Interrelationship of IFN-γ, IL-4, pituitary-thyroid and pituitary-adrenocortical systems in cold airway hyperresponsiveness in patients with asthma

• Aleksey B. Pirogov
• Anna G. Prihodko
• Juliy M. Perelman

Abstract

Introduction. The mechanism of development of thyroid insufficiency in asthma is associated with the influence of Th1 cytokines on the peripheral part of the hypothalamic-pituitary-thyroid axis.

Aim of the study - to assess the profile of cytokines IFN-γ and IL-4, the activity of the pituitary-thyroid and pituitary-adrenocortical systems after exposure to the cold trigger on the respiratory tract of asthma patients.

Material and methods. 57 asthma patients with cold airway hyperresponsiveness (1^st group) and 79 patients without hyperresponsiveness (2^nd group) were examined. Asthma control was assessed using the Asthma Control Test questionnaire (ACT, Quality Metric Inc., 2002). We studied the lung function, the airway reaction to 3-minute isocapnic hyperventilation with cold (-20 °C) air (IHCA). In the exhaled breath condensate, the content of IFN-γ and IL-4 was determined before and after IHCA; in blood serum - thyroid stimulating (TSH) and adrenocorticotropic (ACTH) hormones, thyroid hormone fractions, cortisol; in leukocytes - cyclic adenosine monophosphate (cAMP).

Results. After the IHCA, in the persons of 1^st group, a significant increase in the concentration in the blood serum of only free T₃ was recorded, in 2^nd group - TSH, free T₃, T₃, and free T₄. Patients of 1^st group had lower baseline concentrations of cortisol and cAMP than patients of 2^nd group, and cold air bronchoprovocation promoted an active decrease in the content of cortisol in blood serum and cAMP in leukocytes, in contrast to patients who did not respond to the stimulus. When examining the IL-4 content in the exhaled air condensate, both before and after IHCA, no significant intergroup differences were found. In patients of 1^st group, in response to IHCA, lower IFN-γ values were recorded than in patients of 2^nd group: 12.9 [3.05; 24.85] and 34.5 [29.1; 51.8] pg/mL, respectively, (p = 0.001). Close correlations were found between the fall in FEV1 after IHCA, IFN-γ, IL-4, TSH, thyroid hormone fractions, cortisol, cAMP.

Conclusion. The cytokines IFN-γ and IL-4 are involved in the pituitary-thyroid and pituitary-adrenocortical regulation of the cold airway responsiveness in asthma patients. Thyroid insufficiency contributes to the disadaptation of the respiratory system to effects of cold air and is a factor influencing the imbalance in the cytokine system. Cold airway hyperresponsiveness is associated with low baseline levels of cortisol and leukocyte cAMP.

Keywords:asthma; cold airway hyperresponsiveness; cytokines; thyroid hormones; TSH; cortisol; ACTH; cAMP

References

1. Landyshev Yu.S. Bronchial asthma (neuroendocrine system, immunity, clinical picture, diagnosis, treatment). Blagoveshchensk: AGMA, 2006: 169 р. (in Russian)

2. McEwen B.S. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 2007; 87 (3): 873–904. DOI: http://doi.org/10.1152/physrev.00041.2006

3. Troshina E.A. The role of cytokines in the processes of adaptive integration of immune and neuroendocrine reactions of the human body. Problems of endocrinology. 2021; 67 (2): 4–9. DOI: http://doi.org/10.14341/probl12744 (in Russian)

4. Mal’tseva T.A. Features of functional state of thyroid status in patients with bronchial asthma (review). Bulletin of physiology and pathology of respiration. 2012; (44): 117–23. (in Russian)

5. Akhmedov V.A., Shevchenko A.A. The role of hormonal mechanisms in the formation and course of bronchial asthma. Medical Council. 2015; (16): 108–12. (in Russian)

6. Freydlin I.S. Regulatory T-cells: origin and function. Medical immunology. 2005; 7 (4): 347–54. (in Russian)

7. Troshina E.A., Senyushkina E.S. The value of central regulators of the immune response in the development of autoimmune thyroid diseases. Problems of endocrinology. 2019; 65 (6): 458–65. DOI: http://doi.org/10.14341/probl10304 (in Russian)

8. Glazanova T.V., Bubnova L.N., Trunin E.M., Kuzmichev A.S., Pavlova I.E. Production of some cytokines in patients with autoimmune thyroid disease. Problems of endocrinology. 2004; 50 (3): 29–32. (in Russian)

9. Ganesh B.B., Bhattacharya P., Gopisetty A., Prabhakar B.S. Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity. J. Interferon Cytokine Res. 2011; 31 (10): 721–31. DOI: https://doi.org/10.1089/jir.2011.0049

10. Maklakova T.P., Zorina V.N., Shepel’ T.T., Boyko O.N., Zorina R.M., Zorin N.A. The levels of immunoreactive proteins and cytokines in the blood of the patients presenting with autoimmune thyroid diseases. Problems of endocrinology. 2014; 60 (6): 10–3. DOI: http://doi.org/10.14341/probl201460610-13 (in Russian)

11. Inoue N., Watanabe M., Nanba T., Wada M., Akamizu T., Iwatani Y. Involvement of functional polymorphisms in the TNFA gene in the pathogenesis of autoimmune thyroid diseases and production of anti-thyrotropin receptor antibody. Clin. Exp. Immunol. 2009; 156 (2): 199–204. DOI: http://doi.org/10.1111/j.1365-2249.2009.03884.x

