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Local expression of interferon-alpha and interferon receptors in cervical intraepithelial neoplasia

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Abstract

Purpose

The present study evaluated mRNA expression of interferon-alpha (IFN-α), IFN-α receptor subunits (IFNAR-1 and IFNAR-2) and an IFN-stimulated gene encoding the enzyme 2′,5′-oligoadenylate synthetase (2′5′OAS) in biopsies on patients with varying grades of cervical intraepithelial neoplasia (CIN I, II and III).

Methods

Uterine cervix biopsies were collected from women with CIN I, II and III (n = 28) and controls without CIN lesions or human papilloma virus (HPV) infection (n = 17). The presence of high and low-risk HPV DNA was determined using hybrid capture. The mRNA levels of IFNAR-1, IFNAR-2, IFN-α and 2′5′OAS were determined by RT-PCR with specific primers.

Results

The control group exhibited a greater frequency of IFNAR-1 expression (10/17; 58.3%) than the CIN samples (4/28; 14.2%) (P = 0.0018), while, the expression of IFNAR-2 was also greater in the control samples (11/17; 64.7%) than in the patients with lesions (2/28; 7.1%) (P = 0.0018). Importantly, simultaneous expression of both receptors was observed only in the control group (8/17; 47.0%) (P = 0.0001). Among the CIN samples, there was one case of low expression of mRNA of IFNAR-1 and IFNAR-2. IFN-α was present in 14.2% (4/28) of the CIN samples but was not expressed in the control group. mRNA 2′5′OAS were expressed in 28.5% (8/28) of the CIN samples and 11.7% (2/17) of the control samples (not statistically significant). Fifty percent (14/28) of the CIN samples were positive for HPV DNA.

Conclusions

Cervical biopsy samples from control women or those without neoplasia or HPV infection displayed higher IFN-α receptor expression than those with CIN, while simultaneous expression of both IFN-α receptor subunits was found only in the control group. There was no significant difference in mRNA expression of IFN-α and 2′5′OAS between the control and CIN groups. Then we concluded that the samples obtained from patients with CIN present low levels of the IFN-α receptor mRNA.

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References

  1. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

    Article  PubMed  CAS  Google Scholar 

  2. Arany I, Goel A, Tyring SK (1995) Interferon response depends on viral transcription in human papillomavirus-containing lesions. Anticancer Res 15:2865–2869

    PubMed  CAS  Google Scholar 

  3. Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM, Foster GR, Stark GR (2008) Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov 6(12):975–990

    Article  CAS  Google Scholar 

  4. Chieux V, Hober D, Chehadeh W, Wattr P (1999) Anti-viral proteins: from interferon alpha to its receptor. Ann Biol Clin 57(3):283–290

    CAS  Google Scholar 

  5. Cintorino M, Tripodi SA, Romagnoli R, Ietta F, Ricci MG, Paulesu L (2002) Interferons and their receptors in human papillomavirus lesions of the uterine cervix. Eur J Gynaecol Oncol 23:145–150

    PubMed  CAS  Google Scholar 

  6. Damdinsuren B, Nagano H, Wada H, Noda T, Natsag J, Marubashi S, Miyamoto A, Takeda Y, Umeshita K, Doki Y, Dono K, Monden M (2007) Interferon alpha receptors are important for antiproliferative effect of interferon-alpha against human hepatocellular carcinoma cells. Hepatol Res 37:77–83

    PubMed  CAS  Google Scholar 

  7. De Marco F, Manni V, Guaricci N, Muller A, Marcante ML (1999) Induction of apoptotic cell death by IFN beta on HPV-16 transformed human keratinocytes. Antiviral Res 42:109–120

    Article  PubMed  Google Scholar 

  8. Diop G, Hirtzig T, Do H, Coulonges C, Vasilescu A, Labib T, Spadoni JL, Therwath A, Lathrop M, Matsuda F, Zagury JF (2006) Exhaustive genotyping of the interferon alpha receptor 1 (IFNAR1) gene and association of an IFNAR1 protein variant with AIDS progression or susceptibility to HIV-1 infection in a French AIDS cohort. Biomed Pharmacother 60:569–577

    Article  PubMed  CAS  Google Scholar 

  9. Doan T, Herd K, Street M, Bryson G, Fernando G, Lambert P, Tindle R (1999) Human papillomavirus type 16 E7 oncoprotein expressed in peripheral epithelium tolerizes E7-directed cytotoxic T-lymphocyte precursors restricted through human (and mouse) major histocompatibility complex class I alleles. J Virol 73:6166–6170

    PubMed  CAS  Google Scholar 

  10. Dondi E, Pattyn E, Lutfalla G, Ostade XV, Uzé G, Pellegrini S, Tavernier J (2001) Down-modulation of type i interferon responses by receptor cross-competition for a shared JAK kinase. J Biol Chem 276:47004–47012

