IL-18 E42A mutant is resistant to the inhibitory effects of HPV-16 E6 and E7 oncogenes on the IL-18-mediated immune response

Kyung Ae Lee, Kyung Joo Cho, Soo Hyun Kim, Jung Hyun Shim, Jong Seok Lim, Dae Ho Cho, Min Sung Song, Charles A. Dinarello, Do Young Yoon

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Our previous studies showed that the down-modulation of IL-18-induced immune response caused by oncoproteins E6 and E7 as one of the mechanisms underlying immune escape in HPV-induced cervical cancer cells. E42 residue of IL-18 also appears to be critical in the activity of IL-18. Single point mutation E42 in IL-18 show promise in the study of IL-18 binding motifs for HPV oncoproteins. We attempted to ascertain whether site-specific IL-18 mutant E42A would modulate the inhibitory effects of IL-18-induced immune responses via the HPV 16 E6 and E7 oncoproteins. Compared to wild type IL-18, E42A-induced IFN-γ production was not inhibited by HPV 16 E6 and E7. In vitro and in vivo binding assays have also revealed that E6 and E7 do not result in the inhibition of the binding of E42A to its IL-18 receptor alpha chain. There were no effects on the E42A-induced phosphorylations of p38 and JNK observed in the presence of E6 or E7. The degradation of IκB by E42A was not affected by E6 or E7 in NK0 cells. Moreover, E42A-induced NF-κB activation was also not inhibited by these oncoproteins. These results suggest that E42A is a stronger activator than wild type IL-18, and is not susceptible to inhibition by the HPV oncoproteins E6 and E7. Thus, it is suggested that E42A could be used in immunotherapy for patients with cervical cancer.

Original languageEnglish
Pages (from-to)261-270
Number of pages10
JournalCancer letters
Volume229
Issue number2
DOIs
Publication statusPublished - 2005 Nov 18

Keywords

  • E42A mutant
  • E6
  • E7
  • IL-18

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lee, K. A., Cho, K. J., Kim, S. H., Shim, J. H., Lim, J. S., Cho, D. H., Song, M. S., Dinarello, C. A., & Yoon, D. Y. (2005). IL-18 E42A mutant is resistant to the inhibitory effects of HPV-16 E6 and E7 oncogenes on the IL-18-mediated immune response. Cancer letters, 229(2), 261-270. https://doi.org/10.1016/j.canlet.2005.06.042