Cytokine levels and FOXP3 gene expression in the blood of patients with various stage of pulmonary sarcoidosis
- Authors: Malysheva I.E.1,2, Topchieva L.V.2, Balan O.V.1,2, Kurbatova I.V.2, Tikhonovich E.L.3
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Affiliations:
- Karelian Research Centre Russian Academy of Sciences
- Institute of Biology of the Karelian Research Centre of the Russian Academy of Sciences
- V.A. Baranov Republican Hospital
- Issue: Vol 15, No 6 (2025)
- Pages: 1121-1129
- Section: ORIGINAL ARTICLES
- URL: https://journals.rcsi.science/2220-7619/article/view/380248
- DOI: https://doi.org/10.15789/2220-7619-CLA-17932
- ID: 380248
Cite item
Full Text
Abstract
The cytokine concentration may be related to the level of inflammation and clinical features of diseases. The study was aimed to evaluate blood plasma level for TNFα, sTNFRII, IL-1β, IL-10 and FOXP3 gene expression in patients with different clinical forms of pulmonary sarcoidosis. Materials and methods. Patients with pulmonary sarcoidosis (PS) enrolled in the study were characterized by chronic, progressive and active forms at PS stage 2. Control group was formed by conditionally healthy individuals. The cytokine (TNFα, sTNFRII, IL-1β, IL-10) concentration was examined by enzyme-linked immunosorbent assay (ELISA). Real-time polymerase chain reaction (RT-PCR) was used to analyze FOXP3 gene expression in peripheral blood leukocytes (PBL). Results. The high levels of plasma TNFα and sTNFRII were detected in patients with progressive and active PS vs chronic PS (p = 0.0263, p = 0.0321 and p = 0.0012, p = 0.0009, respectively). Concentration of IL-1β was higher in active PS rather than in chronic and progressive PS (p = 0.0002 and p = 0.0020, respectively). The IL-10 plasma level in patients from all studied groups was lower compare to healthy individuals (p = 0.0009, p = 0.00009, p = 0.0004, respectively). A decreased number of PBL FOXP3 gene transcripts was found in patients with progressive and active PS (p = 0.0008 compared with healthy individuals and patients with chronic PS). Conclusion. The level of cytokines in patients with PS is determined by disease clinical features. Upregulated proinflammatory factor (TNFα, sTNFRII, IL-1β) level as well as downregulated FOXP3 gene expression and the IL-10 concentration may suggest about potentiated inflammatory reactions in patients with progressive and active PS. To clarify disease clinical presentation, it is crucial to gain more information about the molecular biomarker dynamics mirroring magnitude of inflammation in PS. In addition, it is also required to propose proper therapy and its refinement. Moreover, the data obtained can be used to assess pathogenetic mechanisms underlying disease development and progression.
About the authors
Irina E. Malysheva
Karelian Research Centre Russian Academy of Sciences; Institute of Biology of the Karelian Research Centre of the Russian Academy of Sciences
Author for correspondence.
Email: i.e.malysheva@yandex.ru
PhD (Biology), Senior Researcher, Centre of Biomedical Research, Senior Researcher, Laboratory of Genetics
Russian Federation, Petrozavodsk; PetrozavodskL. V. Topchieva
Institute of Biology of the Karelian Research Centre of the Russian Academy of Sciences
Email: i.e.malysheva@yandex.ru
PhD (Biology), Leading Researcher, Laboratory of Genetics
Russian Federation, PetrozavodskO. V. Balan
Karelian Research Centre Russian Academy of Sciences; Institute of Biology of the Karelian Research Centre of the Russian Academy of Sciences
Email: i.e.malysheva@yandex.ru
PhD (Biology), Senior Researcher, Centre of Biomedical Research, Senior Researcher, Laboratory of Genetics
