Th1, Th2 cytokines in airway response to acute cold exposure in patients with bronchial asthma
https://doi.org/10.36604/1998-5029-2022-85-47-55
Abstract
Introduction. The concept of the interaction of multidirectional cytokines that control the cellular and humoral immune response in the cold bronchospasm in asthma has been little studied.
Aim. To evaluate the role of Th1 and Th2 cytokines in the formation of the airway response to a cold stimulus in patients with asthma.
Materials and methods. The spectrum of cytokines (IFN-γ, IL-17А, TNFα, IL-1β, IL-2, IL-6, IL-4), protein IP-10 (chemokine CXCL10), MMP9 metalloproteinase and TIMP1 protein in exhaled breath condensate before and after 3-minute isocapnic hyperventilation with cold (-20ºС) air (IHCA) has been studied in 37 patients.
Results. Patients were divided into two groups: group 1 (n=11) consisted of individuals with cold airway hyperresponsiveness (CAHR), group 2 – 26 individuals with no response to IHCA (ΔFEV1 IHCA = -16.5±2.3 and -1.5±0.85%, respectively, p<0.0001). Pro-inflammatory cytokines TNFα, IL-2, IL-1β, and IL-6 had a predominant effect on the development of CAHR. IFN-γ was considered as a central regulator of the bronchial response to a cold stimulus, the increase in the level of which in cold bronchospasm relative to the group without CAHR (399,52 [237,1; 753,23] and 237,99 [57,63; 304,84] fg/mL, respectively, p<0.05) was accompanied by an increase in the concentration of IFN-γ-induced protein IP-10 (201.12 [199.4; 398.81] and 167.33 [132.94; 212.77] fg/mL, respectively (p<0.05). The absence of dynamics of IL-4 concentration in response to IHCA testified to the minimal involvement of IL-4 in the implementation of CAHR. The involvement of IL-17A could be associated with the activity of Th1 cytokines and the cold-activated proteolysis-antiproteolysis system involved in bronchial remodeling ‒ metalloproteinase MMP9 and a specific inhibitor of metalloproteinases TIMP1, the values of the latter two were higher in individuals with CAHR after the IHCA test.
Conclusion. In patients with asthma, in the implementation of cold bronchospasm, the dominance of the Th1 immune response and a decrease in the functional activity of Th2 cytokines are observed.
About the Authors
A. B. PirogovRussian Federation
Aleksey B. Pirogov, MD, PhD (Med.), Associate Professor, Senior Staff Scientist, Laboratory of Prophylaxis of Non-Specific Lung Diseases
22 Kalinina Str., Blagoveshchensk, 675000
D. E. Naumov
Russian Federation
Denis E. Naumov, PhD (Med.), Head of Laboratory of Molecular and Translational Research
22 Kalinina Str., Blagoveshchensk, 675000
А. G. Prikhodko
Russian Federation
Аnnа G. Prikhodko, MD, PhD, DSc (Med.), Main Staff Scientist, Laboratory of Functional Research of Respiratory System
22 Kalinina Str., Blagoveshchensk, 675000
J. M. Perelman
Russian Federation
Juliy M. Perelman, MD, PhD, DSc (Med.), Corresponding member of RAS, Рrofessor, Deputy Director on Scientific Work, Head of Laboratory of Functional Research of Respiratory System
22 Kalinina Str., Blagoveshchensk, 675000
References
1. Prikhodko A.G., Perelman J.M., Kolosov V.P. [Airway hyperresponsiveness]. Vladivostok: Dal'nauka; 2011 (in Russian). ISBN: 978-5-8044-1220-4
2. pirogov a.b., kolosov v.p., perel'man yu.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 uncontrolled asthma and cold-induced airway hyperresponsiveness]. pulmonologiya 2016; 26(6):701–707 (in russian). https://doi.org/10.18093/086901892016266701707
3. Hastie A.T., Moore W.C., Meyers D.A., Vestal P.L., Li H., Peters S.P., Bleecker E.R. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J. Allergy Clin. Immunol. 2010; 125(5):1028–1036. https://doi.org/10.1016/j.jaci.2010.02.008
4. Petrova E.S., Goryachev D.V., Kuznetsova A.D. [Planning a clinical development programme for medicines for bronchial asthma]. The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products 2021; 11(1):55–69 (in Russian). https://doi.org/10.30895/1991-2919-2021-11-1-55-69
5. 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):143–149. https://doi.org/10.1016/j.alit.2018.11.006
6. Lutckii A.A., Zhirkov A.A., Lobzin D.Yu., Rao M., Alekseeva L.A., Maeurer M., Lobzin Yu.V. [Interferon-γ: biological function and application for study of cellular immune response]. Journal Infectology 2015; 7(4):10–22 (in Russian). https://doi.org/10.22625/2072-6732-2015-7-4-10-22
7. Kostareva O.S., Gabdulkhakov A.G., Kolyadenko I.A., Garber M.B., Tishchenko S.V. Interleukin-17: Functional and structural features, application as a therapeutic target. Biochemistry (Mosc). 2019; 84(Suppl.1):S193–S205. https://doi.org/10.1134/S0006297919140116
