Human papillomavirus E7 oncoprotein increases production of the anti-inflammatory interleukin-18 binding protein in keratinocytes.
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.


OBJECTIVE
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.
School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
Kathryn H
KH
Richards
Rosella
R
Doble
Christopher W
CW
Wasson
Mohammed
M
Haider
G Eric
GE
Blair
Miriam
M
Wittmann
Andrew
A
Macdonald
D020816:Amino Acid Motifs; D052162:Human papillomavirus 16 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D052161:Human papillomavirus 18 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D052163:Human papillomavirus 6 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology* / Q000821:virology; D050725:Papillomavirus E7 Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D030361:Papillomavirus Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015854:Up-Regulation
D036341:Intercellular Signaling Peptides and Proteins; D050725:Papillomavirus E7 Proteins; C118370:interleukin-18 binding protein