12. Mal’tseva T.A., Kolosov V.P., Pirogov A.B., Shcheglova M.Yu., Ushakova E.V. The state of cytokine status and its pathogenetic role at thyroidal insufficiency in patients with bronchial asthma. Bulletin of physiology and pathology of respiration. 2013; (48): 22–7. (in Russian)

13. Antonovich Zh.V., Tsarev V.P., Goncharova N.V. Naturally occurring T-regulatory cells and cytokines in bronchial asthma patients observed during the different periods of the disease. Immunopathology, allergology, infectology. 2009; (4): 35–44. (in Russian)

14. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (2020 update). URL: www.ginasthma.org

15. Prikhod’ko A.G., Perel’man J.M., Kolosov V.P. Airway hyperresponsiveness. Vladivostok: Dal’nauka, 2011: 204 p. (in Russian)

16. Ul’yanychev N.V. Systematic research in medicine. Saarbrücken: LAP LAMBERT; 2014: 140 p. (in Russian)

17. Pirogov A.B., Kolosov V.P., Perel’man Y.M., Prikhod’ko A.G., Zinov’ev S.V., Gassan D.A., Mal’tseva T.A. Airway inflammation patterns and clinical and functional features in patients with severe un-controlled asthma and cold-induced airway hyperresponsiveness. Russian Pul’monologiya. 2016; 26 (6): 701–7. DOI: http://doi.org/10.18093/086901892016266701707 (in Russian)

18. Soodaeva S.K. Free radical mechanisms of injury in respiratory disease. Russian Pul’monologiya. 2012; 22 (1): 5–10. DOI: http://doi.org/10.18093/0869-0189-2012-0-1-5-10 (in Russian)

19. Mayansky A.N., Mayansky N.A., Zaslavskaya M.I. Nuclear factor-kappa B and inflammation. Cytokines and inflammation. 2007; 6 (2): 3–9. (in Russian)

20. Kulikov E.S., Ogorodova L.M., Freydin M.B., Deev I.A., Selivanova P.A., Fedosenko S.V., Kirillova N.A. Molecular mechanisms of severe asthma. Molecular Medicine. 2013; (2): 24–32. (in Russian)

21. Ray A., Kolls J.K. Neutrophilic inflammation in asthma and association with disease severity. Trends Immunol. 2017; 38 (12): 942–54. DOI: http://doi.org/10.1016/j.it.2017.07.003

22. Duvall M.G., Krishnamoorthy N., Levy B.D. Non-type 2 inflammation in severe asthma is propelled by neutrophil cytoplasts and maintained by defective resolution. Allergol. Int. 2019; 68 (2): 143–9. DOI: http://doi.org/10.1016/j.alit.2018.11.006

23. Lutcky A.A., Zhirkov A.A., Lobzin D.Yu., Rao M., Alekseeva L.A., Meyrer M., Lobzin Yu.V. Interferon-γ: biological function and applicationfor study of cellular immune response. Journal of Infectology. 2015; 7 (4): 10–22. (in Russian)

24. Shuai K., Liu B. Regulation of JAK-STAT signalling in the immune system. Nat. Rev. Immunol. 2003; 3 (11): 900–11. DOI: http://doi.org/10.1038/nri1226

25. Mineev V.N., Sorokina L.N., Nyoma M.A. Effects of il-4 upon the activity of stat6 transcription factor in peripheral blood lymphocytes in bronchial asthma. Medical Immunology. 2009; 11 (2–3): 177–84. (in Russian)

26. Kiwamoto T., Ishii Y., Morishima Y., Yoh K., Maeda A., Ishizaki K., Iizuka T., Hegab A.E., Matsuno Y., Homma S., Nomura A., Sakamoto T., Takahashi S., Sekizawa K. Transcription factors T-bet and GATA-3 regulate development of airway remodeling. Am. J. Respir. Crit. Care Med. 2006; 174 (2): 142–51. DOI: http://doi.org/10.1164/rccm.200601-079OC

27. Zhu J., Yamane H., Cote-Sierra J., Guo L., Paul W.E. GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Res. 2006; 16 (1): 3–10. DOI: http://doi.org/10.1038/sj.cr.7310002

28. Mineev V.N., Sorokina L.N., Nyoma M.A., Trofimov V.I. GATA-3 expression in peripheral blood lymphocytes of patients with bronchial asthma. Medical Immunology. 2010; 12 (1–2): 21–8. (in Russian)

29. Usui T., Preiss J.C., Kanno Y., Yao Z.J., Bream J.H., O’Shea J.J., Strober W. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J. Exp. Med. 2006; 203 (3): 755–66. DOI: http://doi.org/10.1084/jem.20052165

30. Mal’tseva T.A., Kolosov V.P., Pirogov A.B. The influence of steroid hormones of adrenal gland cortex on the functional state of hypophisial-thyroidal system of patients with bronchial asthma. Bulletin of physiology and pathology of respiration. 2012; (44): 41–5. (in Russian)

31. Podzolkov A.V., Fadeev V.V. Hypothyroidism, subclinical hypothyroidism, high-normal TSH-level. Clinical and experimental thyroidology. 2009; 5 (2): 4–16. (in Russian)

32. Mal’tseva T.A., Kolosov V.P., Pirogov A.B., Zhou X., Li Q., Perel’man J.M. Effectiveness of variability of thyroid stimulating hormone levels in the blood at the estimation of the changed responsiveness of bronchi in asthmatics. Bulletin of physiology and pathology of respiration. 2012; (46): 19–24 (in Russian)

33. Cain D.W., Cidlowski J.A. Immune regulation by glucocorticoids. Nat. Rev. Immunol. 2017; 17 (4): 233–47. DOI: http://doi.org/10.1038/nri.2017.1

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