Investigating the Relationship between the Levels of IL18, RANKL Gene Expression, MicroRNA-146a and Inflammatory Factors with the Severity of COVID-19
COVID-19 can induce lung inflammation, and inflammatory factors play an essential role in its pathogenesis. This inflammation can be controlled to a great extent by microRNAs(miRs). This study evaluated miR-146a-5p expression levels in the serum of patients with COVID-19 and their association with the expression of interleukin (IL)-18 and receptor activator of nuclear factor kappa-Β ligand (RANKL) genes, and lung damage.
patients with COVID-19 were divided into two groups: mild and severe phases. The severe phase is defined as having a positive polymerase chain reaction (PCR) for SARS-CoV2, and acute pulmonary symptoms. The subjects' demographic, clinical, and paraclinical characteristics were collected according to a pre-prepared checklist. Total RNA was isolated from all samples using the Trizol kit to assess gene expression. The extracted product was then evaluated for the expression of miR-146a and the target genes (i.e., IL-18 and RANKL) using real-time PCR.
The miR-146a gene's mean expression in mild and severe patients was 0.73 and 1.89, respectively, and this difference was statistically significant between the two groups. Also, the mean Expression of the IL-18 gene, 1.37±0.38 in the mild and 2.83±0.58 in the severe groups of the disease, demonstrated a significant difference between the two groups. In contrast, the expression levels of the RANKL gene did not show a significant difference between the two groups.
Therefore, it may be hypothesized that altered levels of miR-146a may contribute to the severe COVID-19 that is more commonly observed in smokers, but further research is required.
2. Sharma A, Ahmad Farouk I, Lal SK. COVID-19: A Review on the Novel Coronavirus Disease Evolution, Transmission, Detection, Control and Prevention. Viruses. 2021 29;13(2):202. doi: 10.3390/v13020202. PMID: 33572857; PMCID: PMC7911532.
3. Oroojalian F, Haghbin A, Baradaran B, Hemmat N, Shahbazi MA, Baghi HB, et al. Novel insights into the treatment of SARS-CoV-2 infection: An overview of current clinical trials. Int J Biol Macromol. 2020;165:18–43.
4. Umakanthan S, Sahu P, Ranade AV, Bukelo MM, Rao JS, Abrahao-Machado LF, Dahal S, Kumar H, Kv D. Origin, transmission, diagnosis and management of coronavirus disease 2019 (COVID-19). Postgrad Med J. 2020;96(1142):753-758. doi: 10.1136/postgradmedj-2020-138234. Epub 2020 Jun 20. PMID: 32563999.
5. Chen L, Wang G, Tan J, Cao Y, Long X, Luo H, et al. Scoring cytokine storm by the levels of MCP-3 and IL-8 accurately distinguished COVID-19 patients with high mortality. Signal Transduct Target Ther. 2020;5(1):1-3
6. Adhikari SP, Meng S, Wu Y-J, Mao Y-P, Ye R-X, Wang Q-Z, et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infect Dis Poverty. 2020;9(1):29-31.
7. Di Gennaro F, Pizzol D, Marotta C, Antunes M, Racalbuto V, Veronese N, et al. Coronavirus Diseases (COVID-19) Current Status and Future Perspectives: A Narrative Review. Int J Environ Res Public Health. 2020;17(8).
8. Goldberg AD, Allis CD, Bernstein E. Epigenetics: A Landscape Takes Shape. Cell. 2007;128(4):635–8.
9. Bird A. Perceptions of epigenetics. Nat. 2007;447(7143):396–8.
10. Sodagar H, Khadem Ansari MH, Asghari R, Alipour S. Evaluation of Serum Levels of MicroRNA-200C and ACE2 Gene Expression in Severe and Mild Phases of Patients with COVID-19. Iran J Allergy Asthma Immunol. 2022;21(3).
11. Lujambio A, Lowe SW. The microcosmos of cancer. Nat. 2012;482(7385):347–55.
12. Orang AV, Safaralizadeh R, Kazemzadeh-Bavili M. Mechanisms of miRNA-mediated gene regulation from common downregulation to mRNA-specific upregulation. Int J Genomics. 2014;2014.
13. Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: MicroRNAs can up-regulate translation. Science. 2007;318(5858):1931–4.
14. Kwa FAA, Jackson DE. Manipulating the epigenome for the treatment of disorders with thrombotic complications. Drug Discov Today. 2018;23(3):719–26.
15. Sato S, Katsushima K, Shinjo K, Hatanaka A, Ohka F, Suzuki S, et al. Histone deacetylase inhibition in prostate cancer triggers miR-320-mediated suppression of the androgen receptor. Cancer Res. 2016;76(14):4192–202.
16. Li Y, He Q, Wen X, Hong X, Yang X, Tang X, et al. EZH2-DNMT1-mediated epigenetic silencing of miR-142-3p promotes metastasis through targeting ZEB2 in nasopharyngeal carcinoma. Cell Death Differ. 2018;26(6):1089–106.
