Abstract
Persistent infection by high-risk (HR) human papillomavirus (HPV) types is a prerequisite for progression to cancer. HR-HPVs may lead to a deregulation of innate immunity by interfering with the epithelial type I interferon (IFN) response, whereas very little is known about type III IFNs, a key component of the mucosal antiviral response. This study reports a first attempt to evaluate the activation of type III IFN genes (IFN lambda 1–3), IFN lambda receptor genes (IFN-lambdaR1 and IL10R2), and IFN-induced genes (MxA, ISG15, ISG56) in HPV-positive and HPV-negative cervical cells from 154 women attending the gynecological unit of a university hospital in Rome. Despite an increased individual variability, a coordinated expression of several IFN lambda-related genes was observed. Furthermore, IFN lambda 1 and IFN-lambdaR1 genes were expressed at higher levels in cervical cells positive to low-risk (LR) HPV compared to HR-HPV and HPV-negative cells. Consistently, ISG15 expression was significantly higher in LR-HPV-infected women than in the other groups. Moreover, IFN lambda 1 expression decreased significantly with abnormal cytological results. This study is the first to show the activation of a type III IFN response in LR-HPV-positive cervical cells and suggests that the lack of this response in HR-HPV infection may be related to lesion progression.
Similar content being viewed by others
References
Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S (2007) Human papillomavirus and cervical cancer. Lancet 370:890–907
Einstein MH, Schiller JT, Viscidi RP, Strickler HD, Coursaget P, Tan T, Halsey N, Jenkins D (2009) Clinician’s guide to human papillomavirus immunology: knowns and unknowns. Lancet Infect Dis 9:347–356. doi:10.1016/S1473-3099(09)70108-2
Stanley MA (2012) Epithelial cell responses to infection with human papillomavirus. Clin Microbiol Rev 25:215–222. doi:10.1128/CMR.05028-11
Ronco LV, Karpova AY, Vidal M, Howley PM (1998) Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev 12:2061–2072
Barnard P, McMillan NA (1999) The human papillomavirus E7 oncoprotein abrogates signaling mediated by interferon-alpha. Virology 259:305–313
Hong S, Mehta KP, Laimins LA (2011) Suppression of STAT-1 expression by human papillomaviruses is necessary for differentiation-dependent genome amplification and plasmid maintenance. J Virol 85:486–9494. doi:10.1128/JVI.05007-11
Donnelly RP, Kotenko SV (2010) Interferon-lambda: a new addition to an old family. J Interferon Cytokine Res 30:555–564. doi:10.1089/jir 2010.0078
Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP (2003) IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol 4:69–77
Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J et al (2003) IL28, IL29 and their class II cytokine receptor IL28R. Nat Immunol 4:63–68
Zhou Z, Hamming OJ, Ank N, Paludan SR, Nielsen AL, Hartmann R (2007) Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J Virol 81:7749–7758
Marcello T, Grakoui A, Barba-Spaeth G, Machlin ES, Kotenko SV, MacDonald MR, Rice CM (2006) Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology 131:1887–1898
Ank N, West H, Bartholdy C, Eriksson K, Thomsen AR, Paludan SR (2006) Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol 80:4501–4509
Ank N, Iversen MB, Bartholdy C, Staeheli P, Hartmann R, Jensen UB, Dagnaes-Hansen F, Thomsen AR, Chen Z, Haugen H et al (2008) An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity. J Immunol 180:2474–2485
Lasfar A, Abushahba W, Balan M, Cohen-Solal KA (2011) Interferon lambda: a new sword in cancer immunotherapy. Clin Dev Immunol. doi:10.1155/2011/349575
Liu D, Chang CH, Rossi EA, Cardillo TM, Goldenberg DM (2013) Interferon-λ1 linked to a stabilized dimer of fab potently enhances both antitumor and antiviral activities in targeted cells. PLoS One. doi:10.1371/journal.pone.0063940