    Article  PubMed  CAS  Google Scholar 

  11. El-Sherif AM, Seth R, Tighe PJ, Jenkins D (2001) Quantitative analysis of IL-10 and IFN-gamma mRNA levels in normal cervix and human papillomavirus type 16 associated cervical precancer. J Pathol 195:179–185

    Article  PubMed  CAS  Google Scholar 

  12. Fenner JE, Starr R, Cornish AL, Zhang JG, Metcalf D, Schreiber RD, Sheehan K, Hilton DJ, Alexander WS, Hertzog PJ (2006) Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nat Immunol 7(1):33–39

    Article  PubMed  CAS  Google Scholar 

  13. Fontaine V, Van der Meijden E, Ter Schegget J (2001) Inhibition of human papillomavirus-16 long control region activity by interferon-gamma overcome by p300 overexpression. Mol Carcinog 31:27–36

    Article  PubMed  CAS  Google Scholar 

  14. Frodsham AJ, Zhang L, Dumpis U, Taib NA, Best S, Durham A, Hennig BJ, Hellier S, Knapp S, Wright M, Chiaramonte M, Bell JI, Graves M, Whittle HC, Thomas HC, Thursz MR, Hill AV (2006) Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence. Proc Natl Acad Sci USA 103:9148–9153

    Article  PubMed  CAS  Google Scholar 

  15. Goodbourn S, Didcock L, Randall RE (2000) Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 81:2341–2364

    PubMed  CAS  Google Scholar 

  16. Hovanessian AG, Justesen J (2007) The human 2′-5′oligoadenylate synthetase family: unique interferon-inducible enzymes catalyzing 2′-5′ instead of 3′-5′ phosphodiester bond formation. Biochimie 89:779–788

    Article  PubMed  CAS  Google Scholar 

  17. Isaacs A, Lindenmann J (1957) Virus interference I. The interferon. Proc R Soc Lond B Biol Sci 147:258–267

    Article  PubMed  CAS  Google Scholar 

  18. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216

    Article  PubMed  CAS  Google Scholar 

  19. Khan MA, Tolleson WH, Gangemi JD, Pirisi L (1993) Inhibition of growth, transformation, and expression of human papillomavirus type 16 E7 in human keratinocytes by alpha interferons. J Virol 67:3396–3403

    PubMed  CAS  Google Scholar 

  20. Koromilas AE, Li S, Matlashewski G (2001) Control of interferon signaling in human papillomavirus infection. Cytokine Growth Factor Rev 12:157–170

    Article  PubMed  CAS  Google Scholar 

  21. Li S, Labrecque S, Gauzzi MC, Cuddihy AR, Wong AH, Pellegrini S, Matlashewski GJ, Koromilas AE (1999) The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha. Oncogene 18:5727–5737

    Article  PubMed  CAS  Google Scholar 

  22. Matsumoto K, Okano J, Murawaki Y (2005) Differential effects of interferon alpha-2b and beta on the signaling on pathways in human liver cancer cells. J Gastroenterol 40:722–732

    Article  PubMed  CAS  Google Scholar 

  23. Michelin MA, Murta EFC (2007) Potential therapeutic vaccine strategies and relevance of immune system in uterine cervical cancer. Eur J Gynaecol Oncol 29:10–18

    Google Scholar 

  24. Muñoz N, Bosch FX DE, Sanjosé S, Herrero R, Castellsagué X, Shah KV, Snijders PJ, Meijer CJ (2003) Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 348(6):518–527

    Article  PubMed  Google Scholar 

  25. Murta EFC (1998) Influência da idade materna, do período gestacional e do número de gestações na infecção pelo papilomavírus humano. Rev Bras Ginecol Obstet 20(1):33–35

    Article  Google Scholar 

  26. Nawa A, Nishiyama Y, Yamamoto N, Maeno K, Goto S, Tomoda Y (1990) Selective suppression of human papilloma virus type 18 mRNA level in HeLa cells by interferon. Biochem Biophys Res Commun 170:793–799

    Article  PubMed  CAS  Google Scholar 

  27. Novick D, Cohen B, Rubinstein M (1994) The human interferon alpha/beta receptor: characterization and molecular cloning. Cell 77:391–400

    Article  PubMed  CAS  Google Scholar 

  28. Ota H, Nagano H, Sakon M, Eguchi H, Kondo M, Yamamoto T, Nakamura M, Damdinsuren B, Wada H, Marubashi S, Miyamoto A, Dono K, Umeshita K, Nakamori S, Wakasa K, Monden M (2005) Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-alpha and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression. Br J Cancer 93:557–564

