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

FEBS Lett. 2001 Jul 20;501(2-3):139-45. doi: 10.1016/s0014-5793(01)02652-7.


To understand modulation of a novel immune-related cytokine, interleukin-18, by human papillomavirus type (HPV) 16 oncogenes, HaCaT, normal keratinocyte cell line, and C-33A, HPV-negative cervical cancer cell line, were prepared to establish stable cell lines expressing E6, E6 mutant (E6m), E6E7, or E7 constitutively. Expressions of various HPV oncogene transcripts were identified 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 decreased IL-18 expression and that of IL-18 was also significantly reduced in HaCaT cells expressing E6. The level of p53 was reduced in C-33A cells expressing E6 whereas not altered in HaCaT cells expressing E6, suggesting that E6 downregulated IL-18 expression via an independent pathway of p53 degradation 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. Cotransfection experiments showed that E6 oncogene did not inhibit the activities of IL-18 promoter P1 and P2, suggesting that E6 oncogene indirectly inhibited IL-18 expression. Taken together, E6, E6m and E6/E7 inhibited IL-18 expression 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 that follow activation of the IL-18 receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding, Competitive
  • Down-Regulation
  • HeLa Cells / drug effects
  • HeLa Cells / metabolism
  • HeLa Cells / virology
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / metabolism
  • Interleukin-18 / genetics
  • Interleukin-18 / metabolism*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / virology
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism
  • Oncogene Proteins, Viral / pharmacology*
  • Papillomaviridae*
  • Promoter Regions, Genetic / drug effects
  • Repressor Proteins*
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism*


  • E6 protein, Human papillomavirus type 16
  • Interleukin-18
  • Oncogene Proteins, Viral
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • Interferon-gamma