Methylation of IFN-γ in sulfur mustard-exposed patients

Authors

Abstract

Introduction: IFN-γ is one of the most important cytokines in the development of chronic inflammatory diseases such as asthma and COPD. The IFN-γ promoter methylation at CpG islands could be altered by various chemical and toxic substances which may have a role in the incidence of chronic pulmonary diseases and its severity. Thereby, the present study was aimed to evaluate the effect of sulfur mustard gas on the methylation status of IFN-γ gene promoter and its correlation with the severity of pulmonary disease in chemical veterans with delayed pulmonary complications.
 
Methods: 46 sulfur mustard-exposed individuals with mild-moderate pulmonary complications, 45 with severe pulmonary complicationsand 41 unexposed individuals as a control group participated. The quality and quantity of extracted DNA were assessed by the nanodrop machine. After treatment with bisulfite, the methylation of IFN-γ gene promoter was evaluated by methylation-specific PCR.
 
Results: The methylation of IFN-γ gene promoter showed a significant increase in exposed-patients with mild to moderate pulmonary complications and a significant reduction in exposed-patients with severe pulmonary complications compared to the control groups. The levels of spirometric parameters were significantly higher in individuals with Methylated DNA compared with those with unmethylated DNA.
 
Conclusion: It could be suggested that hyper-methylation of IFN-γ gene promoter and probable changes in IFN-γ gene expressionhave a positive effect on lung function in SM-exposed individuals.
 

