Skip to main content

Advertisement

Log in

The levels of 12 cytokines and growth factors in tears: hyperthyreosis vs euthyreosis

  • Oculoplastics and Orbit
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Purpose

Simultaneous analyses of the contents and ratios of 12 cytokines and growth factors in single samples of human tears were performed, and the results were compared between a group of healthy subjects and a group of patients with Graves’ hyperthyreosis (GH) without thyroid-associated orbitopathy (TAO).

Methods

Determinations and concentration measurements of interleukins (IL-2, IL4, IL-6, IL-8, IL-10, IL-1α, and IL-1β) interferon (IFN-γ), tumor necrosis factor (TNF-α), monocyte chemoattractant protein (MCP-1), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) were performed with single tear samples from 21 patients with hyperthyreosis and 22 healthy subjects. The analyses were performed using a Randox microchip with an Evidence Biochip Array Analyzer.

Results

We found significant differences between the healthy donor group and the hyperthyreosis group in the levels of IL-6, IL-10, VEGF, IL-1α, and MCP-1. The concentration of IL-6 was considerably higher in the hyperthyreosis group, IL-10 was higher in the healthy donor group, and VEGF and MPC-1 were higher in the hyperthyreosis group. The IL-8 and IFN-γ levels were higher in the hyperthyreosis group. The ratios of all of the cytokines to anti-inflammatory IL-10 were significantly elevated in the hyperthyreosis group.

Conclusion

There are clear differences in the levels of cytokines and growth factors in the tears of healthy subjects and patients with GH without TAO. Tear cytokine changes and related dysfunctional tear syndrome (DTS) could be an early sign of occult TAO in Graves’ hyperthyreosis patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Cook EB, Stahl JL, Lowe L, Chen R, Morgan E, Wilson J, Varro R, Chan A, Graziano FM, Barney NP (2001) Simultaneous measurement of six cytokines in a single sample of human tears using microparticle-based flow cytometry: allergics vs. non-allergics. J Immunol Methods 254:109–118

    Article  CAS  PubMed  Google Scholar 

  2. Baudouin C (2007) A new approach for better comprehension of diseases of the ocular surface. J Fr Ophtalmol 30:239–246

    Article  CAS  PubMed  Google Scholar 

  3. Kenyon NJ, Kelly EA, Jarjour NN (2000) Enhanced cytokine generation by peripheral blood mononuclear cells in allergic and asthma subjects. Ann Allergy Asthma Immunol 85:115–120

    Article  CAS  PubMed  Google Scholar 

  4. Gilbard JP, Farris RL (1983) Ocular surface drying and tear film osmolarity in thyroid eye disease. Acta Ophthalmol 61:108–116

    Article  CAS  Google Scholar 

  5. Iskeleli G, Karakoc Y, Abdula A (2008) A tear film osmolarity in patients with thyroid ophthalmopathy. Jpn J Ophthalmol 52:323–326. https://doi.org/10.1007/s10384-008-0545-7

    Article  PubMed  Google Scholar 

  6. Khurana AK, Sunder S, Ahluwalia BK, Malhotra KC (1992) Tear film profile in Graves’ ophthalmopathy. Acta Ophthalmol 70:346–349

    Article  CAS  Google Scholar 

  7. Villani E, Viola F, Sala R, Salvi M, Mapelli C, Currò N, Vannucchi G, Beck-Peccoz P, Ratiglia R (2010) Corneal involvement in Graves’ orbitopathy: an in vivo confocal study. Invest Ophthalmol Vis Sci 51:4574–4578. https://doi.org/10.1167/iovs.10-5380

    Article  PubMed  Google Scholar 

  8. Khalil HA, Dekeizer RJ, Kijlstra A (1988) Analysis of tear proteins in Graves’ ophthalmopathy by high-performance liquid-chromatography. Am J Ophthalmol 106:186–190

    Article  CAS  PubMed  Google Scholar 

  9. Zoukhri D (2006) Effect of inflammation on lacrimal gland function. Exp Eye Res 82:885–898. https://doi.org/10.1016/j.exer.2005.10.018

