Human Papillomavirus E7 Oncoprotein Increases Production of the Anti-Inflammatory Interleukin-18 Binding Protein in Keratinocytes

被引:27
|
作者
Richards, Kathryn H. [1 ]
Doble, Rosella [1 ]
Wasson, Christopher W. [1 ]
Haider, Mohammed [1 ]
Blair, G. Eric [1 ]
Wittmann, Miriam [2 ,3 ,4 ]
Macdonald, Andrew [1 ]
机构
[1] Univ Leeds, Fac Biol Sci, Sch Mol & Cellular Biol, Leeds, W Yorkshire, England
[2] Univ Leeds, Leeds Inst Rheumat & Musculoskeletal Med, Leeds, W Yorkshire, England
[3] Chapel Allerton Hosp, NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds, W Yorkshire, England
[4] Univ Bradford, Sch Life Sci, Ctr Skin Sci, Bradford BD7 1DP, W Yorkshire, England
关键词
RETINOBLASTOMA TUMOR-SUPPRESSOR; CONSERVED REGION 3; TYPE-16; E7; CERVICAL-CANCER; DOWN-REGULATION; CELL-GROWTH; E6; EXPRESSION; PROMOTER; TRANSFORMATION;
D O I
10.1128/JVI.02546-13
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Human papillomavirus (HPV) can successfully evade the host immune response to establish a persistent infection. We show here that expression of the E7 oncoprotein in primary human keratinocytes results in increased production of interleukin-18 (IL-18) binding protein (IL-18BP). This anti-inflammatory cytokine binding protein is a natural antagonist of IL-18 and is necessary for skin homeostasis. We map increased IL-18BP production to the CR3 region of E7 and demonstrate that this ability is shared among E7 proteins from different HPV types. Furthermore, mutagenesis shows that increased IL-18BP production is mediated by a gamma-activated sequence (GAS) in the IL-18BP promoter. Importantly, the increased IL-18BP levels seen in E7-expressing keratinocytes are capable of diminishing IL-18-mediated CD4 lymphocyte activation. This study provides the first evidence for a virus protein that targets IL-18BP and further validates E7 as a key component of the HPV immune evasion armor. IMPORTANCE Infection with human papillomavirus is a leading cause of morbidity and mortality worldwide. This study demonstrates that the E7 protein increases production of the anti-inflammatory IL-18BP, a major regulator of epithelial homeostasis. A number of E7 proteins can increase IL-18BP production, and a region within the CR3 of E7 is necessary for mediating the increase. A consequence of increased IL-18BP production is a reduction in CD4-positive lymphocyte activation in response to IL-18 costimulation. These findings may shed light on the immune evasion abilities of HPV.
引用
收藏
页码:4173 / 4179
页数:7
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