17. Matsushima K, Isomoto H, Shikuwa S, Yamaguchi N, Ohnita K, Mizuta Y, et al. Esophageal sebaceous glands diagnosed after endoscopic mucosal resection. Gastrointest Endosc. 2009;69(2):337–8.
18. Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet. 2005;38(2):228–33.
19. Kiga K, Mimuro H, Suzuki M, Shinozaki-Ushiku A, Kobayashi T, Sanada T, et al. Epigenetic silencing of miR-210 increases the proliferation of gastric epithelium during chronic Helicobacter pylori infection. Nat Commun. 2014;5.
20. Li S, Fu B, Meshram CD. Innate Immune and Inflammatory Responses to Respiratory Viruses. Mediators Inflamm. 2019;2019:3146065.
21. Manson JJ, Crooks C, Naja M, Ledlie A, Goulden B, Liddle T, et al. COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study. Lancet Rheumatol. 2020;2(10):e594–602.
22. Sodagar H, Alipour S, Hassani S, Ghaleh Aziz SG, Ansari MHK, Asghari R. The role of microRNAs in COVID-19 with a focus on miR-200c. J Circ biomarkers. 2022;11(1):14–23.
23. Wang Q, Li D, Han Y, Ding X, Xu T, Tang B. MicroRNA-146 protects A549 and H1975 cells from LPS-induced apoptosis and inflammation injury. J Biosci. 2017;42(4):637–45.
24. Tang K, Zhao J, Xie J, Wang J. Decreased miR-29b expression is associated with airway inflammation in chronic obstructive pulmonary disease. Am J Physiol - Lung Cell Mol Physiol. 2019;316(4):L621–9.
25. Shahriar A, Ghale-aziz Shiva G, Ghader B, Farhad J, Hosein A, Parsa H. The dual role of mir-146a in metastasis and disease progression. Biomed Pharmacother. 2020;126.
26. Mutlu M, Raza U, Saatci Ö, Eyüpoğlu E, Yurdusev E, Şahin Ö. miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance. J Mol Med (Berl) [Internet]. 2016 Jun 1 [cited 2022 Jul 29];94(6):629–44. Available from: https://pubmed.ncbi.nlm.nih.gov/27094812/
27. Liu Q, Du J, Yu X, Xu J, Huang F, Li X, et al. miRNA-200c-3p is crucial in acute respiratory distress syndrome. Cell Discov. 2017;3.
28. Ye R, Weng S, Li Y, Yan C, Chen J, Zhu Y, et al. Texture Analysis of Three-Dimensional MRI Images May Differentiate Borderline and Malignant Epithelial Ovarian Tumors. Korean J Radiol. 2021;22(1):106–17.
29. Chan JFW, Yuan S, Kok KH, To KKW, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020;395(10223):514–23.
30. Wang YH, Liu YJ. The IL-17 cytokine family and their role in allergic inflammation. Curr Opin Immunol. 2008;20(6):697–702.
31. Jadideslam G, Ansarin K, Sakhinia E, Babaloo Z, Abhari A, Alipour S, et al. Expression levels of miR-21, miR-146b and miR-326 as potential biomarkers in Behcet's disease. Biomark Med. 2019;13(16):1339–48. A
32. Dima E, Koltsida O, Katsaounou P, Vakali S, Koutsoukou A, Koulouris NG, et al. Implication of Interleukin (IL)-18 in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cytokine. 2015;74(2):313–7.
33. Doe C, Bafadhel M, Siddiqui S, Desai D, Mistry V, Rugman P, et al. expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest. 2010;138(5):1140–7.
34. Walsh MC, Kim N, Kadono Y, Rho J, Lee SY, Lorenzo J, et al. Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol. 2006;24(8):33–63.
35. Kaplanski G. Interleukin-18: Biological properties and role in disease pathogenesis. Immunol Rev. 2018;281(1):138–53.
36. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 Regulates Both Th1 and Th2 Responses. Annu Rev Immunol. 2001;19:423-74.
37. Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem. 1997;272(40):25190–4.
38. Kung YY, Felge U, Sarosi I, Bolon B, Taturi A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999;402(6759):304–9.
39. Abdi A, Khabazi A, Sakhinia E, Alipour S, Talei M, Babaloo Z. Evaluation of SOCS1 methylation in patients with Behcet's disease. Immunol Lett. 2018;203:15–20.
40. Zhou S, Liu Y, Li M, Wu P, Sun G, Fei G, et al. Combined Effects of PVT1 and MiR-146a Single Nucleotide Polymorphism on the Lung Function of Smokers with Chronic Obstructive Pulmonary Disease. 2018;14.
41. Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet. 2015;16(7):421–33.