Sommereyns C, Paul S, Staeheli P, Michiels T (2008) IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. doi:10.1371/journal.ppat.1000017
Mordstein M, Neugebauer E, Ditt V, Jessen B, Rieger T, Falcone V, Sorgeloos F, Ehl S, Mayer D, Kochs G et al (2010) Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol 84:5670–5677. doi:10.1128/JVI.00272-10
Iversen MB, Ank N, Melchjorsen J, Paludan SR (2010) Expression of type III interferon (IFN) in the vaginal mucosa is mediated primarily by dendritic cells and displays stronger dependence on NF-kappaB than type I IFNs. J Virol 84:4579–4586. doi:10.1128/JVI.02591-09
Reiser J, Hurst J, Voges M, Krauss P, Münch P, Iftner T, Stubenrauch F (2011) High-risk human papillomaviruses repress constitutive kappa interferon transcription via E6 to prevent pathogen recognition receptor and antiviral-gene expression. J Virol 85:11372–11380. doi:10.1128/JVI.05279-11
Verteramo R, Pierangeli A, Calzolari E, Patella A, Recine N, Mancini E, Marcone V, Masciangelo R, Bucci M, Antonelli G et al (2006) Direct sequencing of HPV DNA detected in gynaecologic outpatients in Rome, Italy. Microbes Infect 8:2517–2521
Pierangeli A, Degener AM, Ferreri ML, Riva E, Rizzo B, Turriziani O, Luciani S, Scagnolari C, Antonelli G (2011) Interferon-induced gene expression in cervical mucosa during human papillomavirus infection. Int J Immunopathol Pharmacol 24:217–223
Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PA, Bartlett NW, Kebadze T, Mallia P, Stanciu LA, Parker HL (2006) Role of deficient type III interferon-λ production in asthma exacerbations. Nat Med 12:1023–1026
Scagnolari C, Midulla F, Selvaggi C, Monteleone K, Bonci E, Papoff P, Cangiano G, Di Marco P, Moretti C, Pierangeli A et al (2012) Evaluation of viral load in infants hospitalized with bronchiolitis caused by respiratory syncytial virus. Med Microbiol Immunol 201:311–317. doi:10.1007/s00430-012-0233-6
Daud II, Scott ME (2008) Validation of reference genes in cervical cell samples from human papillomavirus-infected and -uninfected women for quantitative reverse transcription-PCR assays. Clin Vaccine Immunol 15:1369–1373. doi:10.1128/CVI.00074-08
Castle PE (2009) The evolving definition of carcinogenic human papillomavirus. Infect Agent Cancer 11:4–7. doi:10.1186/1750-9378-4-7
Haller O, Kochs G (2011) Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J Interferon Cytokine Res 31:79–87. doi:10.1089/jir 2010.0076
Durfee LA, Lyon N, Seo K et al (2010) The ISG15 conjugation system broadly targets newly synthesized proteins: implications for the antiviral function of ISG15. Mol Cell 11(38):722–732. doi:10.1016/j.molcel.2010.05.002
Terenzi F, Saikia P, Sen GC (2008) Interferon-inducible protein, P56, inhibits HPV DNA replication by binding to the viral protein E1. EMBO J 27:3311–3321. doi:10.1038/emboj.2008.241
Weinstock-Guttman B, Tamano-Blanco M, Bhasi K (2007) Pharmacogenetics of MxA SNPs in interferon-beta treated multiple sclerosis patients. J Neuro Immunol 128:879–886
Scagnolari C, Antonelli G (2013) Antiviral activity of the interferon α family: biological and pharmacological aspects of the treatment of chronic hepatitis C. Expert Opin Biol Ther 5:693–711
Pitha-Rowe IF, Pitha PM (2007) Viral defense, carcinogenesis and ISG15: novel roles for an old ISG. Cytokine Growth Factor Rev 104:1371–1376
Acknowledgments
This study was supported by grants from Sapienza University of Rome “Ricerca Scientifica 2012” to AP.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cannella, F., Scagnolari, C., Selvaggi, C. et al. Interferon lambda 1 expression in cervical cells differs between low-risk and high-risk human papillomavirus-positive women. Med Microbiol Immunol 203, 177–184 (2014). https://doi.org/10.1007/s00430-014-0330-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00430-014-0330-9