INTERLEUKIN-6 AND INTERLEUKIN-6 SOLUBLE RECEPTOR REGULATE PROLIFERATION OF NORMAL, HUMAN PAPILLOMAVIRUS-IMMORTALIZED, AND CARCINOMA-DERIVEDCERVICAL CELLS IN-VITRO

A variety of sexually transmitted diseases frequently accompany infect ion with human papilomavirus and stimulate inflammation of the cervica l mucosa. Inflammation and cell injury cause release of proinflammator y cytokines, which in turn might regulate growth of human papillomavir us-infected cells. This study compared the interaction of the proinfla mmatory cytokine, interleukin-6 (IL-6), and its soluble receptor with normal ecto- and endocervical cells, human papillomavirus-immortalized ectocervical cells, and squamous carcinoma-dervied cell lines. Prolif eration of normal cervical cells was enhanced by IL-6 but inhibited by its soluble receptor. However, both IL-6 and its soluble receptor sig nificantly stimulated growth of the three immortal and four cervical c arcinoma-derived cell lines analyzed. Stimulation by IL-6 was dose dep endent and was blocked by an antibody that neutralized IL-6 activity. IL-6-mediated proliferation was accompanied by increased expression of RNAs encoding transforming growth factor-alpha and amphiregulin, two epidermal growth factor receptor ligands. Furthermore, growth stimulat ion by IL-6 was significantly inhibited by antibodies that either bloc ked signal transduction by the epidermal growth factor receptor or tha t neutralized transforming growth factor-alpha or amphiregulin activit y. Thus, IL-6 stimulates proliferation of human papillomavirus-immorta lized cervical cells via an epidermal growth factor receptor-dependent pathway involving autocrine stimulation by transforming growth factor factor-alpha and amphiregulin.