Uterine cervical cancer; Human papillomavirus; Langerhans cells; transformation zone; squamous intraepithelial lesions; local immunity
Abstract :
[en] We have addressed the notion that the progression of cancer of the uterine cervix is associated with a preferential constraint on the development of a type 1 cellular mediated response, which is necessary to efficiently eliminate (pre)neoplastic cells. Based on the importance of cytokines in the regulation of an appropriate immune response, we have evaluated the expression of IL-12p40, IL-10 and transforming growth factor-beta 1 (TGF-beta1). Using reverse transcriptase-polymerase chain reaction (RT-PCR), the expression of these three cytokines was evaluated in both low-grade (LG) and high-grade (HG) cervical squamous intraepithelial lesions (SIL) and in normal exocervix and transformation zone biopsies. Our results show that the average level of IL-12 increases within both the LG and HG SIL, compared with both control groups. Interestingly, the percentage of HG SIL expressing IL-12p40 was lower compared with LG SIL. In contrast, the expression of IL-10 increased in parallel with the severity of the lesion to a maximal level in HG SIL. Using immunohistochemistry, we ascertained the presence of IL-12 protein in SIL and IL-10 protein in the transformation zone and SIL biopsies. Both IL-12- and IL-10-producing cells were localized in the stroma, not within the SIL. Furthermore, in this study we also observed that the region of the cervix the most sensitive to lesion development, the transformation zone, was associated with higher average levels of the immunosuppressive cytokines IL-10 and TGF-beta1.
Disciplines :
Immunology & infectious disease Oncology
Author, co-author :
Giannini, Sandra
Al-Saleh, Walid
Piron, Hélène ; Centre Hospitalier Universitaire de Liège - CHU > Centre de diagnostic moleculaire
Jacobs, Nathalie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Doyen, Jean ; Université de Liège - ULiège > Gynécologie-Obstétrique CHR
Boniver, Jacques ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Language :
English
Title :
Cytokine Expression in Squamous Intraepithelial Lesions of the Uterine Cervix: Implications for the Generation of Local Immunosuppression
Publication date :
August 1998
Journal title :
Clinical and Experimental Immunology
ISSN :
0009-9104
eISSN :
1365-2249
Publisher :
Blackwell, Oxford, United Kingdom
Volume :
113
Issue :
2
Pages :
183-9
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Centre de Recherche Interuniversitaire en Vaccinologie (Région Wallonne et GSK)
Zur Hausen H. Roots and perspectives of contemporary papillomavirus research. J Cancer Res Clin Oncol 1996; 122:3-13.
Munger K, Phelps WC. The human papillomavirus E7 protein as a transforming and transactivating factor. Biochem Biophys Acta 1993; 1155:111-23.
Benton C, Shahidullah H, Hunter JAA. Human papillomavirus in the immunosuppressed. Papillomavirus Rep 1992; 3:23-26.
Jochmus-Kudielka I, Scheinder A, Braun R et al. Antibodies against the human papillomavirus type 16 early proteins in human sera: correlation of anti-E7 reactivity with cervical cancer. J Natl Cancer Inst 1989; 81:1698-704.
Viscidi RP, Sun Y, Tsuzaki B, Bosch FX, Munos N, Shah KV. Serologic response in human papillomavirus-associated invasive cervical cancer. Int J Cancer 1993; 55:780-4.
Frazer I, Tindle R. Cell-mediated immunity to papillomaviruses. Papillomavirus Rep 1992; 3:53-58.
Seder RA, Paul WE. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 1994; 12:635-73.
Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996; 17:138-46.
Le Gros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med 1990; 172:921-9.
Manetti R, Parronchi P, Giudizi MG et al. Natural killer cell stimulatory factor (NKSF/IL-12) induces Th1-type specific immune responses and inhibits the development of IL-4 producing Th cells. J Exp Med 1993; 177:1199-204.
Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol 1993; 11:165-90.
Shalaby MR, Ammann AL. Suppression of immune cell function in vitro by recombinant human transforming growth factor-beta. Cell Immunol 1988; 112:343-50.
de Waal Malefyt R, Abrams J, Bennett B, Figdor C, de Vries JE. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991; 174:1209-20.