    Article  CAS  PubMed  Google Scholar 

  10. Amparo F, Dastjerdi MH, Okanobo A, Ferrari G, Smaga L, Hamrah P, Jurkunas U, Schaumberg DA, Dana R (2013) Topical interleukin 1 receptor antagonist for treatment of dry eye disease: a randomized clinical trial. JAMA Ophthalmol 131:715–723. https://doi.org/10.1001/jamaophthalmol.2013.195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sonawane S, Khanolkar V, Namavari A, Chaudhary S, Gandhi S, Tibrewal S, Jassim SH, Shaheen B, Hallak J, Horner JH, Newcomb M, Sarkar J, Jain S (2012) Ocular surface extracellular DNA and nuclease activity imbalance: a new paradigm for inflammation in dry eye disease. Invest Ophthalmol Vis Sci 53:8253–8282. https://doi.org/10.1167/iovs.12-10430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Eckstein AK, Finkenrath A, Heiligenhaus A, Renzing-Köhler K, Esser J, Krüger C, Quadbeck B, Steuhl KP, Gieseler RK (2004) Dry eye syndrome in thyroid-associated ophthalmopathy: lacrimal expression of TSH receptor suggests involvement of TSHR-specific autoantibodies. Acta Ophthalmol Scand 82:291–297

    Article  CAS  PubMed  Google Scholar 

  13. Gupta A, Sadeghi PB, Akpek EK (2009) Occult thyroid eye disease in patients presenting with dry eye symptoms. Am J Ophthalmol 147:919–923. https://doi.org/10.1016/j.ajo.2008.12.007

    Article  PubMed  Google Scholar 

  14. Huang D, Xu N, Song Y, Wang P, Yang H (2012) Inflammatory cytokine profiles in the tears of thyroid-associated ophthalmopathy. Graefes Arch Clin Exp Ophthalmol 250:619–625. https://doi.org/10.1007/s00417-011-1863-x

    Article  CAS  PubMed  Google Scholar 

  15. Huang D, Quan L, Huasheng Y, Yuxiang M (2014) Changes of lacrimal gland and tear inflammatory cytokines in thyroid associated orbitopathy. IOVS 55:4935–4943. https://doi.org/10.1167/iovs.13-13704

    CAS  Google Scholar 

  16. Chang TC, Huang KM, Chang TJ, Lin SL (1990) Correlation of orbital computed tomography and antibodies in patients with hyperthyroid Graves’ disease. Clin Endocrinol 32:551–558

    Article  CAS  Google Scholar 

  17. Ludgate M, Baker G (2002) Unlocking the immunological mechanisms of orbital inflammation in thyroid eye disease. Clin Exp Immunol 2:193–198. https://doi.org/10.1046/j.1365-2249.2002.01792.x

    Article  Google Scholar 

  18. Dias AC, Modulo CM, Jorge AG, Braz AM, Jordao AA, Bertazolli R, de Paula JS, Rocha EM (2007) Influence of thyroid hormone on thyroid hormone receptor beta-1 expression and lacrimal gland and ocular surface morphology. Invest Ophthalmol Vis Sci 48:3038–3042

    Article  PubMed  Google Scholar 

  19. Ujhelyi B, Gogolak P, Erdei AM, Nagy V, Balasz E, Rajnavolgyi E, Berta A, Nagy EV (2012) Graves’ orbitopathy results in profound changes in tear composition: a study of plasminogen activator inhibitor-1 and seven cytokines. Thyroid 22:407–414. https://doi.org/10.1089/thy.2011.0248

    Article  CAS  PubMed  Google Scholar 

  20. Mourits MP (1990) Current concepts on Graves’ ophthalmopathy. In: Mourits MP (ed) Management of Graves’ ophthalmopathy. Rodopi, Amsterdam, pp 7–8

