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Interleukins as markers of inflammation in malignant and benign thyroid disease

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Abstract

Background

Thyroid disorders, including thyroid cancer and autoimmune thyroid diseases, have been closely associated with inflammation.

Objective

This study aims to investigate the role of inflammation in thyroid disease by assessing serum cytokine levels in patients with malignant and benign thyroid conditions.

Methods

Serum levels of ten interleukins (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 and IL-13) were quantitatively determined in 20 patients with thyroid cancer, 38 patients with benign thyroid disease and 50 healthy controls by multiplex technology.

Results

Serum IL-1β, IL-2, IL-4, IL-5 and IL-6 levels were strongly associated with each other. IL-10 and IL-12 correlated with IL-1β, IL-5, IL-6, and with each other. Age was inversely correlated with serum levels of IL-2, IL-4 and IL-13. A positive correlation between T3 and IL-13 levels was also observed. Significantly higher levels of IL-6, IL-7, IL-10 and IL-13, as well as significantly lower levels of IL-8 were observed in patients with benign and malignant thyroid disease compared to controls. The combination of IL-13 and IL-8 in a two-marker panel was highly efficient in discriminating thyroid disorders (AUC 0.90).

Conclusions

Malignant and benign thyroid conditions are associated with altered expression levels of interleukins, supporting the association between thyroid disease and underlying inflammatory processes.

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Abbreviations

AITDs:

Αutoimmune thyroid diseases

AUC:

Area under the curve

β:

Beta

BMI:

Body mass index

CI:

Confidence interval

EGF:

Epidermal growth factor

GD:

Graves’ disease

HGF:

Hepatocyte growth factor

HT:

Hashimoto’s thyroiditis

IL:

Interleukin

MAPK:

Mitogen-activated protein kinase

MIG:

Monokine induced by gamma interferon

MWW:

Mann–Whitney–Wilcoxon

OOR:

Out-of-range

RANTES:

Regulated on activation, normal T cell expressed and secreted

ROC:

Receiver operating characteristic

Tregs:

Regulatory T cells

References

  1. Curado MP, Edwards B, Shin HR, et al. Cancer incidence in five continents. Vol. IX. Lyon: IARC Scientific Publication No. 160; 2007.

  2. SEER Stat Fact Sheets. Cancer of The Thyroid. 2013. http://seer.cancer.gov/statfacts/html/thyro.html. Accessed 13 Sep 2013.

  3. American Thyroid Association. Thyroid Nodules. 2012. http://www.thyroid.org/wp-content/uploads/patients/brochures/Nodules_brochure.pdf. Accessed 13 Sep 2013.

  4. Hegedüs L. Clinical Practice. The thyroid nodule. N Engl J Med. 2004;351:1764–71.

    Article  PubMed  Google Scholar 

  5. Bozec A, Lassalle S, Hofman V, Ilie M, Santini J, Hofman P. The thyroid gland: a crossroad in inflammation-induced carcinoma? An ongoing debate with new therapeutic potential. Curr Med Chem. 2010;17:3449–61.

    Article  CAS  PubMed  Google Scholar 

  6. Guarino V, Castellone MD, Avilla E, Melillo RM. Thyroid cancer and inflammation. Mol Cell Endocrinol. 2010;321:94–102.

    Article  CAS  PubMed  Google Scholar 

  7. Russell JP, Shinohara S, Melillo RM, Castellone MD, Santoro M, Rothstein JL. Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors. Oncogene. 2003;22:4569–77.

    Article  CAS  PubMed  Google Scholar 

  8. Iwahashi N, Murakami H, Nimura Y, Takahashi M. Activation of RET tyrosine kinase regulates interleukin-8 production by multiple signalling pathways. Biochem Biophys Res Commun. 2002;294:642–9.

    Article  CAS  PubMed  Google Scholar 

  9. Russell JP, Engiles JB, Rothstein JL. Proinflammatory mediators and genetic background in oncogene mediated tumor progression. J Immunol. 2004;172:4059–67.

    Article  CAS  PubMed  Google Scholar 

  10. Shinohara S, Rothstein JL. Interleukin 24 is induced by the RET/PTC3 oncoprotein and is an autocrine growth factor for epithelial cells. Oncogene. 2004;23:7571–9.

    Article  CAS  PubMed  Google Scholar 

  11. Puxeddu E, Knauf JA, Sartor MA, et al. RET/PTC-induced gene expression in thyroid PCCL3 cells reveals early activation of genes involved in regulation of the immune response. Endocr Relat Cancer. 2005;12:319–34.

    Article  CAS  PubMed  Google Scholar 

  12. Melillo RM, Castellone MD, Guarino V, et al. The RET/PTC-RAS-BRAF linear signalling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest. 2005;115:1068–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Borello MG, Alberti L, Fischer A, et al. Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. PNAS. 2005;102:14825–30.

    Article  Google Scholar 

  14. Castellone MD, Celetti A, Guarino V, et al. Autocrine stimulation by osteopontin plays a pivotal role in the expression of the mitogenic and invasive phenotype of RET/PTC-transformed thyroid cells. Oncogene. 2004;23:2188–96.

