Interleukin IL-1α, IL-6, IL-8, IL-10 Expression in Different Staging of Cervical Intraepithelial Neoplasia

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Introduction. Cervical cancer is the fourth most common form of cancer in women [19]. The precancerous stages are divided into three distinctive stages, labelled cervical intraepithelial neoplasia (CIN) I, II and III. One of the aetiological factors is chronic inflammation in cervical tissue, most often induced by Human papilloma virus (HPV). 88,5% of the patients regress from low grade intraepithelial changes to unchanged epithelium [14]. It has been proposed that cytokine balance plays a key role in the development of high grade epithelial changes (CIN I – CIN III) in the remaining 11.5% of patients, however, the exact trigger of this event remains to be found.

Aim of the Study. The aim of the study was to determine three pro-inflammatory (IL-1α, IL-6, IL-8) and one anti-inflammatory (IL-10) interleukin expression in different CIN cervix uteri biopsies.

Material and methods. 16 biopsies were obtained with different CIN staging: one with CIN I stage, five with CIN II stage and 10 with CIN III stage. The samples were stained with haematoxylin and eosin and immunohistochemistry for IL-1α, IL-6, IL-8 and IL-10. Slides were evaluated semi-quantitatively grading the intensity of positively stained structures in the visual field.

Results. Examination of the samples yielded the following: IL-1α expression increased from CIN II to CIN III in squamous epithelium, while IL-8 expression decreased. A few IL-1α containing inflammatory cells were found in all CIN stages. IL-8 expression in subepithelium and the number of inflammatory cells decreased from CIN II stage to CIN III, although, it increased in the blood vessel endothelium.

Conclusions. There was constant moderate expression of both IL-6 and IL-10 during all CIN stages, except for inflammatory cells, where IL-6 expression was high during all stages, yet there were few IL-10 containing cells during CIN. The balanced expression of both cytokines suggests that pro- and anti-inflammatory cytokine balance has an important role in CIN morfopathogenesis. The high expression of IL-6 in inflammatory cells and constant expression trough CIN staging indicates sustentation of chronic inflammation and production of other cytokines, such as IL-8, IL-1α. The variable IL-8 expression and its decrease in CIN III stage suggests the depletion of IL-8 production. The high expression of cytokines in blood vessel endothelium indicates their important role in CIN morfopathogenesis.

1. Adurthi S, Mukherjee G, Krishnamurthy H, Sudhir K, Bafna UD, Umadevi K, Jayshree RS. Functional tumour infiltrating TH1 and TH2 effectors in large early-stage cervical cancer are suppressed by regulatory T cells // Int J Gynecol Cancer, 2012; 22:1130 – 1137

2. Arany I, Grattendick KG, Tyring SK. Interleukin-10 induces transcription of the early promoter of human papillomavirus type 16 (HPV16) through the 5’-segment of the upstream regulatory region (URR) // Antiviral Res, 2002; 55:331-339

3. Azar KK, Tani M, Yasuda H, Sakai A, Inoue M, Sasagawa T. Increased secretion patterns of interleukin-10 and tumour necrosis factor-alpha in cervical squamous intraepithelial lesions // Hum Pathol, 2004; 35:1376 – 1384

4. Bae JY, Kim EK, Yang DH, Zhang X, Park YJ, Lee DY, Che CM, Kim J. Reciprocal interaction between carcinoma-associated fibroblasts and squamous carcinoma cells through interleukin-1α induces cancer progression // Neoplasia, 2014; 16:928 – 938

5. Bais AG, Beckmann I, Lindemans J, Ewing PC, Meijer CJ, Snijders PJ, Helmerhost TJ. A shift to a peripheral Th2-type cytokine pattern during the carcinogenesis of cervical cancer becomes manifest in CIN III lesions // J Clin Pathol, 2005; 58: 1096 – 1100

6. Behbakht K, Friedman J, Heimler I, Aroutcheva A, Simoes J, Fao S. Role of the vaginal microbiological ecosystem and cytokine profile in the promotion of cervical dysplasia: a case–control study // Infect Dis Obstet Gynecol, 2002; 10:181 – 186

7. Belokrinitskaia TE, Vitkovskii IuA, Ponomareva IuN. Role of cytokines in the development of immunologic and homeostatic disorders in advanced dysplasia and carcinoma of the uterine cervix // Vopr Onkol, 2003; 49:51 – 54

8. Bermundez-Morales VH, Gutierrez LX, Alcocer-Gonzalez JM, Burguete A, Madrid-Marina V. Correlation between IL-10 gene expression and HPV infection in cervical cancer: a mechanism for immune response escape // Cancer Invest, 2008; 26:1037 – 1043

9. Berti FCB, Pereira APL, Cebinelli GCM, Trugilo KP, Brajao de Oliveira K. The role of interleukin 10 in human papilloma virus infection and progression to cervical carcinoma // Cytokine Growth Factor Rev, 2017; 34:1 – 13

10. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shah KV. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group // J Natl Cancer Inst, 1995; 87:796-802

11. Carrero Y, Mosquera J, Callejas D, Alvarez-Mon M. In situ increased chemokine expression in human cervical intraepithelial neoplasia // Pathol Res Pract, 2015; 211:281 – 285

12. Castrilli G, Tatone D, Diodoro MG, Rosini S, Piantelli M, Musiani P. Interleukin 1alpha and interleukin 6 promote the in vitro growth of both normal and neoplastic human cervical epithelial cells // Br J Cancer, 1997; 75:855 – 859

13. Chua KL, Hjerpe A. Persistence of human papillomavirus (HPV) infections preceding cervical carcinoma // Cancer, 1996; 77:121-127

14. Ciavattini A, Clemente N, Tsiroglou D, Sopracordevole F, Serri M, Delli Carpini G, Papiccio M, Cattani P. Follow up in women with biopsy diagnosis of cervical low-grade squamous intraepithelial lesion (LSIL): how long should it be? // Arch Gynecol Obstet, 2017; 295:997 – 1003

15. Clerici M, Shearer GM, Clerici E. Cytokine dysregulation in invasive cervical carcinoma and other human neoplasias: time to consider the TH1/ TH2 paradigm // J Natl Cancer Inst, 1998; 90: 261 – 263

16. Commins SP, Borish L, Steinke JW. Immunologic messenger molecules: cytokines, interferons, and chemokines // J Allergy Clin Immunol, 2010; 125:S53 – S72

17. Crowley-Nowick PA, Ellenberg JH, Vermund SH, Douglas SD, Holland CA, Moscicki AB. Cytokine profile in genital tract secretions from female adolescents: impact of human immunodeficiency virus, human papillomavirus, and other sexually transmitted pathogens // J Infect Dis, 2000; 181:939 – 945

18. Daniilidis A, Koutsos J, Oikonomou Z, Nasioutziki M, Hatziparadisi K, Tantanasis T. Cytokines of cervical mucosa and human papilloma virus infection of the cervix: A descriptive study // Acta Cytol, 2016; 60:58 – 64

19. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 // Int J Cancer, 2015; 136:E359-386

20. Fernandes AP, Goncalves Ma, Duarte G, Cunha FQ, Simoes RT, Donadi EA. HPV16, HPV18, and HIV infection may influence cervical cytokine intralesional levels // Virology, 2005; 334:294 – 298

21. Fichorova RN, Andreson DJ. Differential expression of immunobiological mediators by immortalized human cervical and vaginal epithelial cells // Biol Reprod. 1999; 60:508 – 514

22. Gonzalez-Bosquet E, Fernandez S, Sabra S, Lailla JM. Negative HPV testing among patients with biopsy-proven cervical intraepithelial neoplasia grade 2/3 or cervical cancer // INT J Gynaecol Obstet, 2017; 136:229 – 231

23. Iglesias M, Yen K, Gaiotti D, Hildesheim A, Stoler MH, Woodworth CD. Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1alpha // Oncogene, 1998; 17:1195 – 1205

24. Iwata T, Fujii T, Morii T, Saito M, Sugiyama J, Nishio H, Morisada T, Tanaka K, Yaguchi T, Kawakami Y, Aoki D. Cytokine profile in cervical mucosa of Japanese patients with cervical intraepithelial neoplasia // Int J Clin Oncol, 2015; 20:126 – 133

25. Karim R, Meyers C, Backendorf C, Ludigs K, Offringa R, van Ommen GJ, Melief CJ, van der Burg SH, Boer JM. Human papillomavirus deregulates the response of a cellular network comprising of chemotactic and proinflammatory genes // PLoS One, 2011; 6:e17848

26. Kumar V, Abbas A, Aster J. Female genital system and breast // In: Kumar R. Robbins Basic pathology. 9th ed. Philadelphia: Saunders/Elsavier; 2012: 685 – 689

27. Liu LB, Xie F, Chang KK, Li MQ, Meng YH, Wang XH, Li H, Li DJ, Yu JJ. Hypoxia promotes the proliferation of cervical carcinoma cells through stimulating the secretion of IL-8 // Int J Clin Exp Pathol, 2014;7:575 – 583

28. Long X, Yingnan Y, Zhang L, Liu P, Yu W, Wei F, Ren X, Yu J. IL-8, a novel messenger to cross-link inflammation and tumour EMT via autocrine and paracrine pathways (review) // Int J Oncol, 2015; 48:5 – 12

29. Merrick DT, Winberg G, McDougall JK. Reexpression of interleukin 1 in human papillomavirus 18 immortalized keratinocytes inhibits their tumorigenicity in nude mice // Cell Growth Differ, 1996; 7:1661 – 1669

