Both E6 and E7 oncoproteins of human papillomavirus 16 inhibit IL-18-induced IFN-gamma production in human peripheral blood mononuclear and NK cells

Cervical carcinoma is the predominant cancer among malignancies in women th roughout the world, and human papillomavirus (HPV) 16 is the most common ag ent linked to human cervical carcinoma. The present study was performed to investigate the mechanisms of immune escape in HPV-induced cervical cancer cells. The presence of HPV oncoproteins E6 and E7 in the extracellular flui ds of HPV-containing cervical cancer cell lines SiHa and CaSki was demonstr ated by ELISA. The effect of HPV 16 oncoproteins E6 and E7 on the productio n of IFN-gamma by IL-18 was assessed. E6 and E7 proteins reduced IL-18-indu ced IFN-gamma production in both primary PBMCs and the NK0 cell line. FACS analysis revealed that the viral oncoproteins reduced the binding of IL-18 to its cellular surface receptors on NK0 cells, whereas there was no effect of oncoproteins on IL-1 binding to its surface IL-1 receptors on D10S, a s ubclone of the murine Th cell D10.G4.1. In vitro pull-down assays also reve aled that the viral oncoproteins and IL-18 bound to IL-18R alpha -chain com petitively. These results suggest that the extracellular HPV 16 E6 and E7 p roteins may inhibit IL-18-induced IFN-gamma production locally in HPV lesio ns through inhibition of IL-18 binding to its a-chain receptor. Down-modula tion of IL-18-induced immune responses by HPV oncoproteins may contribute t o viral pathogenesis or carcinogenesis. The Journal of Immunology, 2001.