    Article  CAS  PubMed  Google Scholar 

  15. Ameri P, Ferone D. Diffuse endocrine system, neuroendocrine tumors and immunity: what’s new? Neuroendocrinology. 2012;95:267–76.

    Article  CAS  PubMed  Google Scholar 

  16. Barzon L, Bonaguro R, Castagliuolo I, et al. Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and Herpes Simplex Virus thymidine kinase. Eur J Endocrinol. 2003;148:73–80.

    Article  CAS  PubMed  Google Scholar 

  17. Vitale G, Lupoli G, Guarrasi R, et al. Interleukin-2 and lanreotide in the treatment of medullary thyroid cancer: in vitro and in vivo studies. J Clin Endocrinol Metab. 2013;98:E1567–74.

    Article  CAS  PubMed  Google Scholar 

  18. Fusco A, Chiappetta G, Hui P, et al. Assessment of RET/PTC oncogene activation and clonality in thyroid nodules with incomplete morphological evidence of papillary carcinoma: a search for the early precursors of papillary cancer. Am J Pathol. 2002;160:2157–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Alberti L, Carniti C, Miranda C, Roccato E, Pierotti MA. RET and NTRK1 proto-oncogenes in human diseases. J Cell Physiol. 2003;195:168–86.

    Article  CAS  PubMed  Google Scholar 

  20. Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of RAS mutations. Am J Clin Pathol. 2003;120:71–7.

    Article  CAS  PubMed  Google Scholar 

  21. Nikiforova MN, Kimura ET, Gandhi M, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metabol. 2003;88:5399–404.

    Article  CAS  Google Scholar 

  22. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003;63:1454–7.

    CAS  PubMed  Google Scholar 

  23. Xu X, Quiros RM, Gattuso P, Ain KB, Peinz RA. High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res. 2003;63:4561–7.

    CAS  PubMed  Google Scholar 

  24. Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003;22:4578–80.

    Article  CAS  PubMed  Google Scholar 

  25. Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Nat Cancer Inst. 2003;95:625–7.

    Article  CAS  PubMed  Google Scholar 

  26. Wirtschafter A, Schmidt R, Rosen D, et al. Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto’s thyroiditis. Laryngoscope. 1997;107:95–100.

    Article  CAS  PubMed  Google Scholar 

  27. Sheils OM, O’eary JJ, Uhlmann V, Lättich K, Sweeney EC. RET/PTC-1 activation in Hashimoto thyroiditis. Int J Surg Pathol. 2000;8:185–9.

    Article  CAS  PubMed  Google Scholar 

  28. Elisei R, Romei C, Vorontsova T, et al. RET/PTC rearrangements in thyroid nodules: studies in irradiated and non irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metabol. 2001;86:3211–6.

    CAS  Google Scholar 

  29. Williams D. Cancer after nuclear fallout: lessons from the Chernobyl accident. Nat Rev Cancer. 2002;2:543–9.

    Article  CAS  PubMed  Google Scholar 

  30. Pisanu A, Piu S, Cois A, Uccheddu A. Coexisting Hashimoto’s thyroiditis with differentiated thyroid cancer and benign thyroid disease: indications for thyroidectomy. Chir Ital. 2003;55:365–72.

    PubMed  Google Scholar 

  31. Khatami M. Inflammation, aging, and cancer: tumoricidal versus tumorigenesis of immunity. Cell Biochem Biophys. 2009;55:55–79.

    Article  CAS  PubMed  Google Scholar 

  32. Ahn D, Heo SJ, Park JH, et al. Clinical relationship between Hashimoto’s thyroiditis and papillary thyroid cancer. Acta Oncol. 2011;50:1228–34.

    Article  PubMed  Google Scholar 

  33. Huang BY, Hseuh C, Chao TC, Lin KJ, Lin JD. Well-differentiated thyroid carcinoma with concomitant Hashimoto’s thyroiditis present with less aggressive clinical stage and low recurrence. Endocr Pathol. 2011;22:144–9.

    Article  PubMed  Google Scholar 

  34. Lun Y, Wu X, Xia Q, et al. Hashimoto’s thyroiditis as a risk factor of papillary thyroid cancer may improve cancer prognosis. Otolaryngol Head Neck Surg. 2013;148:396–402.

    Article  PubMed  Google Scholar 

  35. Dvorkin S, Robenshtok E, Hirsch D, Strenov Y, Shimon I, Benbassat CA. Differentiated thyroid cancer is associated with less aggressive disease and better outcome in patients with coexisting Hashimotos thyroiditis. J Clin Endocrinol Metab. 2013;98:2409–14.