    Article  PubMed  CAS  Google Scholar 

  29. Pannetier D, Faure C, Georges-Courbot MC, Deubel V, Baize S (2004) Human macrophages, but not dendritic cells, are activated and produce alpha/beta interferons in response to Mopeia virus infection. J Virol 78(19):10516–10524

    Article  PubMed  CAS  Google Scholar 

  30. Pao CC, Lin CY, Yao DS, Tseng CJ (1995) Differential expression of cytokine genes in cervical cancer tissues. Biochem Biophys Res Commun 214:1146–1151

    Article  PubMed  CAS  Google Scholar 

  31. Perea SE, Lopez-Ocejo O, Garcia-Milian R, Arana MJ (1995) Interferon-alpha elicits downregulation of human papillomavirus 18 mRNA in HeLa cells by selective repression of endogenous viral transcription. J Interferon Cytokine Res 15:495–501

    Article  PubMed  CAS  Google Scholar 

  32. Platanias LC, Uddin S, Colamonici OR (1994) Tyrosine phosphorylation of the D and E subunits of the type I interferon receptor. J Biol Chem 269:17761–17764

    PubMed  CAS  Google Scholar 

  33. Richart RM, Shingleton HM, Wiener J, Spiro D (1968) Human cervical intraepithelial neoplasia: fine structure of dysplasia and carcinoma in situ. Cancer Res 28(4):695–706

    PubMed  Google Scholar 

  34. 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

    Article  PubMed  CAS  Google Scholar 

  35. Saito T, Ji G, Shinzawa H, Okumoto K, Hattori E, Adachi T, Takeda T, Sugahara K, Ito JI, Watanabe H, Saito K, Togashi H, Ishii K, Matsuura T, Inageda K, Muramatsu M, Kawata S (2004) Genetic variations in humans associated with differences in the course of hepatitis C. Biochem Biophys Res Commun 30:335–341

    Article  CAS  Google Scholar 

  36. Samuel CE (2001) Antiviral actions of interferons. Clin Microbiol Rev 14:778–809

    Article  PubMed  CAS  Google Scholar 

  37. Song SH, Lee JK, Lee NW, Saw HS, Kang JS, Lee KW (2008) Interfeon-γ: a possible prognostic marker for clearance of high-risk human papilomavirus (HPV). Gynecol Oncol 108(3):543–548

    Article  PubMed  CAS  Google Scholar 

  38. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD (1998) How cells respond to interferons. Annu Rev Biochem 67:227–264

    Article  PubMed  CAS  Google Scholar 

  39. Stoler MH, Rhodes CR, Whitbeck A, Wolinsky SM, Chow LT, Broker TR (1992) Human papillomavirus type 16 and 18 gene expression in cervical neoplasias. Hum Pathol 23(2):117–128

    Article  PubMed  CAS  Google Scholar 

  40. Uthaisangsook S, Day NK, Bahna SL, Good RA, Haraguchi S (2002) Innate immunity and its role against infections. Ann Allergy Asthma Immunol 88:253–264

    Article  PubMed  Google Scholar 

  41. Uze G, Lutfalla G, Bandu MT, Proudhon D, Moogensen KE (1992) Behaviour of a cloned murine interferon alpha/beta receptor expressed in homospecific or heterospecific background. Proc Natl Acad Sci USA 89:4774–4778

    Article  PubMed  CAS  Google Scholar 

  42. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Muñoz N (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189(1):12–19

    Article  PubMed  CAS  Google Scholar 

  43. Woodworth CD, Lichti U, Simpson S, Evans CH, Di Paolo JA (1992) Leukoregulin and gamma-interferon inhibit human papillomavirus type 16 gene transcription in human papillomavirus-immortalized human cervical cells. Cancer Res 52:456–463

    PubMed  CAS  Google Scholar 

  44. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5(7):730–737

    Article  PubMed  CAS  Google Scholar 

  45. Zimmerer JM, Lesinski GB, Kondadasula SV, Karpa VI, Lehman A, Raychaudhury A, Becknell B, Carson WE (2007) IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. J Immunol 178:4832–4845

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Research and Projects Financing (FINEP), the Support Research Foundation of State of Minas Gerais (FAPEMIG), and the National Council for Scientific and Technological Development (CNPq) for financial support.

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Correspondence to Marcia A. Michelin.

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Tirone, N.R., Peghini, B.C., Barcelos, A.C.M. et al. Local expression of interferon-alpha and interferon receptors in cervical intraepithelial neoplasia. Cancer Immunol Immunother 58, 2003–2010 (2009). https://doi.org/10.1007/s00262-009-0707-6

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  • DOI: https://doi.org/10.1007/s00262-009-0707-6

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