A comparative study on proinflammatory cytokines interleukin-17A and interleukin-17F expressions in whole blood of patients with COVID-19
-
Zeynab Rahni
,
Seyed Reza Mohebbi
,
Seyed Masoud Hosseini
,
Shahrzad Shoraka
,
Kambiz Nabati
,
Mahsa Saeedi Niasar
,
Shabnam Shahrokh
,
Amir Sadeghi
,
Mohammad Reza Zali
Abstract
Background and Objectives: Coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has expanded rapidly to all over the world. Interleukin-17 is one of the inflammatory cytokines which is highly expressed in the blood of individuals with COVID-19. Our aim in the present survey was to assess the mRNA expression levels of cytokine IL-17A, IL-17F and TNF-α in the blood of COVID-19 patients compared with healthy control individuals.
Materials and Methods: A total of 69 patients including 32 mild patients, 20 severe and 17 asymptomatic patients in comparison with 25 healthy controls were evaluated. To measure the expression profile of IL-17A and IL-17F in whole blood, quantitative PCR was used.
Results: Asymptomatic, mild, and severe SARS-CoV-2 infections were found to have significantly higher levels of IL-17A and IL-17F mRNAs than the healthy group (fold change IL-17A: 3.778; p= 0.002, 4.003; p= 0.001, 2.608; p= 0.0001 respectively, fold change IL-17F: 2.967; p= 0.003, 3.819; p= 0.001, 2.617; p= 0.0012 respectively). TNF-α mRNA expression was also measured, which shows an approximately similar increase compared to IL-17 (fold change: 2.726; p= 0.002, 2.383; P= 0.001, 2.631; p= 0.001, respectively).
Conclusion: SARS-CoV-2 infection severity was associated with blood levels of IL-17A and IL-17F mRNA.
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3. Xu X-W, Wu X-X, Jiang X-G, Xu K-J, Ying L-J, Ma C-L, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020; 368: m606.
4. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun 2020; 109: 102433.
5. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol 2020; 94(7): e00127-20.
6. Blume C, Jackson CL, Spalluto CM, Legebeke J, Nazlamova L, Conforti F, et al. A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection. Nat Genet 2021; 53: 205-514.
7. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8: 420-422.
8. Tan M, Liu Y, Zhou R, Deng X, Li F, Liang K, et al. Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, China. Immunology 2020; 160: 261-268.
9. Liu Y, Zhang C, Huang F, Yang Y, Wang F, Yuan J, et al. Elevated plasma levels of selective cytokines in COVID-19 patients reflect viral load and lung injury. Natl Sci Rev 2020; 7: 1003-1011.
10. Liu J, Li S, Liu J, Liang B, Wang X, Wang H, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 2020; 55: 102763.
11. Wang J, Jiang M, Chen X, Montaner LJ. Cytokine storm and leukocyte changes in mild versus severe SARS‐CoV‐2 infection: Review of 3939 COVID‐19 patients in China and emerging pathogenesis and therapy concepts. J Leukoc Biol 2020; 108: 17-41.
12. Rotondo JC, Martini F, Maritati M, Mazziotta C, Di Mauro G, Lanzillotti C, et al. SARS-CoV-2 infection: new molecular, phylogenetic, and pathogenetic insights. Efficacy of current vaccines and the potential risk of variants. Viruses 2021; 13: 1687.
13. Jin W, Dong C. IL-17 cytokines in immunity and inflammation. Emerg Microbes Infect 2013; 2(9): e60.
14. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6: 1123-1132.
15. Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 2010; 10: 479-489.
16. Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, et al. Differential roles of interleukin-17A and-17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 2009; 30: 108-119.
17. Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR, et al. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J Clin Invest 2010; 120: 1762-1773.
18. Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 2008; 14: 275-281.
19. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang Y-H, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133-1141.
20. Waite JC, Skokos D. Th17 response and inflammatory autoimmune diseases. Int J Inflam 2012; 2012: 819467.
21. Hou W, Jin Y-H, Kang HS, Kim BS. Interleukin-6 (IL-6) and IL-17 synergistically promote viral persistence by inhibiting cellular apoptosis and cytotoxic T cell function. J Virol 2014; 88: 8479-8489.
22. Pacha O, Sallman MA, Evans SE. COVID-19: a case for inhibiting IL-17? Nat Rev Immunol 2020; 20: 345-346.
23. Avdeev SN, Trushenko NV, Tsareva NA, Yaroshetskiy AI, Merzhoeva ZM, Nuralieva GS, et al. Anti-IL-17 monoclonal antibodies in hospitalized patients with severe COVID-19: A pilot study. Cytokine 2021; 146: 155627.
24. Casillo GM, Mansour AA, Raucci F, Saviano A, Mascolo N, Iqbal AJ, et al. Could IL-17 represent a new therapeutic target for the treatment and/or management of COVID-19-related respiratory syndrome? Pharmacol Res 2020; 156: 104791.
25. Megna M, Napolitano M, Fabbrocini G. May IL-17 have a role in COVID-19 infection? Med Hypotheses 2020; 140: 109749.
26. Ghafouri-Fard S, Oskooei VK, Omrani MD, Taheri M. Dysregulation of cytokine coding genes in peripheral blood of bipolar patients. J Affect Disord 2019; 256: 578-583.