    Article  CAS  PubMed  Google Scholar 

  36. Linkov F, Ferris RL, Yurkovetsky Z, et al. Multiplex analysis of cytokines as biomarkers that differentiate benign and malignant thyroid diseases. Proteomics Clin Appl. 2008;2:1575–85.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Perkins NJ, Schisterman EF. The inconsistency of ‘optimal’ cutpoints obtained using two criteria based on the receiver operating characteristic curve. Am J Epidemiol. 2006;163:670–5.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Veselý D, Astl J, Lastůvka P, Matucha P, Sterzl I, Betka J. Serum levels of IGF-I, HGF, TGFbeta1, bFGF and VEGF in thyroid gland tumors. Physiol Res. 2004;53:83–9.

    PubMed  Google Scholar 

  39. Ling MM, Ricks C, Lea P. Multiplexing molecular diagnostics and immunoassays using emerging microarray technologies. Expert Rev Mol Diagn. 2007;7:87–98.

    Article  CAS  PubMed  Google Scholar 

  40. Breen EC, Reynolds SM, Cox C, et al. Multisite comparison of high-sensitivity multiplex assays. Clin Vaccine Immunol. 2011;18:1229–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Kobawala TP, Patel GH, Gajjar DR, et al. Clinical utility of serum interleukin-8 and interferon-alpha in thyroid diseases. J Thyroid Res. 2011;. doi:10.4061/2011/270149.

    PubMed Central  PubMed  Google Scholar 

  42. Zhao ZF, Wei Q, Zhao Y, et al. Genetic copy number alterations and IL-13 expression differences in papillary thyroid cancers and benign nodules. Endocrine. 2009;36:155–60.

    Article  CAS  PubMed  Google Scholar 

  43. Ozgen AG, Karadeniz M, Erdogan M, et al. The (−174) G/C polymorphism in the interleukin-6 gene is associated with risk of papillary thyroid carcinoma in Turkish patients. J Endocrinol Inv. 2009;32:491–4.

    Article  CAS  Google Scholar 

  44. Erdogan M, Karadeniz M, Ozbek M, Ozgen AG, Berdeli A. Interleukin-10 gene polymorphisms in patients with papillary thyroid cancer in Turkish population. J Endocrinol Inv. 2008;31:750–4.

    Article  CAS  Google Scholar 

  45. Basolo F, Fiore L, Pollina L, Fontanini G, Conaldi PG, Toniolo A. Reduced expression of interleukin 6 in undifferentiated thyroid carcinoma: in vitro and in vivo studies. Clin Cancer Res. 1998;4:381–7.

    CAS  PubMed  Google Scholar 

  46. Ruggeri RM, Villary D, Simone A, et al. Co-expression of interleukin-6 (IL-6) and inteleukin-6 receptor (IL-6R) in thyroid nodules is associated with co-expression of CD30 ligand/CD30 receptor. J Endocrinol Inv. 2002;25:959–66.

    Article  CAS  Google Scholar 

  47. Muzza M, Degl′Innocenti D, Colombo C, et al. The tight relationship between papillary thyroid cancer, autoimmunity and inflammation: clinical and molecular studies. Clin Endocrinol. 2010;72:702–8.

    Article  CAS  Google Scholar 

  48. Fujarewicz K, Jarzab M, Eszlinger M, et al. A multi-gene approach to differentiate papillary thyroid carcinoma from benign lesions: gene selection using support vector machines with bootstrapping. Endocr Rel Cancer. 2007;14:809–26.

    Article  CAS  Google Scholar 

  49. Bossowski A, Urban M. Serum levels of cytokines in children nd adolescents with Graves’ disease and non-toxic nodular goiter. J Pediatr Endocrinol Metab. 2011;14:741–7.

    Google Scholar 

  50. Senturk T, Kozaci LD, Kok F, Kadikoylu G, Bolaman Z. Proinflammatory cytokine levels in hyperthyroidism. Clin Invest Med. 2003;26:58–63.

    CAS  PubMed  Google Scholar 

  51. Domberg J, Liu C, Paperwalis C, et al. Circulating chemokines in patients with autoimmune thyroid diseases. Horm Metab Res. 2008;40:416–21.

    Article  CAS  PubMed  Google Scholar 

  52. Gu LQ, Jia HY, Zhao YJ, et al. Association studies of interleukin-8 gene in Graves’ disease and Graves’ ophthalmopathy. Endocrine. 2009;36:452–6.

    Article  CAS  PubMed  Google Scholar 

  53. Inoue N, Watanabe M, Morita M, et al. Association of functional polymorphisms in promoter regions of IL5, IL6 and IL13 genes with development and prognosis of autoimmune thyroid diseases. Clin Exp Immunol. 2011;163:318–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The study was financially supported by the Hellenic Anticancer Institute. We would like to thank Mr. E. Fragkoulis and Ms. V. Stasinopoulou for their support and contribution. All authors declare no conflict of interests.

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Correspondence to Antonia Gounaris.

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Responsible Editor: Bernhard Gibbs.

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Provatopoulou, X., Georgiadou, D., Sergentanis, T.N. et al. Interleukins as markers of inflammation in malignant and benign thyroid disease. Inflamm. Res. 63, 667–674 (2014). https://doi.org/10.1007/s00011-014-0739-z

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  • DOI: https://doi.org/10.1007/s00011-014-0739-z

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