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Nat Commun. 2015 Mar 13;6:6537. doi: 10.1038/ncomms7537.

The interferon-related developmental regulator 1 is used by human papillomavirus to suppress NFκB activation.

Author information

1
Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
2
Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
3
Center for Gynaecological Oncology, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
4
Department of Gynaecology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
5
Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, USA.
6
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
7
Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.

Abstract

High-risk human papillomaviruses (hrHPVs) infect keratinocytes and successfully evade host immunity despite the fact that keratinocytes are well equipped to respond to innate and adaptive immune signals. Using non-infected and freshly established or persistent hrHPV-infected keratinocytes we show that hrHPV impairs the acetylation of NFκB/RelA K310 in keratinocytes. As a consequence, keratinocytes display a decreased pro-inflammatory cytokine production and immune cell attraction in response to stimuli of the innate or adaptive immune pathways. HPV accomplishes this by augmenting the expression of interferon-related developmental regulator 1 (IFRD1) in an EGFR-dependent manner. Restoration of NFκB/RelA acetylation by IFRD1 shRNA, cetuximab treatment or the HDAC1/3 inhibitor entinostat increases basal and induced cytokine expression. Similar observations are made in IFRD1-overexpressing HPV-induced cancer cells. Thus, our study reveals an EGFR-IFRD1-mediated viral immune evasion mechanism, which can also be exploited by cancer cells.

PMID:
26055519
PMCID:
PMC4382698
DOI:
10.1038/ncomms7537
[Indexed for MEDLINE]
Free PMC Article

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