Abstract. It is known that cardiovascular diseases, particularly arterial hypertension (AH), are factors in the severe course of the coronavirus (COVID-19). The presence of hypertension worsens the course of COVID-19, which is probably related to the activation of the immune system in hypertension. However, the mechanism of involvement of the immune response in hypertension remains poorly understood.

The aim of the work was to analyze the prognostic value of determination of IL-1β, IL-2, IL-6, IL-7, IL-8, IL-25, and IL-32α cytokines in the blood serum of patients with hypertension against the background of COVID-19.

Methods. 50 patients with hypertension and confirmed SARS-CoV-2 by PCR test were examined. They were divided into 2 groups: the first – 25 people with hypertension who were admitted to the hospital with a hypertensive crisis, the second – 25 patients with hypertension and polysegmental pneumonia against the background of coronavirus infection, the control group consisted of 20 practically healthy people. All patients underwent an anthropometric examination, biochemical blood analysis, and determination of IL-1β, IL-2, IL-6, IL-7, IL-8, IL-25, and IL-32α cytokines using immunoenzymatic analysis in blood serum. Results. A significant prevalence of IL-1β, IL-6, IL-7, IL-8, and IL-25 was noted both among patients with combined pathology compared to controls, and among patients with isolated hypertension compared to controls. The content of IL-32α in patients with hypertension significantly increased compared to both controls and hypertension combined with COVID-19.

Conclusions. Unidirectional changes in the content of IL-1β, IL-6, and IL-8 under the conditions of hypertension and COVID-19 probably have a common etiological factor related to endothelial damage. A sharp increase in IL-25 in the blood serum of patients with isolated hypertension and in combination with COVID-19 may indicate not only the activation of the immune system but also evidence of adaptive processes aimed at stimulating angiogenesis.

Article received: 20.03.2023

Ключові слова: arterial hypertension, COVID-19, interleukins, endothelium

Повний текст: PDF (Ukr)

