Down modulation of IL-18 expression by human papillomavirus type 16 E6 oncogene via binding to IL-18

To understand modulation of a novel immune-related cytokine, interleukin-18 , by human papillomavirus type (HPV) 16 oncogenes, HaCaT, normal keratinocy te cell line, and C-33A, HPV-negative cervical cancer cell line, were prepa red to establish stable cell lines expressing E6, E6 mutant (E6m), E6E7, or E7 constitutively. Expressions of various HPV oncogene transcripts were id entified by RT-PCR. Expression of HPV oncogene E6 was reversely correlated to the expression of interleukin-18, a novel pro-inflammatory cytokine. The expression of E6 in C-33A, independent of E6 splicing, resulted in decreas ed IL-18 expression and that of IL-18 was also significantly reduced in HaC aT cells expressing E6. The level of p53 was reduced in C-33A cells express ing E6 whereas not altered in HaCaT cells expressing E6, suggesting that E6 downregulated IL-18 expression via an independent pathway of p53 degradati on in HaCaT cells which have a mutated p53 form. However, E7 did not affect IL-18 expression significantly in both C-33A and HaCaT cells. Cotransfecti on experiments showed that E6 oncogene did not inhibit the activities of IL -18 promoter PI and P2, suggesting that E6 oncogene indirectly inhibited IL -18 expression. Taken together, E6, E6m and E6/E7 inhibited IL-18 expressio n with some variation, assuming that cells expressing E6 oncogene can evade immune surveillance by downregulating the expression of immune stimulating cytokine gene, IL-18, and inhibiting the cascade of downstream effects tha t follow activation of the IL-18 receptor. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserv ed.