Carcinogenesis Advance Access originally published online on June 18, 2009
Carcinogenesis 2009 30(8):1336-1344; doi:10.1093/carcin/bgp150
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Interferon-beta treatment increases human papillomavirus early gene transcription and viral plasmid genome replication by activating interferon regulatory factor (IRF)-1
1 Veterans Affairs Medical Center, 601 Highway 6 West, Iowa City, IA 52246, USA
2 Department of Pathology
3 Department of Microbiology, The Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
4 Department of Internal Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
5 Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
* To whom correspondence should be addressed. Tel: +1 319 338 0581 ext. 7504; Fax: +1 319 339 7178; Email: michael-lace{at}uiowa.edu
Interferons (IFNs) have been used to treat mucosal lesions caused by human papillomavirus (HPV) infection, such as intraepithelial precursor lesions to cancer of the uterine cervix, genital warts or recurrent respiratory papillomatosis, to potentially reduce or eliminate replicating HPV plasmid genomes. Mucosal HPVs have evolved mechanisms that impede IFN-β synthesis and downregulate genes induced by IFN. Here we show that these HPV types directly subvert a cellular transcriptional response to IFN-β as a potential boost in infection. Treatment with low levels of human IFN-β induced initial amplification of HPV-16 and HPV-11 plasmid genomes and increased HPV-16 or HPV-31 DNA copy numbers up to 6-fold in HPV-immortalized keratinocytes. IFN treatment also increased early gene transcription from the major early gene promoters in HPV-16, HPV-31 and HPV-11. Furthermore, mutagenesis of the viral genomes and ectopic interferon regulatory factor (IRF) expression in transfection experiments using IRF-1–/–, IRF-2–/– and dual knockout cell lines determined that these responses are due to the activation of IRF-1 interaction with a conserved interferon response element demonstrated in several mucosal HPV early gene promoters. Our results provide a molecular explanation for the varying clinical outcomes of IFN therapy of papillomatoses and define an assay for the modulation of the HPV gene program by IFNs as well as other cytokines and signaling molecules in infection and therapy.
Abbreviations: HFK, human foreskin keratinocyte; HPV, human papillomavirus; IFN, interferon; IRE, interferon response element; IRF, interferon regulatory factor; PCR, polymerase chain reaction; SCC, squamous cell carcinoma; Stat, signal transducer and activator of transcription; wt, wild-type
Received April 15, 2009; revised May 17, 2009; accepted June 11, 2009.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. J. Lace, J. R. Anson, A. J. Klingelhutz, J. H. Lee, A. D. Bossler, T. H. Haugen, and L. P. Turek Human Papillomavirus (HPV) Type 18 Induces Extended Growth in Primary Human Cervical, Tonsillar, or Foreskin Keratinocytes More Effectively than Other High-Risk Mucosal HPVs J. Virol., November 15, 2009; 83(22): 11784 - 11794. [Abstract] [Full Text] [PDF]
|
|