1. 1. Lopez-Castaneda S, García-Larragoiti N, Cano-Mendez A, Blancas-Ayala K, Damian-V'azquez G, Perez-Medina AI, et al. Inflammatory and Prothrombotic Biomarkers Associated With the Severity of COVID-19 Infection. Clin Appl Thromb Hemost. 2021; 27: 1076029621999099.doi.org/10.1177/1076029621999099
2. 2. Cameli P, Bergantini L, d'Alessandro M, Bargagli E. High-dose steroids for the treatment of severe COVID-19: a new therapeutic tool? Intern Emerg Med. 2021; 16:1329-30.doi.org/10.1007/s11739-021-02722-y
3. 3. Greenland JR, Michelow MD, Wang L, London MJ. COVID-19 Infection: Implications for Perioperative and Critical Care Physicians, Anesthesiology. 2020; 132:1346-61.doi.org/10.1097/ALN.0000000000003303
4. 4. Hu B, Guo H, Zhou P, Shi Z-L. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021; 19(3):141-54.doi.org/10.1038/s41579-020-00459-7
5. 5. Bergantini L, d'Alessandro M, Cameli P, Otranto A, Luzzi S, Bianchi F et al. Cytokine profiles in the detection of severe lung involvement in hospitalized patients with COVID-19: The IL-8/IL-32 axis. Cytokine. 2022 Mar;151:155804.doi.org/10.1016/j.cyto.2022.155804
6. 6. Lutgens E, Atzler D, Döring Y, Duchene J, Steffens S, Weber C. Immunotherapy for cardiovascular disease. Eur Heart J. 2019 Dec;40(48):3937-46.doi.org/10.1093/eurheartj/ehz283
7. 7. Fawzy S, Ahmed MM, Alsayed BA, Mir R, Amle D. IL-2 and IL-1β Patient Immune Responses Are Critical Factors in SARS-CoV-2 Infection Outcomes. J Pers Med. 2022; 12:1729.doi.org/10.3390/jpm12101729
8. 8. Adamo S, Chevrier S, Cervia C, Zurbuchen Y, Raeber ME,Yang L et al. Profound dysregulation of T cell homeostasis and function in patients with severe COVID-19. Allergy. 2021;76(9):2866-81.doi.org/10.1111/all.14866
9. 9. Fernandes MB, Barata JT. IL-7 and IL-7R in health and disease: An update through COVID times. Adv Biol Regul. 2023,87:100940.doi.org/10.1016/j.jbior.2022.100940
10. 10. Castelli V, Cimini A, Ferri C. Cytokine Storm in COVID-19: «When You Come Out of the Storm, You Won't Be the Same Person Who Walked in». Frontiers in Immunology. 2020 Sep;11.doi.org/10.3389/fimmu.2020.02132
11. 11. Zhang J, Crowley SD. Role of T lymphocytes in hypertension. Curr Opin Pharmacol. 2015 Apr; 21:14-9.doi.org/10.1016/j.coph.2014.12.003
12. 12. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018 Sep;39(33):3021-104.doi.org/10.1093/eurheartj/ehy439
13. 13. Aass KR, Kastnes MH, Standal T. Molecular interactions and functions of IL-32. Journal of Leukocyte Biology. 2021 Jan;109(1):143-59.doi.org/10.1002/JLB.3MR0620-550R
14. 14. Bielecka-Dabrowa A, Cichocka-Radwan A, Lewek J, Pawliczak F, Maciejewski M, Banach M. Cardiac manifestations of COVID-19. Rev Cardiovasc Med. 2021 Jun;22(2):365-71.doi.org/10.31083/j.rcm2202043
15. 15. Samchuk ОO, Sklyarova OY, Bochar OM, Magiyovych SR, Kobylinska LI, Bochar VT, et al. IL-6 levels in patients with hypertension in combination with coronavirus disease. Experimental and clinical physiology and biochemistry. 2022;94(1):38-43.doi.org/10.25040/ecpb2022.01-02.038
16. 16. Zhang B, Zhang Y, Xiong L, Li Y, Zhang Y, Zhao J, et al. CD127 imprints functional heterogeneity to diversify monocyte responses in inflammatory diseases. J Exp Med. 2022 Feb;219(2):e20211191.doi.org/10.1084/jem.20211191
17. 17. Zamani B, Najafizadeh M, Motedayyen H, Arefnezhad R. Predicting roles of IL-27 and IL-32 in determining the severity and outcome of COVID-19. Int J Immunopathol Pharmacol.2022 Jan-Dec;36:3946320221145827.doi.org/10.1177/03946320221145827
18. 18. Krishnan SM, Sobey CG, Latz E, Mansell A, Drummond GR. IL-1β and IL-18: inflammatory markers or mediators of hypertension? Br J Pharmacol. 2014 Dec;171(24):5589-602.doi.org/10.1111/bph.12876
19. 19. Cracowski JL, Chabot F, Labarère J, Faure P, Degano B, Schwebel C, et al. Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension. European Respiratory Journal. 2014;43:915-7.doi.org/10.1183/09031936.00151313
20. 20. Williams TC, Loo SL, Nichol KS, Reid AT, Veerati PC, Esneau C, et al. IL-25 blockade augments antiviral immunity during respiratory virus infection. Commun Biol. 2022 May;5(1):415.doi.org/10.1038/s42003-022-03367-z
21. 21. Lin YJ, Kwok CF, Juan CC, Hsu YP, Shih KC, Chen CC, et al. Angiotensin II enhances endothelin-1-induced vasoconstriction through upregulating endothelin type A receptor. Biochemical and Biophysical Research Communications. 2014;451(2):263-9.doi.org/10.1016/j.bbrc.2014.07.119
22. 22. Okamura A, Rakugi H, Ohishi M, Yanagitani Y, Takiuchi S, Moriguchi K, et al. Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages. Journal of Hypertension. 1999 Apr; 17(4):537-45.doi.org/10.1097/00004872-199917040-00012
23. 23. Cunningham ME, Huribal M, Bala RJ, McMillen, Marvin A. Endothelin-1 and endothelin-4 stimulate monocyte production of cytokines. Critical Care Medicine. 1997 Jun; 25(6):958-64.doi.org/10.1097/00003246-199706000-00011
24. 24. Jafarzadeh A, Chauhan P, Saha B, Jafarzadeh S, Nemati M. Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions. Life Sciences. 2020; 257:118102. doi.org/10.1016/j.lfs.2020.118102
