IL-18 E42A mutant is resistant to the inhibitory effects of HPV-16 E6 and E7 oncogenes on the IL-18-mediated immune response.
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-gamma 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 IkappaB by E42A was not affected by E6 or E7 in NK0 cells. Moreover, E42A-induced NF-kappaB 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.
Lee
Kyung-Ae
KA
Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology, Yuseong, P. O. Box 115, Daejeon 305-600, South Korea.
Cho
Kyung-Joo
KJ
Kim
Soo-Hyun
SH
Shim
Jung-Hyun
JH
Lim
Jong-Seok
JS
Cho
Dae-Ho
DH
Song
Min-Sung
MS
Dinarello
Charles A
CA
Yoon
Do-Young
DY
D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D052162:Human papillomavirus 16 / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000235:genetics* / Q000276:immunology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000276:immunology* / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D012097:Repressor Proteins / Q000276:immunology* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C068651:E6 protein, Human papillomavirus type 16; D020672:I-kappa B Proteins; D020382:Interleukin-18; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4