8. Nikolskii A.A., Shilovskiy I.P., Yumashev K.V., Vishniakova L.I., Barvinskaia E.D., Kovchina V.I., Korneev A.V., Turenko V.N., Kaganova M.M., Brylina V.E., Nikonova A.A., Kozlov I.B., Kofi adi I.A., Sergeev I.V., Maerle A.V., Petukhova O.A., Kudlay D.A., Khaitov M.R. [Effect of local suppression of Stat3 gene expression in a mouse model of pulmonary neutrophilic inflammation]. Immunologiya 2021; 42 (6):600–614 (in Russian). https://doi.org/10.33029/0206-4952-2021-42-6-600-614
9. Smolnikova M.V., Gorbacheva N.N., Shubina M.V., Tereschenko S.Yu. Plasma Th1/Th2/Th17 cytokine profile and cytokine gene polymorphisms (IL12B, IL13, IL31, IL33) in asthmatic children: a magnetic multiplex assay. Medical Immunology (Russia) 2021; 23(4):887–894. https://doi.org/10.15789/1563-0625-STC-2279
10. Pirogov A.B., Naumov D.E., Gassan D.A., Afanaseva E.Yu., Kotova O.O., Sheludko E.G., Ushakova E.V., Prikhodko A.G., Perelman J.M. [Cellular inflammation and the profile of bronchial cytokines in patients with bronchial asthma with cold airway hyperresponsiveness]. Bûlleten' fiziologii i patologii dyhaniâ = Bulletin Physiology and Pathology of Respiration 2020; (75):21–31 (in Russian). https://doi.org/10.36604/1998-5029-2020-75-21-31
11. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (2021 update). Available at: www.ginasthma.org
12. Sylvester K.P., Clayton N., Cliff I., Hepple M., Kendrick A., Kirkby J., Miller M., Moore A., Rafferty G.F., O'Reilly L., Shakespeare J., Smith L., Watts T., Bucknall M., Butterfield K. ARTP statement on pulmonary function testing 2020. BMJ Open Respir. Res. 2020; 7(1):e000575. https://doi.org/10.1136/bmjresp-2020-000575
13. Ul'yanychev N.V. [Systematic research in medicine]. Saarbrücken: LAP LAMBERT; 2014 (in Russian). ISBN: 9783659513220
14. Akira S. The role of IL-18 in innate immunity. Curr. Opin. Immunol. 2000; 12(1):59–63. https://doi.org/10.1016/s0952-7915(99)00051-5
15. Hamza T., Barnett J.B., Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int. J. Mol. Sci. 2010; 11(3):789–806. https://doi.org/10.3390/ijms11030789
16. Mayansky A.N., Mayansky N.A., Zaslavskaya M.I. [Nuclear factor-kappab and inflammation]. Cytokines and inflammation 2007; 6(2):3–9 (in Russian).
17. Kulikov E.S., Ogorodova L.M., Freidin 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).
18. Schroder K., Hertzog P.J., Ravasi T., D.A. Hume Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 2004; 75(2):163–189. https://doi.org/10.1189/jlb.0603252
19. Gattoni A., Parlato A., Vangieri B., Bresciani M., Derna R. Interferon-gamma: biologic functions and HCV therapy (type I/II) (1 of 2 parts). Clin. Ter. 2006; 157(4):377–386. PMID: 17051976
20. 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).
21. Shuai K., Liu B. Regulation of JAK-STAT signalling in the immune system. Nat. Rev. Immunol. 2003; 3(11):942– 954. https://doi.org/10.1038/nri1226
22. 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 (Russia) 2009; 11(2-3):177–184 (in Russian). https://doi.org/10.15789/1563-0625-2009-2-3-177-184
23. 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):142–151. https://doi.org/10.1164/rccm.200601-079OC
24. 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):755–766. https://doi.org/10.1084/jem.20052165
25. 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. https://doi.org/10.1038/sj.cr.7310002
26. 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 (Russia) 2010; 12(1-2):21–28 (in Russian). https://doi.org/10.15789/1563-0625-2010-1-2-21-28
27. Schwandner R., Yamaguchi K., Caoa Z. Requirement of Tumor Necrosis Factor Receptor–Associated Factor (Traf)6 in Interleukin 17 Signal Transduction. J. Exp. Med. 2000; 191(7):1233–1240. https://doi.org/10.1084/jem.191.7.1233
28. Ruddy M.J., Wong G.C., Liu X.K., Yamamoto H., Kasayama S., Kirkwood K.L., Gaffen S.L. Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. J. Biol. Chem. 2004; 279(4):2559–2567. https://doi.org/10.1074/jbc.M308809200
29. Kurbacheva O.M., Dyneva M.E., Shilovskiy I.P., Savlevich E.L., Kovchina V.I., Nikol'skiy A.A., Savushkina E.Yu., Khaitov M.R. [Pathogenetic molecular mechanisms of chronic rhinosinusitis with nasal polyps associated with asthma]. Pulmonologiya 2021; 31(1):7‒19 (in Russian). https://doi.org/10.18093/0869-0189-2021-31-1-7-19
30. Nevzorova V.A., Tilik T.V., Gilifanov E.A., Vakhrusheva S.E., Panchenko E.A., Kudryavtseva V.A., Lukyanov P.A. [Concentration of free metalloproteinase MMP9 and complex MMP9/TIMP1 in blood serum in patients with co-existing stable chronic obstructive lung disease and ischemic heart disease]. Pulmonologiya 2011; (2):75‒80 (in Russian). https://doi.org/10.18093/0869-0189-2011-0-2-75-80
Review
For citations:
Pirogov A.B., Naumov D.E., Prikhodko А.G., Perelman J.M. Th1, Th2 cytokines in airway response to acute cold exposure in patients with bronchial asthma. Bulletin Physiology and Pathology of Respiration. 2022;(85):47-55. (In Russ.) https://doi.org/10.36604/1998-5029-2022-85-47-55