25. 25. Cahill CM, Rogers JT. Interleukin (IL) 1β Induction of IL-6 Is Mediated by a Novel Phosphatidylinositol 3-Kinase-dependent AKT/IκB Kinase α Pathway Targeting Activator Protein-1. Journal of Biological Chemistry. 2008;283(38):25900-12.doi.org/10.1074/jbc.M707692200
26. 26. Chang MC, Lin SI, Pan YH, Lin LD, Wang YL, Yeung SY, et al. IL-1β-induced ICAM-1 and IL-8 expression/secretion of dental pulp cells is differentially regulated by IRAK and p38. Journal of the Formosan Medical Association. 2018;118 (8):1247-54.doi.org/10.1016/j.jfma.2018.11.015
27. 27. Pavlovic M, Jovanovic I, Arsenijevic N. Nebojsa. Interleukin-32 in Infection, Inflammation and Cancer Biology. Serbian Journal of Experimental and Clinical Research. 2020 Jun;21(1):75-82.doi.org/10.1515/sjecr-2016-0085
28. 28. Melero I, Villalba-Esparza M, Recalde-Zamacona B, Jiménez-Sánchez D, Teijeira Á, Argueta A, et al. Neutrophil Extracellular Traps, Local IL-8 Expression, and Cytotoxic T-Lymphocyte Response in the Lungs of Patients With Fatal COVID-19. Chest. 2022 Nov;162(5):1006-1016.doi.org/10.1016/j.chest.2022.06.007
29. 29. Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) Induces Insulin Resistance in 3T3-L1 Adipocytes and Is, Like IL-8 and Tumor Necrosis Factor-α, Overexpressed in Human Fat Cells from Insulin-resistant Subjects. Journal of Biological Chemistry. Mechanisms of signal transduction. 2003 Nov;278(46):45777-84. doi.org/10.1074/jbc.M301977200
30. 30. Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J. Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. PNAS. 2009 Oct;106(40):17031-6.doi.org/10.1073/pnas.0905299106
31. 31. Deer E, Amaral LM, Campbell N, Fitzgerald S, Herrock O, Ibrahim T, et al. Low Dose of IL-2 Normalizes Hypertension and Mitochondrial Function in the RUPP Rat Model of Placental Ischemia. Cells. 2021; 10:2797.doi.org/10.3390/cells10102797
32. 32. Shi H, Wang W, Yin J, Ouyang Y, Pang L, Feng Y, et al. The inhibition of IL-2/IL-2R gives rise to CD8+ T cell and lymphocyte decrease through JAK1-STAT5 in critical patients with COVID-19 pneumonia. Cell Death Dis. 2020 Jun;11(6):429. doi.org/10.1038/s41419-020-2636-4
33. 33. Cavusoglu E, Marmur JD, Yanamadala S, Chopra V, Hegde S, Nazli A, et al. Elevated baseline plasma IL-8 levels are an independent predictor of long-term all-cause mortality in patients with acute coronary syndrome. Atherosclerosis. 2015;242(2):589-94.doi.org/10.1016/j.atherosclerosis.2015.08.022
34. 34. Jagroop IA, Daskalopoulou SS, Mikhailidis DP. Endothelin-1 and Human Platelets.Current Vascular Pharmacology. 2005;3(4):393-9. doi.org/10.2174/157016105774329453
35. 35. Roncati L, Nasillo V, Lusenti B, Riva G. Signals of Th2 immune response from COVID-19 patients requiring intensive care. Ann Hematol. 2020 Jun;99(6):1419-20.doi.org/10.1007/s00277-020-04066-7
36. 36. Dhayni K, Zibara K, Issa H, Kamel S, Bennis Y. Targeting CXCR1 and CXCR2 receptors in cardiovascular diseases. Pharmacol Ther. 2022 Sep;237:108257.doi.org/10.1016/j.pharmthera.2022.108257
37. 37. Khawar MB, Abbasi MH, Sheikh N. IL-32: A Novel Pluripotent Inflammatory Interleukin, towards Gastric Inflammation, Gastric Cancer, and Chronic Rhino Sinusitis. Mediators of Inflammation. 2016; 2016: 8413768.doi.org/10.1155/2016/8413768
38. 38. Ribeiro-Dias F, Saar Gomes R, de Lima Silva LL, Dos Santos JC, Joosten LA. Interleukin 32: a novel player in the control of infectious diseases". Journal of Leukocyte Biology. 2017 Jan;101(1):39-52.doi.org/10.1189/jlb.4RU0416-175RR
39. 39. Silva-Filho JL, Conceição Souza M, das Graças Henriques M, Morrot A, Savino W, Pinheiro Nunes M, et al. AT1 receptor-mediated angiotensin II activation and chemotaxis of T lymphocytes. Molecular Immunology. 2011;48(15-16),1835-43. doi.org/10.1016/j.molimm.2011.05.008
40. 40. Ariizumi K, Meng Y, Bergstresser PR, Takashima A. IFN-gamma-dependent IL-7 gene regulation in keratinocytes. J Immunol. 1995 Jun;154 (11):6031-9.doi.org/10.4049/jimmunol.154.11.6031
41. 41. Juan H, Zhiyao L, Renyong J, Mingshu W, Dekang Z, Mafeng L, et al. The Broad Immunomodulatory Effects of IL-7 and Its Application In Vaccines. Frontiers in Immunology. 2021;12:680442. doi.org/10.3389/fimmu.2021.680442
42. 42. Bordoni V, Tartaglia E, Sacchi A, Fimia GM, Cimini E, Casetti R, et al. The unbalanced p53/SIRT1 axis may impact lymphocyte homeostasis in COVID-19 patients. International Journal of Infectious Diseases. 2021;105:49-53. doi.org/10.1016/j.ijid.2021.02.019
43. 43. Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity. 2011 Feb;34(2):149-62.doi.org/10.1016/j.immuni.2011.02.012
44. 44. Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, et al. IL-25 Induces IL-4, IL-5, and IL-13 and Th2-Associated Pathologies In Vivo. Immunity. 2001;15(6):985-95. doi.org/10.1016/S1074-7613(01)00243-6
45. 45. Mantani PT, Duner P, Bengtsson E, Nilsson J, Björkbacka H, Fredrikson GN, et al. Interleukin-25 (IL-25) has a protective role in atherosclerosis development in the aortic arch in mice. Immunology.2018 May;|293(18):6791-801.doi.org/10.1074/jbc.RA117.000292
46. 46. Meng Q, Wang W, Fang C, Lee TH, Corrigan CJ, Ying S. IL-25 and Its Receptor (IL-25R) in Allergic Inflammation: Its Role in VEGF-mediated Angiogenesis. The Journal of Allergy and Clinical Immunology. 2014 Mar; 143(2):S58.doi.org/10.1016/j.jaci.2008.12.190