30. Mhatre M, McAndrew T, Carpenter C, Burk RD, Einstein MH, Herold BC. Cervical intraepithelial neoplasia is associated with genital tract mucosal inflammation // Sex Transm Dis, 2012; 39: 591 – 597

31. Mota F, Rayment N, Chong S. The antigenpresenting environment in normal and human papillomavirus (HPV)-related premalignant cervical epithelium // Clin Exp Immunol, 1999; 116:33 – 40

32. Multhoff G, Molls M, Radons J. Chronic inflammation in cancer development // Front Immunol, 2012; 2:98

33. Muraille E, Leo O. Revisiting the Th1/Th2 paradigm // Scand J Immunol, 1998; 47:1 – 9

34. Paradkar PH, Joshi JV, Mertia PN, Agashe SV, Vaidaya RA. Role of cytokines in genesis, progression and prognosis of cervical cancer // Asian Pac J Cancer Prev, 2014; 15:3851 – 3864

35. Peghini BC, Abdalla DR, Barcelos AC, Teodoro Ld, Murta EF, Michelin MA. Local cytokine profiles of patients with cervical intraepithelial and invasive neoplasia // Hum Immunol, 2012; 73:920-926

36. Pilmane M, Rumba I, Sundler F, Luts A. Patterns of distribution and occurrence of neuroendocrine elements in lungs of humans with chronic lung diseases // Proc. Of Latvian Academy of Sciences, Section B, 1998; 52:144-152

37. Rider P, Carmi Y, Voronov E, Apte RN. Interleukin-1α // Semin Immunol, 2013; 25:430-438

38. Romagnani S. Type 1 T helper and type 2 T helper cells: functions, regulation and role in protection and disease // Int J Clin Lab Res, 1991; 21:152 – 158

39. Santin AD, Hermonat PL, Ravaggi A, Bellone S, Pecorelli S, Roman JJ, Parham GP, Cannon MJ. Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirusspecific CD8(+) cytotoxic T lymphocytes // J Virol, 2000; 74:4729 – 4737

40. Scott ME, Ma Y, Kuzmich L, Moscicki AB. Diminished IFN-gamma and elevated Foxp3 mRNA expression in the cervix are associated with CIN 2 or 3 // Int J Cancer, 2009; 124:1379 – 1383

41. Song SH, Lee JK, Seok OS, Saw HS. The relationship between cytokines and HPV-16, HPV-16 E6, E7, and high-risk HPV viral load in the uterine cervix // Gynecol Oncol, 2007; 104:732 – 738

42. Tavares-Murta BM, de Resende AD, Cunha FQ, Murta EF. Local profile of cytokines and nitric oxide in patients with bacterial vaginosis and cervical intraepithelial neoplasia // Eur J Obstet Gynecol Reprod Biol, 2008; 138:93 – 99

43. The centre of disease and control of Latvia. Provisional statistical data on citizen mortality // Statistical yearbook of health care in Latvia 2015, 2015; 1:104

44. Tjiong MY, van der Vange N, ten Kate FJ, Tjong- A-Hung SP, ter Schegget J, Burger MP, Out TA. Increased IL-6 and IL-8 levels in cervicovaginal secretions of patients with cervical cancer // Gynecol Oncol, 1999; 73:285 – 291

45. Tjiong MY, van der Vange N, ter Schegget JS, Burger MP, ten Kate FW, Out TA. Cytokines in cervicovaginal washing fluid from patients with cervical neoplasia // Cytokine, 2001; 14:357 – 360

46. Wei LH, Kuo ML, Chen CA, Cheng WF, Cheng SP, Hsieh FJ, Hsieh CY. Interleukin-6 in cervical cancer: the relationship with vascular endothelial growth factor // Gynecol Oncol, 2001; 82:49 – 56

47. Wei LH, Kuo ML, Chen CA, Chou CH, Cheng WF, Chang MC, Su JL, Hsieh CY. The anti-apoptotic role of interleukin-6 in human cervical cancer is mediated by up-regulation of Mcl-1 through a PI 3-K/Akt pathway // Oncogene, 2001; 20:5799 – 5809

48. Wei LH, Kuo ML, Chen CA, Chou CH, Lai KB, Lee CN, Hsieh CY. Interleukin-6 promotes cervical tumour growth by VEGF-dependent angiogenesis via a STAT3 pathway // Oncogene, 2003; 22:1517 – 1527

49. Woodworth CD, McMullin E, Iglesias M, Plowman GD. Interleukin 1 alpha and tumour necrosis factor alpha stimulate autocrine amphiregulin expression and proliferation of human papillomavirusimmortalized and carcinoma-derived cervical epithelial cells // Proc Natl Acad Sci U S A, 1995; 92:2840 – 2844

50. Woodworth CD, Simpson S. Comparative lymphokine secretion by cultured normal human cervical keratinocytes, papillomavirusimmortalized, and carcinoma cell lines // Am J Pathol, 1993; 142:1544 – 1555

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