INTERLEUKIN-1-ALPHA AND TUMOR-NECROSIS-FACTOR-ALPHA STIMULATE AUTOCRINE AMPHIREGULIN EXPRESSION AND PROLIFERATION OF HUMAN PAPILLOMAVIRUS-IMMORTALIZED AND CARCINOMA-DERIVED CERVICAL EPITHELIAL-CELLS

Infection with multiple sexually transmitted agents has been associate d with inflammation of the cervix and an increased risk of cervical ca ncer in women infected with human papillomaviruses (HPVs). Two proinfl ammatory cytokines, interleukin 1 alpha (IL-1 alpha) and tumor necrosi s factor alpha (TNF-alpha), inhibited proliferation of normal epitheli al cells cultured from human cervix. In contrast, both cytokines signi ficantly stimulated proliferation of cervical cell lines (5 of 7) immo rtalized by transfection with HPV-16 or -18 DNAs or lines derived from cervical carcinomas (7 of 11). Stimulation was dose dependent from 0. 01 to 1.0 nM and was blocked by specific inhibitors, such as the IL-1 receptor antagonist or the TNF type 1 or 2 soluble receptors. Growth s timulation by IL-1 alpha or TNF-alpha was accompanied by a 6- to 10-fo ld increase in RNA encoding amphiregulin, an epidermal growth factor ( EGF) receptor ligand. Recombinant human amphiregulin (0.1 nM) was as e ffective as IL-1 alpha or TNF-alpha in promoting proliferation. Monocl onal antibodies that blocked signal transduction by the EGF receptor o r that neutralized amphiregulin activity prevented mitogenic stimulati on by IL-1 alpha or TNF-alpha. These studies indicate that IL-1 alpha and TNF-alpha stimulate proliferation of immortal and malignant cervic al epithelial cells by an EGF receptor-dependent pathway requiring aut ocrine stimulation by amphiregulin. Furthermore, they suggest that chr onic inflammation and release of proinflammatory cytokines might provi de a selective growth advantage for abnormal cervical cells in vivo.