Keywords


1. Balali M, Hefazi M. The pharmacology, toxicology and medical treatment of sulfur mustard poisoning. Fundamental & Clinical Pharmacology 2005;19:297–315 2. Balali-Mood M, Balali-Mood K, Danei G, Ghaeninejad E. Organophosphorous nerve agents poisoning. Journal of Birjand University of Medical Sciences 2006;13:5–24 3. Mansour Razavi S, Salamati P, Saghafinia M, Abdollahi M. A review on delayed toxic effects of sulfur mustard in Iranian veterans. DARU Journal of Pharmaceutical Sciences 2012 Oct 9;20(1):51 4. Dadpey M, Ghahari L. Respiratory complication of mustard gas in Iraq-Iran war victims living in Kermanshah. Journal of Army University of Medical Sciences of the I.R. Iran 2007;5:1331–1335. 5. Ghasemi Broumand M, Karamy G, Pourfarzam S, Emadi SN, Ghasemi H. Late concurrent ophthalmic, respiratory, cutaneous and psychiatric complications of chemical weapons exposure in 479 war patients. Daneshvar Medcine 2007;70:81–92 6. Bagheri MH, Hosseini SK, Mostafavi SH, Alavi SA. High-resolution CT in chronic pulmonary changes after mustard gas exposure. Acta Radiologica 2003;44:241–245 7. Ghanei M, Amiri S, Akbari H, Kosari F, HosseiniKhalili AR, Alaeddini F, Aslani J, Giardina C, Haines DD. Correlation of sulfur mustard exposure and tobacco use with expression ( immune reactivity) of p53 protein in bronchial epithelium of Iranian mustard lung patints. MilMed Journal 2007;172:70–74. 8. Einollahi B, Jadidi K. A study of ophthalmic complications due the Mustard gas in the chemical war injured. Kowsar Medical Journal 2000;4:285–287. 9. Ghanei M, Harandi AA. Long term consequences from exposure to sulfur mustardreview. Inhalation Toxicology 2007;19:451–456 10. Alavian SM, Fallahian F, Shohrati M, Fakher-Yaseri H, Zamani F. Long term effects of mustard gas on Iranian veterans. Shiraz E-Medical Journal 2009;10:1–10. 11. Rosenbloom J, Feldman G, Freundlich B, Jimenez SA.Transcriptional control of human diploid fibroblast collagen synthesis by γ-interferon. Biochemical and Biophysical Research Communications 1984; 123: 365–372. 12. Hyde DM, Henderson TS, Giri SN, et al. Effect of murine-gamma interferon on the cellular responses to bleomycin in mice. Experimental Lung Research 1988; 14: 686–704. 13. Prior C, Haslam P. In vivo levels and in vitro production of interferon gamma in fibrosing interstitial lung diseases. Clinical and Experimental Immunology 1992; 88: 280–287 14. Rybka J, Korte SM, Czajkowska-Malinowska M, Wiese M, Kędziora-Kornatowska K, Kędziora J. The links between chronic obstructive pulmonary disease and comorbid depressive symptoms: role of IL-2 and IFN-γ. Clinical and Experimental Medicine 2016;16(4):493-502. 15. Bayarsaihan D. Epigenetic mechanisms in inflammation. Journal of Dental Research 2011;90(1):9-17. 16. Yang IV, Schwartz DA. Epigenetic control of gene expression in the lung. American Journal of Respiratory and Critical Care Medicine 2011;183(10):1295-301. 17. Yasmin R, Siraj S, Hassan A, Khan AR, Abbasi R, Ahmad N. Epigenetic regulation of inflammatory cytokines and associated genes in human malignancies. Mediators of Inflammation 2015. 18. Selman M, Pardo A. Revealing the pathogenic and aging-related mechanisms of the enigmatic idiopathic pulmonary fibrosis. An integral model. American Journal of Respiratory and Critical Care Medicine 2014 15;189(10):1161-72. 19. Steinritz D, Schmidt A, Balszuweit F, Thiermann H, Simons T, Striepling E, et al. Epigenetic modulation in early endothelial cells and DNA hyper methylation in human skin after sulfurmustard exposure. Toxicology Letters 2016;244:95-102. 20. Imani S, Panahi Y, Salimian J, Fu J, Ghanei M. Epigenetic: A missing paradigm in cellular and molecular pathways of sulfur mustard lung: a prospective and comparative study. Iranian Journal of Basic Medical Sciences 2015;18(8):723. 21. Ouyang B, David I, Zana L. Interferon-γ promoter is hypermethylated in blood DNA from workers with confirmed Diisocyanateasmthma. Toxicological Sciences 2013; 133(2): 218–224. 22. Kohli A. Secondhand smoke in combination with ambient air pollution exposure is associated with increased CpG methylation and decreased expression of IFN-γ in T effector cells and Foxp3 in T regulatory cells in children. Clinical Epigenetics 2012,4:17. 23. Ouyang B, Baxter CS, Lam H-M, Yeramaneni S, Levin L, Haynes E, et al. Hypomethylation of dual specificity phosphatase 22 promoter correlates with duration of service in firefighters and is inducible by low-dose benzo [a] pyrene. Journal of Occupational and Environmental Medicine 2012;54(7):774. 24. Imani S, Panahi Y, Salimian J, Fu J, Ghanei M. Epigenetic: A missing paradigm in cellular and molecular pathways of sulfur mustard lung: a prospective and comparative study. Iranian Journal of Basic Medical Sciences 2015;18(8):723. 25. Durham AL, Adcock IM. Basic science: Epigenetic programming and the respiratory system. Breathe 2013;9(4):278-88. 26. Lu KC, Jaramillo A, Lecha RL, Schuessler RB, Aloush A, Trulock EP, Mendeloff EN, Huddleston CB, Patterson GA, Mohanakumar T. Interleukin-6 and interferon-γ gene polymorphisms in the development of bronchiolitis obliterans syndrome after lung transplantation1. Transplantation 2002;74(9):1297-302. 27. Grumelli S, Corry DB, Song LZ, Song L, Green L, Huh J, Hacken J, Espada R, Bag R, Lewis DE, Kheradmand F. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Medicine 2004;1(1):e8 28. Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 2002 295(5557):1079–8210. 29. Chen ZX, Riggs AD. DNA methylation and demethylation in mammals. Journal of Biological Chemistry 2011;286(21):18347-53.