Macmoondongtang modulates Th1-/Th2-related cytokines and alleviates asthma in a murine model

Autoři: Soon-Young Lee aff001;  Bossng Kang aff002;  So-Hyeon Bok aff001;  Seung Sik Cho aff003;  Dae-Hun Park aff001
Působiště autorů: College of Oriental Medicine, Dongshin University, Naju, Jeonnam Korea aff001;  Department of Emergency Medicine, College of Medicine, Hanyang University, Guri, Gyunggi, Korea aff002;  Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan, Jeonnam Korea aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224517



Macmoondongtang has been used as a traditional medicine to treat pulmonary disease in Korea. However, the mechanism underlying its therapeutic effect has yet to be reported. In the present study, the role of macmoondongtang as a respiratory medicine, especially as an anti-asthmatic agent, has been attributed to the down-regulation of interleukin (IL)-4 and tumor necrosis factor (TNF)-α.

Materials & methods

BALB/c mice were divided into five groups: control, asthma-induced control, dexamethasone treatment, treatment with 150 mg/kg macmoondongtang, and treatment with 1500 mg/kg macmoondongtang. To evaluate the anti-asthmatic effect of macmoondongtang, we investigated its suppressive or inhibitory effects against typical asthmatic changes such as differential cell count in bronchioalveolar fluid (BALF), serum IgE levels, lung morphology, expression of Th1/Th2 cell transcription factors such as T-bet and GATA-3, and Th1-/Th2-/Th17-related cytokines such as interferon (IFN)-γ, IL-12p40, IL-4, -5, -13, TNF-α, and IL-6. The active ingredients in macmoondongtang were further analyzed.


Macmoondongtang treatment down-regulated serum IgE level, a very important marker of hyper-responsiveness. It reversed typical morphological changes such as mucous hypersecretion, lung epithelial cell hyperplasia, and inflammatory cell infiltration near bronchioalveolar space and veins. Macmoondongtang significantly decreased neutrophil count in BALF, as well as reduced T-bet, IFN-γ, and TNF-α expression in the lung. It also showed a dose-dependent control of inflammatory cells in BALF, controlled the expression of IL-12, IL-4, and IL-5 genes in the lung, and the protein expression of IL12p40, GATA-3, IL-4, IL-5, and IL-13. The component analysis revealed glycyrrhizin and liquiritin as the active ingredients.


Macmoondongtang treatment alleviates asthma symptoms and modulate the Th1-/Th2- related cytokines. Glycyrrhizin and liquiritin could be the major the active therapeutic components.

Klíčová slova:

Asthma – Cytokines – Eosinophils – Gene expression – Inflammation – T helper cells – Transcription factors – Bronchioles


1. World Health Organization. Asthma Fact Sheet No307. November 2013.

2. Kay AB. Allergy and allergic diseases. First of two parts. N Engl J Med. 2000; 344: 30–37.

3. National asthma education and prevention program. Expert panel report: Guidelines for the diagnosis and management of asthma update on selected topics. J Allergy Clin Immunol. 2002; 110: S141–219. 12542074

4. Kumar RK, Webb CC, Herbert C and Foster PS. Interferon-gamma as a possible target in chronic asthma. Inflamm Allergy-Drug Targets. 2006; 5: 253–256. doi: 10.2174/187152806779010909 17168796

5. Hamaza T, Barnett JB and Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int J Mol Sci. 2010; 11: 789–806. doi: 10.3390/ijms11030789 20479986

6. Mattes J, Yang M, Mahalingam S, Kuehr J, Webb DC, Simson L, et al. Intrinsic defect in T cell production of Interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma. J Exp Med. 2002; 195: 1433–1444. doi: 10.1084/jem.20020009 12045241

7. Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, et al. Natural killer cell stimulatory factor (interleukin 12 (IL-12)) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4 producing Th cells. J Exp Med. 1993; 177: 1199–1204. doi: 10.1084/jem.177.4.1199 8096238

8. Allswede DM, Buka SL, Yoken RH, Torrey EF, Cannon TD. Elevated maternal cytokine levels at birth and risk for psychosis in adult offspring. Schizophr Res. 2016; 172: 41–45. doi: 10.1016/j.schres.2016.02.022 26897476

9. Yagi R, Zhu J and Paul WE. An updated view on transcription factor GATA3-mediated regulation on Th1 and Th2 cell differentiation. Int Immunol. 2011; 23: 415–420. doi: 10.1093/intimm/dxr029 21632975