    Google Scholar 

  21. Wang Y, Smith TJ (2014) Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 55:1735–1748. https://doi.org/10.1167/iovs.14-14002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yoon JS, Choi SH, Lee JH, Lee SJ, Lee SY (2010) Ocular surface inflammation, and nerve growth factor level in tears in active thyroid-associated ophthalmopathy. Graefes Arch Clin Exp Ophthalmol 248:271–276. https://doi.org/10.1007/s00417-009-1215-2

    Article  CAS  PubMed  Google Scholar 

  23. Rajaii F, McCoy AN, Smith TJ (2014) Cytokines are both villains and potential therapeutic targets in thyroid-associated ophthalmopathy: from bench to bedside. Expert Rev Ophthalmol 9:227–234. https://doi.org/10.1586/17469899.2014.917960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tan X, Sun S, Liu Y, Zhu T, Wang K, Ren T, Wu Z, Xu H, Zhu L (2014) Analysis of Th17-associated cytokines in tears of patients with dry eye syndrome. Eye 28:608–613. https://doi.org/10.1038/eye.2014.38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Barabino S, Chen Y, Chauhan S, Dana R (2012) Ocular surface immunity: homeostatic mechanisms and their disruption in dry eye disease. Prog Retin Eye Res 31:271–285. https://doi.org/10.1016/j.preteyeres.2012.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mathers WD (2000) Why the eye becomes dry: a cornea and lacrimal gland feedback model. CLAO J 26:159–165

    CAS  PubMed  Google Scholar 

  27. Dartt DA (2004) Dysfunctional neural regulation of lacrimal gland secretion and its role in the pathogenesis of dry eye syndromes. Ocul Surf 2:76–91

    Article  PubMed  Google Scholar 

  28. Knop E, Knop N, Brewitt H (2003) Dry eye disease as a complex dysregulation of the functional anatomy of the ocular surface. New concepts for understanding dry eye disease. Ophthalmologe 100:917–928

    Article  CAS  PubMed  Google Scholar 

  29. Feldmann M, Brennan FM, Chantry D, Haworth C, Turner M, Katsikis P, Londei M, Abney E, Buchan G, Barrett K et al (1991) Cytokine assays—role in evaluation of the pathogenesis of autoimmunity. Immunol Rev 119:105–123

    Article  CAS  PubMed  Google Scholar 

  30. Salvi M, Girasole G, Pedrazzoni M, Passeri M, Giuliani N, Minelli R, Braverman LE, Roti E (1996) Increased serum concentrations of interleukin-6 (IL-6) and soluble IL-6 receptor in patients with Graves’ disease. J Clin Endocrinol Metab 81:2976–2979

    CAS  PubMed  Google Scholar 

  31. Gorman CA (2005) Pathogenesis of graves’ ophthalmopathy. In: Rootman JJ (ed) Orbital disease: present status and future challenges. Taylor and Francis, New York, pp 147–148

    Chapter  Google Scholar 

  32. Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC (2009) Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol 147:198–205. https://doi.org/10.1016/j.ajo.2008.08.032

    Article  CAS  PubMed  Google Scholar 

  33. Shen J, Li Z, Li W, Ge Y, Xie M, Lv M, Fan Y, Chen Z, Zhao D, Han Y (2015) Th1, Th2, and Th17 cytokine involvement in thyroid associated ophthalmopathy. Disease Markers 2015:609593–609598. https://doi.org/10.1155/2015/609593

    Article  PubMed  PubMed Central  Google Scholar 

  34. Nanba T, Watanabe M, Inoue N, Iwatani Y (2009) Increases of the Th1/Th2 cell ratio in severe Hashimoto’s disease and in the proportion of Th17 cells in intractable Graves’ disease. Thyroid 19:495–501. https://doi.org/10.1089/thy.2008.0423

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jelena Juri Mandić.

Ethics declarations

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mandić, J.J., Kozmar, A., Kusačić-Kuna, S. et al. The levels of 12 cytokines and growth factors in tears: hyperthyreosis vs euthyreosis. Graefes Arch Clin Exp Ophthalmol 256, 845–852 (2018). https://doi.org/10.1007/s00417-017-3892-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-017-3892-6

Keywords

Navigation