Russian Federation, Petrozavodsk; PetrozavodskI. V. Kurbatova
Institute of Biology of the Karelian Research Centre of the Russian Academy of Sciences
Email: i.e.malysheva@yandex.ru
PhD (Biology), Senior Researcher, Laboratory of Genetics
Russian Federation, PetrozavodskE. L. Tikhonovich
V.A. Baranov Republican Hospital
Email: i.e.malysheva@yandex.ru
PhD (Medicine), Head of the Respiratory Therapy Department
Russian Federation, PetrozavodskReferences
- Alavi Foumani G.S., Geranmayeh S., Tangestani Nejad A., Pour Kazemi A., Kazem Nejad Leili E., Jafari A., Amooei Khanabbasi M. Comparison of serum interleukin-10 level of fungal exposure among patients with pulmonary sarcoidosis and healthy people. Sarcoidosis Vasc. Diffuse Lung Dis., 2018, vol. 35, no. 4, pp. 294–298. doi: 10.36141/svdld.v35i4.6757
- Agostini C., Adami F., Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr. Opin. Rheumatol., 2000, vol. 12, no. 1, pp. 71–76. doi: 10.1097/00002281-200001000-00012
- Antoniu S.A. Targeting the TNF-alpha pathway in sarcoidosis. Expert Opin. Ther. Targets, 2010, vol. 14, no. 1, pp. 21–29. doi: 10.1517/14728220903449244
- Atretkhany K.S., Gogoleva V., Drutskaya M.S., Nedospasov S.A. Distinct modes of TNF signaling through its two receptors in health and disease. J. Leukoc. Biol., 2020, vol. 107, pp. 893–905. doi: 10.1002/JLB.2MR0120-510R
- Borthwick L.A. The IL-1 cytokine family and its role in inflammation and fibrosis in the lung. Semin. Immunopathol., 2016, vol. 38, no. 4, pp. 517–534. doi: 10.1007/s00281-016-0559-z
- Broos C., Hendriks R.W., Kool M. T-cell immunology in sarcoidosis: disruption of a delicate balance between helper and regulatory T-cells. Curr. Opin. Pulm. Med., 2016, vol. 22, no. 5, pp. 476–483. doi: 10.1097/MCP.0000000000000303
- Broos C.E., van Nimwegen M., Kleinjan A., ten Berge B., Muskens F., in 't Veen J.C., Annema J.T., Lambrecht B.N., Hoogsteden H.C., Hendriks R.W., Kool M., van den Blink B. Impaired survival of regulatory T cells in pulmonary sarcoidosis. Respir. Res., 2015, vol. 16: 108. doi: 10.1186/s12931-015-0265-8
- Chaudhry A.A., Rudensky A.Y. Control of inflammation by integration of environmental cues by regulatory T cells. J. Clin. Invest., 2013, vol. 123, no. 3, pp. 939–944. doi: 10.1172/JCI57175
- Chen E.I., Moller D.R. Etiologies of sarcoidosis. Clin. Rev. Allergy Immunol., 2015, vol. 49, no. 1, pp. 6–18. doi: 10.1007/s12016-015-8481-z
- Criado E., Sánchez M., Ramírez J., Arguis P., de Caralt T.M., Perea R.J., Xaubet A. Pulmonary sarcoidosis: typical and atypical manifestations at high-resolution CT with pathologic correlation. Radiographics, 2010, vol. 30, no. 6, pp. 1567–1586. doi: 10.1148/rg.306105512
- Dong Y., Dekens W.L., Deyn Naudé P., Eisel U.L.M. Targeting of tumor necrosis factor alpha receptors as a therapeutic strategy for neurodegenerative disorders. Antibodies, 2015, vol. 4, no. 4, pp. 369–408. doi: 10.3390/antib4040369
- Fischer R., Kontermann R.E., Pfizenmaier K. Selective targeting of TNF receptors as a novel therapeutic approach. Front. Cell Dev. Biol., 2020, vol. 8: 401. doi: 10.3389/fcell.2020.00401
- Fuse K., Kodama M., Okura Y., Ito M., Aoki Y., Hirono S., Kato K., Hanawa H., Aizawa Y. Levels of serum interleukin-10 reflect disease activity in patients with cardiac sarcoidosis. Jpn. Circ. J., 2001, vol. 64, no. 10, pp. 755–759. doi: 10.1253/jcj.64.755
- Georgiev P.A., Charbonnier L.M., Chatila T.A. Regulatory T cells: the many faces of Foxp3. Clin. Immunol., 2019, vol. 39, no. 7, pp. 623–640. doi: 10.1007/s10875-019-00684-7