10. Mosmann TR and Coffiman RL. Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989; 7: 145–168. doi: 10.1146/annurev.iy.07.040189.001045 2523712

11. Stadnyk AW. Cytokine production by epithelial cells. FASEB J. 1994; 8: 1041–1047. doi: 10.1096/fasebj.8.13.7926369 7926369

12. Rincon M and Irvin CG. Role of IL-6 in asthma and other inflammatory pulmonary diseases. Int J Biol Sci. 2012; 8: 1281–1290. doi: 10.7150/ijbs.4874 23136556

13. Hershey GK. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol. 2003; 111: 677–690. doi: 10.1067/mai.2003.1333 12704343

14. Rankin JA, Picarella DE, Geba GP, Temann UA, Prasad B, DiCosmo B, et al. Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc Natl Acad Sci USA. 1996; 93: 7821–7825. doi: 10.1073/pnas.93.15.7821 8755560

15. Will-Karp M and Chiaramonte M. Interleukine-13 in asthma. Curr Opin Pulm Med. 2003; 9: 21–27. doi: 10.1097/00063198-200301000-00004 12476080

16. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, sub-epithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999; 103: 779–788. doi: 10.1172/JCI5909 10079098

17. Kriegler M, Perez C, DeFay K, Albert I, Lu SD. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell. 1988; 53: 45–53. doi: 10.1016/0092-8674(88)90486-2 3349526

18. Lukacs NW, Strieter RM, Chensue SW, Widmer M, Kunkel SL. TNF-alpha mediates recruitment of neutrophils and eosinophils during airway inflammation. J Immunol. 1995; 154: 5411–5417. 7730642

19. Scheurich P, Thoma B, Ucer U, Pfizenmaier K. Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. J Immunol. 1987; 138: 1786–1790. 3029221

20. Berry M, Brightling C, Pavord I, Wardlaw AJ. TNF-α in asthma. Curr Opin Pharmacol. 2007; 7: 279–282. doi: 10.1016/j.coph.2007.03.001 17475560

21. Barnes PJ. Current issues for establishing inhaled corticosteroids as the anti-inflammatory agents of choice in asthma. J Allergy Clin Immunol. 1998; 101: S427–S433. doi: 10.1016/s0091-6749(98)70154-x 9563367

22. Wise J. Corticosteroids for asthma may suppress growth in children in first year of treatment, researchers say. BMJ. 2014; 349: g4623. doi: 10.1136/bmj.g4623 25035241

23. Ciriaco M, Ventrice P, Russo G, Scicchitano M, Mazzitello G, Scicchitano F, et al. Corticosteroid-related central nervous system side effects. J Pharmacol Pharmacother. 2013; 4(1): s94–s98.

24. Huh J: Donguibogam. Bubinmunhwasa, 2002.

25. Shin JW, Seo I, Son CG. Interpretation of animal dose and human equivalent dose for drug development. J Korean Med Sci. 2010; 31: 1–7.

26. Skipper R, DeStephano D. Diff-Quik stain set. J Histotechnol. 1989; 12: 303.

27. Bang MA, Seo JH, Seo JW, Jo GH, Jung SK, Yu R, et al. Bacillus subtilis KCTC 11782BP-produced alginate oligosaccharide effectively suppresses asthma via T-helper cell type 2-related cytokines. PLOS ONE. 2015; 10: e0117524. doi: 10.1371/journal.pone.0117524 25658604

28. Shefrin AE, Goldman RD. Use of dexamethasone and prednisone in acute asthma exacerbations in pediatric patients. Can Fam Physician. 2009; 55: 704–706. 19602654

29. Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989; 320: 271–277. doi: 10.1056/NEJM198902023200502 2911321

30. Zhu J, Jankovic D, Oler AJ, Wei G, Sharma S, Hu G, et al. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous T helper-2 program during T helper-1 responses. Immunity. 2012; 37: 660–673. doi: 10.1016/j.immuni.2012.09.007 23041064

31. Lazarevic V, Glimcher LH. T-bet in disease. Nat Immunol. 2011; 12: 597–606. doi: 10.1038/ni.2059 21685955

32. Galli SJ, Tsai TM, Piliponsky AM. The development of allergic inflammation. Nature. 2008; 454: 445–454. doi: 10.1038/nature07204 18650915