Kang K, Kubin M, Cooper KD, Lessin SR, Trinchieri G, Rook AH. IL-12 synthesis by human Langerhans cells. J Immunol 1996; 156:1402-7.
Aragane Y, Riemann H, Bhardwaj RS et al. IL-12 is expressed and released by human keratinocytes and epidermoid carcinoma cell lines. J Immunol 1994; 153:5366-72.
Clerici M, Merola M, Ferrario E et al. Cytokine production patterns in cervical intraepithelial neoplasia: association with human papilloma-virus infection. J Natl Cancer Inst 1997; 89:245-50.
Jacobs N, Giannini SL, Doyen J et al. Inverse modulation of interleukin-10 and -12 in the blood of women with preneoplastic lesion of the uterine cervix. Clin Exp Immunol 1998; 111:219-24.
Tartour E, Gey A, Sastre-Garau X et al. Analysis of interleukin 6 expression in cervical neoplasia using a quantative polymerase chain reaction assay: evidence for enhanced interleukin 6 gene expression in invasive carcinoma. Cancer Res 1994; 54:6243-8.
Al-Saleh W, Giannini SL, Jacobs N et al. Correlation of T-helper secretory differentiation and types of antigen-presenting cells in squamous intraepithelial lesions of the uterine cervix. J Pathol 1998; 184:283-90.
Huang M, Wang J, Lee P et al. Human non-small cell lung cancer cells express a type 2 cytokine pattern. Cancer Res 1995; 55:3847-53.
Huettner C, Paulus W, Roggendorf W. Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. Am J Pathol 1995; 146:317-22.
Nakagomi H, Pisa P, Pisa EK et al. Lack of interleukin-2 (IL-2) expression and selective expression of IL-10 mRNA in human renal cell carcinoma. Int J Cancer 1995; 63:366-71.
Kim J, Moldin RL, Dubinett SM, McHugh T, Nickoloff BJ, Uyemura K. IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response. J Immunol 1995; 155:2240-7.
Jacobs MV, De Roda Husman AM, Van den Brule AJC, Snijders PJF, Meijer CJLM, Walboomer JMM. Group-specific differentiation between high-and low-risk human papillomavirus genotypes by general primer-mediated PCR and two cocktails of oligonucleotide probes. J Clin Microbiol 1995; 33:901-5.
Chan SH, Perussia B, Gupta JW et al. Induction of interferon γ production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med 1991; 173:869-78.
Gately MK, Desai BB, Wolitzky AG et al. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic maturation factor). J Immunol 1991; 147:874-82.
Chen L, Chen D, Block E, O'Donnell M, Kufe DW, Clinton SK. Eradication of murine bladder carcinoma by intratumor injection of a bicistronic adenoviral vector carrying cDNAs for the IL-12 helerodimer and its inhibition by the IL-12 p40 subunit homodimer. J Immunol 1997; 159:351-9.
Brunda MJ, Luistro L, Warrier RR et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med 1993; 178:1223-30.
Nastala CL, Edington HD, McKinney TG et al. Recombinant IL-12 administration induces tumor regression in association with IFN-γ production. J Immunol 1994; 153:1697-706.
Voest EE, Kenyon BM, O'Reilly MS, Truitt G, D'Arnato RJ, Folkman J. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 1995; 87:581-6.
Ma X, Aste-Amevaga M, Trincheri G. Regulation of interleukin-12 production. Ann NY Acad Sci 1996; 795:13-23.
Ling P, Gately MK, Gulbler U et al. Human IL-12 p40 homodimer binds to the IL12 receptor but does not mediate biological activity. J Immunol 1995; 154:116-27.
Chang CH, Furue M, Tamaki K. B7-1 expression of Langerhans cells is upregulated by pro-inflammatory cytokines, and is down-regulated by interferon gamma or by interleukin-10. Eur J Immunol 1995; 25:394-8.