- Genre J.L., Errante P.G., Kokron C., Toledo-Barros M., Câmara N.O.S., Rizzo L.V. Reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells and diminished FOXP3 expression in patients with common variable immunodeficiency: a link to autoimmunity. Clin. Immunol., 2009, vol. 132, no. 2, pp. 215–221. doi: 10.1016/j.clim.2009.03.519
- Grunewald J. Genetics of sarcoidosis. Curr. Opin. Pulm. Med., 2008, vol. 14, pp. 434–439. doi: 10.1097/MCP.0b013e3283043de7
- Herfarth H.H., Mohanty S.P., Rath H.C., Tonkonogy S.L., Sartor R.B. Interleukin 10 suppresses experimental chronic, granulomatous inflammation induced by bacterial cell wall polymers. Gut, 1996, vol. 39, no. 6, pp. 836–845. doi: 10.1136/gut.39.6.836
- Hutyrová B., Pantelidis P., Drábek J., Zůrková M., Kolek V., Lenhart K., Welsh K.I., Bois R.M., Petrek M. Interleukin-1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med., 2002, vol. 165, no. 2, pp. 148–151. doi: 10.1164/ajrccm.165.2.2106004
- Idali F., Wikén M., Wahlström J., Mellstedt H., Eklund A., Rabbani H., Grunewald J. Reduced Th1 response in the lungs of HLA-DRB1*0301 patients with pulmonary sarcoidosis. Eur. Respir. J., 2006, vol. 27, pp. 451–459. doi: 10.1183/09031936.06.00067105
- Josefowicz S.Z., Lu L.F., Rudensky A.Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol., 2012, vol. 30, pp. 531–564. doi: 10.1146/annurev.immunol.25.022106.141623
- Kachamakova-Trojanowska N., Jazwa-Kusior A., Szade K., Kasper L.M., Soja J., Andrychiewicz A., Jakiela B., Plutecka H., Sanak M., Jozkowicz A., Sladek K., Dulak J. Molecular profiling of regulatory T cells in pulmonary sarcoidosis. J. Autoimmun., 2018, vol. 94, pp. 56–69. doi: 10.1016/j.jaut.2018.07.012
- Kieszko R., Krawczyk P., Chocholska S., Bojarska-Junak A., Jankowska O., Król A., Roliński J., Milanowski J. Tumor necrosis factor receptors (TNFRs) on T lymphocytes and soluble TNFRs in different clinical courses of sarcoidosis. Respir. Med., 2007, vol. 101, pp. 645–654. doi: 10.1016/j.rmed.2006.06.004
- Kolb M., Margetts P.J., Anthony D.C., Pitossi F., Gauldie J. Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis. J. Clin. Invest., 2001, vol. 107, no. 12, pp. 1529–1536. doi: 10.1172/JCI12568
- Kumari R., Chakraborty S., Jain R., Mitra S., Mohan A., Guleria R., Pandey S., Chaudhury U., Mitra D.K. Inhibiting OX40 restores regulatory T-cell function and suppresses inflammation in pulmonary sarcoidosis. Chest, 2021, vol. 160, no. 3, pp. 969–982. doi: 10.1016/j.chest.2021.04.032
- Lepzien R., Liu S., Czarnewski P., Nie M., Österberg B., Baharom F., Pourazar J., Rankin G., Eklund A., Bottai M., Kullberg S., Blomberg A., Grunewald J., Smed-Sörensen A. Monocytes in sarcoidosis are potent tumour necrosis factor producers and predict disease outcome. Eur. Respir. J., 2021, vol. 58, no. 1: 2003468. doi: 10.1183/13993003.03468-2020
- Mortaz E., Rezayat F., Amani D., Kiani A., Garssen J., Adcock I.M., Velayati A. The roles of T helper 1, T helper 17 and regulatory T cells in the pathogenesis of sarcoidosis. Allergy Asthma Immunol., 2016, vol. 15, no. 4, pp. 334–339
- Oltmanns U., Schmidt B., Hoernig S., Witt C., John M. Increased spontaneous interleukin-10 release from alveolar macrophages in active pulmonary sarcoidosis. Exp. Lung Res., 2003, vol. 29, no. 5, pp. 315–328. doi: 10.1080/01902140303786
- Pinto J.M., Dias V., Zoller H., Porto G., Carmo H., Carvalho F., de Sousa M. Hepcidin messenger RNA expression in human lymphocytes. Immunology, 2010, vol. 130, no. 2, pp. 217–230. doi: 10.1111/j.1365-2567.2009.03226.x
- Richards D.M., Fernandez M., Caulfield J., Hawrylowicz C.M. Glucocorticoids drive human CD8+ T cell differentiation towards a phenotype with high IL-10 and reduced IL-4, IL-5, and IL-13 production. Eur. J. Immunol., 2000, vol. 30, no. 8, pp. 2344–2354. doi: 10.1002/1521-4141(2000)30:8<2344::AID-IMMU2344>3.0.CO;2-7
