Original Article
 

Immunomodulatory Effect of Curcumin in the Upregulation of Inflammasome Pathway Genes Induced by Sulfur Mustard Analog: An In-vitro Study

Curcumin Effect in Upregulated Inflammasome Genes

Abstract

Sulfur Mustard (SM) induces cell injury via exerting oxidative stress, protease-anti protease imbalance, and inflammation. Inflammasome as one part of innate immunity has a critical role in the recognition of cell injuries and the initiation of the inflammation process by releasing IL-1β. Hence, the present study investigated the effects of the sub-lethal doses of 2-chloroethyl ethyl sulfide (CEES) as SM analog on the gene expression level of inflammasome-related genes as well as the potential protective effects of curcumin on this process.
The effects of sub-lethal doses (500, 1000, and 2500 mM) of CEES on pulmonary epithelial cell line (A549) were determined at various time points (12, 24, and 48 h). Following the treatment of cells with CEES, the kinetic alterations of the expression levels of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB1), NLR family pyrin domain containing 1 (NLRP1), Caspase-1 (Casp1), and Interleukin-1β (IL-1β)  genes were analyzed; using real-time PCR. In addition, the concurrent protective effects of different doses of curcumin (20, 40, 80, and 160 mM) on modulating the effects of CEES were studied.
Although it was found that the lowest sub-lethal dose of CEES (500 mM) was able to up-regulate the inflammasome-related genes, the maximum alterations occurred 48 h after the treatment with the higher sub-lethal dose (2500 mM) of CEES. The maximum alteration occurred in Casp1 (38 fold), IL-1β (19 fold), and NLRP1 (~4 fold) genes (p<0.0001). However, the NF-ĸB gene expression level did not alter following CEES exposure. Even though low doses of curcumin (20, 40, and 80 mM) were able to down-regulate the studied genes, it was found that the treatment of cells with 160 mM of curcumin for 48 h was able to normalize the expression level of all genes.
The present study concludes that curcumin as an anti-inflammatory agent may have beneficial immunomodulatory effects following CEES exposure.