27. Yang T, Ouyang Y, Gao Y, Liu D, Zang Y, Chen D. Enriched high‑throughput reverse transcription‑quantitative PCR template preparation without pre‑amplification. Mol Med Rep 2020; 22: 3541-3548.
28. Yin J, Tian L. Joint confidence region estimation for area under ROC curve and Youden index. Stat Med 2014; 33: 985-1000.
29. World Health Organization (2020). Clinical management of COVID-19: interim guidance, 27 May 2020: World Health Organization. https://iris.who.int/handle/10665/332196
30. Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol 2020; 92: 424-432.
31. Tufan A, Avanoğlu Güler A, Matucci-Cerinic M. COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. Turk J Med Sci 2020; 50: 620-632.
32. Bartee E, McFadden G. Cytokine synergy: an underappreciated contributor to innate anti-viral immunity. Cytokine 2013; 63: 237-240.
33. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 2017; 9: 7204-7218.
34. Gaffen SL, Jain R, Garg AV, Cua DJ. IL-23-IL-17 immune axis: discovery, mechanistic understanding, and clinical testing. Nat Rev Immunol 2014; 14: 585-600.
35. Yang Y, Dai J, Yan M, Yue M, Wang XH, Min X, et al. Expression of interleukin-17 is associated with different immune phases in patients with chronic hepatitis B. Eur J Inflamm 2018; 16: 205873921879688.
36. Du W-J, Zhen J-H, Zeng Z-Q, Zheng Z-M, Xu Y, Qin L-Y, et al. Expression of interleukin-17 associated with disease progression and liver fibrosis with hepatitis B virus infection: IL-17 in HBV infection. Diagn Pathol 2013; 8: 40.
37. Wang L, Chen S, Xu K. IL-17 expression is correlated with hepatitis B‑related liver diseases and fibrosis. Int J Mol Med 2011; 27: 385-392.
38. Chang Q, Wang YK, Zhao Q, Wang CZ, Hu YZ, Wu BY. Th17 cells are increased with severity of liver inflammation in patients with chronic hepatitis C. J Gastroenterol Hepatol 2012; 27: 273-278.
39. Fathy A, Ahmed AS, Metwally L, Hassan A. T helper type 1/T helper type 17-related cytokines in chronic hepatitis C patients before and after interferon and ribavirin therapy. Med Princ Pract 2011; 20: 345-349.
40. Alvarez Y, Tuen M, Nàdas A, Hioe CE. In vitro restoration of Th17 response during HIV infection with an antiretroviral drug and Th17 differentiation cytokines. AIDS Res Hum Retroviruses 2012; 28: 823-834.
41. Prendergast A, Prado JG, Kang Y-H, Chen F, Riddell LA, Luzzi G, et al. HIV-1 infection is characterized by profound depletion of CD161+ Th17 cells and gradual decline in regulatory T cells. AIDS 2010; 24: 491-502.
42. Sánchez-Vargas LA, Hernández-Flores KG, Thomas-Dupont P, Izaguirre-Hernández IY, Sánchez-Marce EE, Remes-Ruiz R, et al. Characterization of the IL-17 and CD4+ Th17 cells in the clinical course of dengue virus infections. Viruses 2020; 12: 1435.
43. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe 2020; 27: 992-1000.e3.
44. Mahmoudi S, Rezaei M, Mansouri N, Marjani M, Mansouri D. Immunologic features in coronavirus disease 2019: functional exhaustion of T cells and cytokine storm. J Clin Immunol 2020; 40: 974-976.
45. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395: 1033-1034.
46. Hoe E, Anderson J, Nathanielsz J, Toh ZQ, Marimla R, Balloch A, et al. The contrasting roles of Th17 immunity in human health and disease. Microbiol Immunol 2017; 61: 49-56.
47. Faure E, Poissy J, Goffard A, Fournier C, Kipnis E, Titecat M, et al. Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? PloS One 2014; 9(2): e88716.
48. Josset L, Menachery VD, Gralinski LE, Agnihothram S, Sova P, Carter VS, et al. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. mBio 2013; 4(3): e00165-13.
49. Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine 2018; 104: 8-13.
50. Pierce JD, McCabe S, White N, Clancy RL. Biomarkers: an important clinical assessment tool. Am J Nurs 2012; 112: 52-58.
51. Kim N, Yoon Y-I, Yoo HJ, Tak E, Ahn C-S, Song G-W, et al. Combined detection of serum IL-10, IL-17, and CXCL10 predicts acute rejection following adult liver transplantation. Mol Cells 2016; 39: 639-644.
52. Niu Y, Liu H, Yin D, Yi R, Chen T, Xue Ha, et al. The balance between intrahepatic IL-17+ T cells and Foxp3+ regulatory T cells plays an important role in HBV-related end-stage liver disease. BMC Immunol 2011; 12: 47.
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| Files | ||
| Issue | Vol 17 No 6 (2025) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijm.v17i6.20376 | |
| Keywords | ||
| COVID-19 Gene expressionss Cytokines Interleukin-17 Tumor necrosis factor-alpha | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Rahni Z, Mohebbi SR, Hosseini SM, Shoraka S, Nabati K, Saeedi Niasar M, Shahrokh S, Sadeghi A, Zali MR. A comparative study on proinflammatory cytokines interleukin-17A and interleukin-17F expressions in whole blood of patients with COVID-19. Iran J Microbiol. 2025;17(6):1049-1058.