D'Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G. Interleukin 10 (IL10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer stimulatory factor/IL12 synthesis in accessory cells. J Exp Med 1993; 178:1041-8.
Koch F, Stanzl U, Jennewein P et al. High level IL-12 production by murine dendritic cells: upregulalion via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10. J Exp Med 1996; 184:741-6.
Matsuda M, Salazar F, Peterson M et al. Interleukin-10 pretreatmant protects target cells from tumor-and allo-specific cytotoxic T cells and downregulates HLA class I expression. J Exp Med 1994; 180: 2371-6.
Yssel H, de Waal Malefyt R, Roncarolo M-G et al. IL-10 is produced by subsets of human CD4+ T cell clones and peripheral blood T cells. J Immunol 1992; 149:2378-84.
Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 1993; 150:353-60.
Pisa P, Halapi E, Pisa EK et al. Selective expression of interleukin 10, interferon γ, and granulocyte-macrophage colony-stimulating factor in ovarian cancer biopsies. Proc Natl Acad Sci USA 1992; 89:7708-12.
Yamamura M, Modlin RL, Ohmen JD, Moy RL. Local expression of antiinflammatory cytokines in cancer. J Clin Invest 1993; 91:1005-10.
Krüger-Krasagakes S, Krasagakis K, Garbe C et al. Expression of interleukin 10 in human melanoma. Br J Cancer 1994; 70:1182-5.
Kucharzik T, Lügering N, Winde G, Domschke W, Stoll R. Colon carcinoma cell lines stimulate monocytes and lamina propria mononuclear cells to produce IL-10. Clin Exp Immunol 1997; 110:296-302.
Gerosa F, Paganin C, Peritt D et al. Interleukin-12 primes human CD4 and CD8 T cell clones for high production of both interferon-γ and interleukin-10. J Exp Med 1996; 183:2559-69.
Windhagen A, Anderson DE, Camzosa A, Williams RE, Hafler DA. IL-12 induces human T cells secreting IL-10 with IFN-γ. J Immunol 1996; 157:1127-31.
Mosmann TR, Moore KW. The role of IL-10 in crossregulation of Th1 and Th2 responses. Immunol Today 1991; 12:A49-A53.
Hsu DH, Moore KW, Spits H. Differential effects of IL-4 and IL-10 on IL-2-induced IFN-gamma synthesis and lymphokine-activated killer activity. Int Immunol 1992; 4:563-9.
Ahuja SS, Paliogianni F, Yamada H, Balow JE, Boumpas DT. Effect of transforming growth factor-beta on early and late activation events in human T cells. J Immunol 1993; 150:3109-18.
Pardoux C, Asselin-Paturel C, Chehimi J, Gay F, Mami-Chouaib F, Chouaib S. Functional interaction between TGF-β and IL-12 in human primary allogeneic cytotoxicity and proliferative response. J Immunol 1997; 158:136-43.
Maeda H, Kuwahara H, Ichimura Y, Ohtsuki M, Kurakata S, Shiraishi A. TGF-β enhances macrophages' ability to produce IL-10 in normal and tumor bearing mice. J Immunol 1995; 155:4926-32.
Coffey RJ, Sipes NJ, Bascom CC et al. Growth modulation of mouse keratinocytes by transforming growth factors. Cancer Res 1988; 48:1596-602.
Woodworth CD, Notario V, DiPaolo JA. Transforming growth factors beta 1 and 2 transcriptionally regulate human papillomavirus (HPV) type 16 early gene expression in HPV-immortalized human genital epithelial cells. J Virol 1990; 64:4767-75.
Comerci JT, Runowicz CD, Flanders KC et al. Altered expression of transforming growth factor-β1 in cervical neoplasia, as an early biomarker in carcinogenesis of the uterine cervix. Cancer 1996; 77:1107-14.
Maeda H, Shiraishi A. TGF-β contributes to the shift toward Th2-type responses through direct and IL-10-mediated pathways in tumor-bearing mice. J Immunol 1996; 156:73-78.
Eron U, Judson F, Tucker S et al. Interferon therapy for condylomata acuminata. N Engl J Med 1986; 315:1059-64.