42. El Kholy AA, Mostafa NA, Ali AA, Soliman MMS, El-Sherbini SA, Ismail RI, et al. The use of multiplex PCR for the diagnosis of viral severe acute respiratory infection in children: a high rate of co-detection during the winter season. Eur J Clin Microbiol Infect Dis. 2016;35(10):1607–13.
43. Mutlu M, Raza U, Saatci Ö, Eyüpoğlu E, Yurdusev E, Şahin Ö. miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance. J Mol Med. 2016;94(6):629–44.
44. Liu Q, Du J, Yu X, Xu J, Huang F, Li X, et al. miRNA-200c-3p is crucial in acute respiratory distress syndrome. Cell Discov. 2017;3(2):8-11.
45. Schooling CM, Li M, Au Yeung SL. Interleukin-18 and COVID-19. Epidemiol Infect. 2022;150.
46. Galván-Peña S, Leon J, Chowdhary K, Michelson DA, Vijaykumar B, Yang L, et al. Profound Treg perturbations correlate with COVID-19 severity. Proc Natl Acad Sci U S A. 2021;118(37):19-21.
47. Zhang Y, Wang S, Xia H, Guo J, He K, Huang C, et al. Identification of Monocytes Associated with Severe COVID-19 in the PBMCs of Severely Infected patients Through Single-Cell Transcriptome Sequencing. Eng (Beijing, China). 2021.
48. Fujioka N, Akazawa R, Ohashi K, Fujii M, Ikeda M, Kurimoto M. Interleukin-18 protects mice against acute herpes simplex virus type 1 infection. J Virol. 1999;73(3):2401–9.
49. Keikha R, Jebali A. Los biomarcadores neuroinflamatorios miARN en pacientes con COVID-19 con diferente gravedad de la enfermedad [The miRNA neuroinflammatory biomarkers in COVID-19 patients with different severity of illness]. Neurologia (Engl Ed). 2021 Jul 16. doi: 10.1016/j.nrl.2021.06.005. Epub ahead of print. PMID: 34305233; PMCID: PMC8282440.
50. Donyavi T, Bokharaei-Salim F, Bannazadeh Baghi H, Khanaliha KH, M Alaei Janat-Makan M, et al. Acute and post-acute phase of COVID-19: Analyzing expression patterns of miRNA-29a-3p, 146a-3p, 155-5p, and let-7b-3p in PBMC. Int Immunopharmacol. 2021;97(8):11-9.
51. Sabbatinelli J, Giuliani A, Matacchione G, Latini S, Laprovitera N, Pomponio G, et al. Decreased serum levels of the inflammaging marker miR-146a are associated with non-clinical response to tocilizumab in COVID-19 patients. Mech Ageing Dev. 2021;193.
52. Olivieri F, Lazzarini R, Recchioni R, Marcheselli F, Rippo MR, Di Nuzzo S, et al. MiR-146a as marker of senescence-Associated pro-inflammatory status in cells involved in vascular remodelling. Age (Omaha). 2013;35(4):1157–72.
53. Mensà E, Guescini M, Giuliani A, Bacalini MG, Ramini D, Corleone G, et al. Small extracellular vesicles deliver miR-21 and miR-217 as pro-senescence effectors to endothelial cells. J Extracell Vesicles. 2020;9(1):1725285.
54. Grants JM, Wegrzyn J, Hui T, O'Neill K, Shadbolt M, Knapp DJHF, et al. Altered microRNA expression links IL6 and TNF-induced inflammaging with myeloid malignancy in humans and mice. Blood. 2020;135(25):2235–51.
55. Bonafè M, Prattichizzo F, Giuliani A, Storci G, Sabbatinelli J, Olivieri F. Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes. Cytokine Growth Factor Rev. 2020;53(12):33–7.
56. Garth J, Barnes JW, Krick S. Targeting Cytokines as Evolving Treatment Strategies in Chronic Inflammatory Airway Diseases. Int J Mol Sci. 2018;19(11):8-12.
57. Mastroianni N, De Fusco M, Zollo M, Arrigo G, Zuffardi O, Bettinelli A, et al. Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3). Genomics. 1996;35(3):486–93.
58. Alipour S, Sakhinia E, Khabbazi A, Samadi N, Babaloo Z, Azad M, et al. Methylation status of interleukin-6 gene promoter in patients with behcet's disease. Reumatol Clin. 2020;16(3):229-34.
59. Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020;588(7837):315–20.
60. Li K, Wu J, Wu F, Guo D, Chen L, Fang Z, et al. The Clinical and Chest CT Features Associated with Severe and Critical COVID-19 Pneumonia. Invest Radiol. 2020;55(6):327–31.
61. Zhou P, Yang X Lou, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–3.
|Issue||Vol 22 No 1 (2023)|
|COVID-19 Interleukin-18 MicroRNA-146a-5p Respiratory disease Receptor activator of nuclear factor kappa-Β ligand|
|Rights and permissions|
|This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.|