Interleukin-6 and interleukin-6 soluble receptor regulate proliferation of normal, human papillomavirus-immortalized, and carcinoma-derived cervical cells in vitro

Abstract

A variety of sexually transmitted diseases frequently accompany infection with human papillomavirus and stimulate inflammation of the cervical mucosa. Inflammation and cell injury cause release of proinflammatory cytokines, which in turn might regulate growth of human papillomavirus-infected cells. This study compared the interaction of the proinflammatory cytokine, interleukin-6 (IL-6), and its soluble receptor with normal ecto- and endocervical cells, human papillomavirus-immortalized ectocervical cells, and squamous carcinoma-derived cell lines. Proliferation of normal cervical cells was enhanced by IL-6 but inhibited by its soluble receptor. However, both IL-6 and its soluble receptor significantly stimulated growth of the three immortal and four cervical carcinoma-derived cell lines analyzed. Stimulation by IL-6 was dose dependent 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 stimulation by IL-6 was significantly inhibited by antibodies that either blocked signal transduction by the epidermal growth factor receptor or that neutralized transforming growth factor-alpha or amphiregulin activity. Thus, IL-6 stimulates proliferation of human papillomavirus-immortalized cervical cells via an epidermal growth factor receptor-dependent pathway involving autocrine stimulation by transforming growth factor-alpha and amphiregulin.