- Ruiz A., Palacios Y., Garcia I., Chavez-Galán L. Transmembrane TNF and its receptors TNFR1 and TNFR2 in mycobacterial infections. Int. J. Mol. Sci., 2021, vol. 22: 5461. doi: 10.3390/ijms22115461
- Sabat R. IL-10 family of cytokines. Cytokine Growth Factor Rev., 2010, vol. 21, no. 5, pp. 315–324. doi: 10.1016/j.cytogfr.2010.11.001
- Sabat R., Grütz G., Warszawska K., Kirsch S., Witte E., Wolk K., Geginat J. Biology of interleukin-10. Cytokine Growth Factor Rev., 2010, vol. 5, pp. 331–344. doi: 10.1016/j.cytogfr.2010.09.002
- Saussine A., Tazi A., Feuillet S., Rybojad M., Juillard C., Bergeron A., Dessirier V., Bouhidel F., Janin A., Bensussan A., Bagot M., Bouaziz J.D. Chronic sarcoidosis is characterized by increased transitional blood B cells, increased IL-10-producing regulatory B cells and high BAFF levels. PLoS One, 2012, vol. 7, no. 8: e43588. doi: 10.1371/journal.pone.0043588
- Sharma S.K., Ghosh B., Sharma S.K. Association of TNF polymorphisms with sarcoidosis, its prognosis and tumour necrosis factor (TNF)-alpha levels in Asian Indians. Clin. Exp. Immunol., 2008, vol. 151, no. 2, pp. 251–259. doi: 10.1111/j.1365-2249.2007.03564.x
- Sharma S., Rathored J., Ghosh B., Sharma S. Genetic polymorphisms in TNF genes and tuberculosis in North Indians. BMC Infect. Dis., 2010, vol. 10: 165. doi: 10.1186/1471-2334-10-165
- Smith D., Irving S., Sheldon J., Cole D., Kaski J. Serum levels of the antiinflammatory cytokine interleukin-10 are decreased in patients with unstable angina. Circulation, 2001, vol. 104, no. 7, pp. 746–749. doi: 10.1161/hc3201.094973
- Terčelj M., Stopinšek S., Ihan A., Salobir B., Simčič S., Rylander R. Fungal exposure and low levels of IL-10 in patients with sarcoidosis. Pulm. Med., 2014: 164565. doi: 10.1155/2014/164565
- Verwoerd A., Hijdra D., Vorselaars A.D.M., Crommelin H.A., van Moorsel C.H.M., Grutters J.C., Claessen A.M.E. Infliximab therapy balances regulatory T cells, tumour necrosis factor receptor 2 (TNFR2) expression and soluble TNFR2 in sarcoidosis. Clin. Exp. Immunol., 2016, vol. 185, no. 2, pp. 263–270. doi: 10.1111/cei.12808
- Yamaguchi T., Wing J.B., Sakaguchi S. Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions. Semin. Immunol., 2011, vol. 23, no. 6, pp. 424–430. doi: 10.1016/j.smim.2011.10.002
- Zhang H., Jiang D., Zhu L., Zhou G., Xie B., Cui Y., Costabel U., Dai H. Imbalanced distribution of regulatory T cells and Th17.1 cells in the peripheral blood and BALF of sarcoidosis patients: relationship to disease activity and the fibrotic radiographic phenotype. Front. Immunol., 2023, vol. 14: 1185443. doi: 10.3389/fimmu.2023.1185443
- Zhang L., Zhao Y. The regulation of Foxp3 expression in regulatory CD4(+)CD25(+) T cells: multiple pathways on the road. J. Cell Physiol., 2007, vol. 3, pp. 590–597. doi: 10.1002/jcp.21001
- Zheng L., Teschler H., Guzman J., Hübner K., Striz I., Costabel U. Alveolar macrophage TNF release and BAL cell phenotypes in sarcoidosis. Am. J. Respir. Crit. Care Med., 1995, vol. 152, pp. 1061–1066. doi: 10.1164/ajrccm.152.3.7663784
- Ziegenhagen M.W., Fitschen J., Martinet N., Schlaak M., Müller-Quernheim J. Serum level of soluble tumour necrosis factor receptor II (75 kDa) indicates inflammatory activity of sarcoidosis. J. Intern. Med., 2000, vol. 248, pp. 33–41. doi: 10.1046/j.1365-2796.2000.00685.x
- Zissel G., Prasse A., Müller-Quernheim J. Immunologic response of sarcoidosis. Semin. Respir. Crit. Care Med., 2010, vol. 31, no. 4, pp. 390–403. doi: 10.1055/s-0030-1262208
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