT PROTEIN (MCP-1) IN CERVICAL-CARCINOMA CELLS AND DERIVED HYBRIDS

Malignant human papillomavirus type 18 (HPV18)-positive cervical carci noma cells can be reverted to a nonmalignant phenotype by generation o f somatic cell hybrids with normal human fibroblasts. Although nontumo rigenic hybrids, their tumorigenic segregants, and the parental HeLa c ells have similar in vitro properties, inoculation only of nontumorige nic cells into nude mice results in a selective suppression of HPV18 t ranscription which precedes cessation of cellular growth. Our present study, aimed at understanding the differential regulation in vitro and in vivo, shows that the JE gene, encoding the monocyte chemoattractan t protein (MCP-1), is expressed only in nontumorigenic hybrids. Althou gh the gene, including its regulatory region, is intact, no JE (MCP-1) mRNA is detected in the tumorigenic segregants and in other malignant HPV-positive cervical carcinoma cell lines. Tests of several monocyte -derived cytokines showed that only tumor necrosis factor alpha strong ly induces the JE (MCP-1) gene in nontumorigenic cells and that this i s accompanied by a dose-dependent reduction of HPV transcription. The JE (MCP-1) up-regulation occurs within 2 h and does not require de nov o protein synthesis. The response to tumor necrosis factor alpha seems to be mediated by an NF-kappa B-related mechanism, since the inductio n can be completely abrogated by pretreating the cells with an antioxi dant such as pyrrolidine dithiocarbamate. Interestingly, cocultivation of nonmalignant hybrids with monocyte-enriched fractions from human p eripheral blood also results in an induction of the JE (MCP-1) gene an d a concomitant suppression of HPV18 transcription. Neither effect is observed in malignant cells. These data suggest that JE (MCP-1) may pl ay a pivotal role in the intercellular communication by triggering an intracellular pathway which negatively interferes with viral transcrip tion in HPV-positive nontumorigenic cells.