1. Arabipour I, Amani J, Mirhosseini SA, Salimian J. The study of genes and signal transduction pathways involved in mustard lung injury: A gene therapy approach. Gene 2019;714:143968.
2. Menacher G, Steinritz D, Schmidt A, Popp T, Worek F, Gudermann T, et al. Effects of anti-inflammatory compounds on sulfur mustard injured cells: Recommendations and caveats suggested by in vitro cell culture models. Toxicol Lett. 2018;293:91-7.
3. McElroy CS, Min E, Huang J, Loader JE, Hendry-Hofer TB, Garlick RB, et al. From the cover: catalytic antioxidant rescue of inhaled sulfur mustard toxicity. J Toxicol Sci. 2016;154:341-53.
4. 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. Iran JBasic Med Sci. 2015;18:723.
5. Ghasemi H, Javadi MA, Ardestani SK, Mahmoudi M, Pourfarzam S, Mahdavi MRV, et al. Alteration in inflammatory mediators in seriously eye-injured war veterans, long-term after sulfur mustard exposure. Int Immunopharmacol. 2020;80:105897.
6. Shahriary A, Seyedzadeh MH, Ahmadi A, Salimian J. The footprint of TGF-β in airway remodeling of the mustard lung. Inhal toxicol. 2015;27:745-53.
7. Iman M, Rezaei R, Azimzadeh Jamalkandi S, Shariati P, Kheradmand F, Salimian J. Th17/Treg immunoregulation and implications in treatment of sulfur mustard gas-induced lung diseases. Expert Rev Clin Immunol. 2017;13:1173-88.
8. Yazdani S, Karimfar MH, Imani Fooladi AA, Mirbagheri L, Ebrahimi M, Ghanei M, et al. Nuclear factor κB1/RelA mediates the inflammation and/or survival of human airway exposed to sulfur mustard. J Recept Signal Transduct Res. 2011;31:367-73.
9. Asnaf SE, Sabetghadam M, Jaafarinejad H, Halabian R, Parvin S, Vahedi E, et al. Is the Inflammasome Pathway Active in the Peripheral Blood of Sulfur Mustard-exposed Patients? Iran J Allergy, Asthma Immunol. 2019 ;18:218-24.
10. García-Niño WR, Pedraza-Chaverrí J. Protective effect of curcumin against heavy metals-induced liver damage. Food Chem Toxicol. 2014;69:182-201.
11. Shimizu K, Funamoto M, Sunagawa Y, Shimizu S, Katanasaka Y, Miyazaki Y, et al. Anti-inflammatory action of curcumin and its use in the treatment of lifestyle-related diseases. Euro Cardio R. 2019;14:117.
12. Li H, Liu B, Li P, Feng L, Ma H, Xuan S, et al. Inhibitory effects of curcumin on inflammatory cytokines in rats with paraquat poisoning. Zhonghua lao dong wei sheng zhi ye bing za zhi= Zhonghua laodong weisheng zhiyebing zazhi= Chin J Indust Hygiene Occupat Dis. 2015;33:689-92.
13. Alp H, Aytekin I, Hatipoglu N, Alp A, Ogun M. Effects of sulforophane and curcumin on oxidative stress created by acute malathion toxicity in rats. Eur Rev Med Pharmacol Sci. 2012;16(Suppl 3):144-8.
14. Saber TM, Abo-Elmaaty AM, Abdel-Ghany HM. Curcumin mitigates mancozeb-induced hepatotoxicity and genotoxicity in rats. Ecotoxicol Environ Saf. 2019;183:109467.
15. Tyagi N, Dash D, Singh R. Curcumin inhibits paraquat induced lung inflammation and fibrosis by extracellular matrix modifications in mouse model. Inflammopharmacology. 2016;24:335-45.
16. Jain AK, Tewari-Singh N, Orlicky DJ, White CW, Agarwal R. 2-Chloroethyl ethyl sulfide causes microvesication and inflammation-related histopathological changes in male hairless mouse skin. Toxicology. 2011;282(3):129-38.
17. Tewari-Singh N, Agarwal R. Mustard vesicating agents–induced toxicity in the skin tissue and silibinin as a potential countermeasure. Annals of the New York Academy of Sciences. 2016;1374(1):184.
18. Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012;481(7381):278-86.
19. Sayer N, Whiting R, Green A, Anderson K, Jenner J, Lindsay C. Direct binding of sulfur mustard and chloroethyl ethyl sulphide to human cell membrane-associated proteins; implications for sulfur mustard pathology. J Chromatography B. 2010;878(17-18):1426-32.
20. McElroy CS, Day BJ. Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals. Biochem pharmacol. 2016;100:1-11.
21. Wang L, Fu H, Nanayakkara G, Li Y, Shao Y, Johnson C, et al. Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study. J Hematol Oncolo. 2016;9(1):122.
22. Lee D-J, Du F, Chen S-W, Nakasaki M, Rana I, Shih VF, et al. Regulation and Function of the Caspase-1 in an Inflammatory Microenvironment. J Invest Dermatol. 2015;135:2012-20.
23. Liu T, Zhang L, Joo D, Sun S-C. NF-κB signaling in inflammation. Signal transduct Target ther. 2017;2(1):1-9.
24. Moloudizargari M, Moradkhani F, Asghari N, Fallah M, Asghari MH, Moghadamnia AA, et al. NLRP inflammasome as a key role player in the pathogenesis of environmental toxicants. Life Sci. 2019;231:116585.
25. Guglielmo A, Sabra A, Elbery M, Cerveira MM, Ghenov F, Sunasee R, et al. A mechanistic insight into curcumin modulation of the IL-1β secretion and NLRP3 S-glutathionylation induced by needle-like cationic cellulose nanocrystals in myeloid cells. Chem Biol Interact. 2017;274:1-12.
26. Kahkhaie KR, Mirhosseini A, Aliabadi A, Mohammadi A, Mousavi MJ, Haftcheshmeh SM, et al. Correction to: Curcumin: a modulator of inflammatory signaling pathways in the immune system. Inflammopharmacology. 2019;27:901.
27. Hassanzadeh S, Read MI, Bland AR, Majeed M, Jamialahmadi T, Sahebkar A. Curcumin: an inflammasome silencer. Pharmacol Res. 2020:104921.
28. Yin H, Guo Q, Li X, Tang T, Li C, Wang H, et al. Curcumin suppresses IL-1β secretion and prevents inflammation through inhibition of the NLRP3 inflammasome. J Immunol. 2018;200:2835-46.
29. Kong F, Ye B, Cao J, Cai X, Lin L, Huang S, et al. Curcumin represses NLRP3 inflammasome activation via TLR4/MyD88/NF-κB and P2X7R signaling in PMA-induced macrophages. Frontpharmacol. 2016;7:369.
30. Sun Y, Liu W, Zhang H, Li H, Liu J, Zhang F, et al. Curcumin prevents osteoarthritis by inhibiting the activation of inflammasome NLRP3. J Interferon Cytokine Res. 2017;37(10):449-55.
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IssueVol 20 No 2 (2021) QRcode
SectionOriginal Article(s)
Published2021-04-17
DOI https://doi.org/10.18502/ijaai.v20i2.6050
Keywords
Curcumin Genes Inflammasomes Sulfur mustard 2-chloroethyl ethyl sulfide

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How to Cite
1.
Chehardoli B, Nadi M, Khamis Abadi A, Kia A, Shahriary A, Salimian J. Immunomodulatory Effect of Curcumin in the Upregulation of Inflammasome Pathway Genes Induced by Sulfur Mustard Analog: An In-vitro Study. Iran J Allergy Asthma Immunol. 20(2):169-177.