33. Platts-Mills TA. The role of immunoglobulin E in allergy and asthma. Am J Respir Crit Care Med. 2001; 164: S1–S5. doi: 10.1164/ajrccm.164.supplement_1.2103024 11704610

34. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of lymphokine activities and secreted proteins. J Immunol. 1986; 136: 2348–2357. 2419430

35. Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003; 8: 223–246. 12946237

36. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000; 100: 655–669. doi: 10.1016/s0092-8674(00)80702-3 10761931

37. Antczak A, Domanska-Senderowska D, Gorski P, Pastuszak-Lewandoska D, Nielepkowicz-Gozdzinska A, et al. Analysis of changes in expression of IL-4/IL-13/STAT6 pathway and correlation with the selected clinical parameters in patients with atopic asthma. Int J Immunopathol Pharmacol. 2016; 29: 195–204. doi: 10.1177/0394632015623794 26781462

38. Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med. 1996; 183: 195–201. doi: 10.1084/jem.183.1.195 8551223

39. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an iterleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007; 370: 1422–1431. doi: 10.1016/S0140-6736(07)61600-6 17950857

40. Larche M, Robinson DS, Kay AB. The role of T lymphocytes in the pathogenesis of asthma. J Allergy Clin Immunol. 2003; 111: 450–463. doi: 10.1067/mai.2003.169 12642820

41. Singh A, Yamamoto M, Ruan J, Choi JY, Gauvreau GM, Olek S, et al. Th17/Treg ratio derived using DNA methylation analysis is associated with the late phase asthmatic response. Allergy Asthma Clin Immunol. 2014; 10: 32. doi: 10.1186/1710-1492-10-32 24991220

42. Slungaard A, Vercellotti GM, Walker G, Nelson RD, Jacob HS. Tumor necrosis factor alpha/cachectin stimulates eosinophil oxidant production and toxicity towards human endothelium. J Exp Med. 1990; 171: 2025–2041. doi: 10.1084/jem.171.6.2025 1972179

43. Monteseirin J. Neutrophils and asthma. J Investig Allergol Clin Immunol. 2009; 19(5): 340–354. 19862934

44. Neveu WA, Allard JL, Raymond DM, Bourassa LM, Burns SM, Bunn JY, et al. Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function. Respir Res. 2010; 11(1): 28.

45. Lee SY, Bae CS, Choi YH, Seo NS, Na CS, Yoo JC, et al. Opuntia humifusa modulates morphological changes characteristic of asthma via IL-4 and IL-13 in an asthma murine model. Food Nutr Res. 2017; 61: 1–12.

46. Lee SY, Bae CS, Seo JH, Cho SS, Oh DS, Park DH. Mycoleptodonoides aitchisoii suppresses asthma via IL-6 and IL-13 in ovalbumin-induced asthma mouse model. Mol Med Rep. 2018; 17(1): 11–20. doi: 10.3892/mmr.2017.7901 29115454

47. Seo JH, Bang MA, Cho SS, Park DH. Erythronium japonicum significantly suppresses OVA-induced asthma via upregulation the IFN-γ expression and downregulation the expression of TNF-α and IL-4. Int J Mol Med. 2016; 37: 1221–1228. doi: 10.3892/ijmm.2016.2541 27035741

48. Seo JW, Park SJ, Lee EJ, Lee JH, Han SS, Pyo BS, et al. 1'-Acetoxychavicol acetate isolated from Alpinia galanga ameliorates ovalbumin-induced asthma in mice. PLOS ONE. 2013; 8: e56447. doi: 10.1371/journal.pone.0056447 23451048

49. Ram A, Mabalirajan U, Das M, Bhattacharya I, Dinda AK, Gangal SV, et al. Glycyrrhizin alleviates experimental allergic asthma in mice. Int Immunopharmacol. 2006; 6: 1468–1477. doi: 10.1016/j.intimp.2006.04.020 16846841

50. Wang J, Wang D, Yu J, Liu C, Li L, Zhang Y. Isolation of liquiritigenin-4’-apiosylglucoside and liquiritin form the root of Glycyrrhiza uralensis by high-performance centrifugal partition chromatography. J Chromatogr Sci. 2014; 52: 310–314. doi: 10.1093/chromsci/bmt029 23552847

51. Yu JY, Ha JY, Kim KM, Jung YS, Jung JC, Oh S. Anti-inflammatroy activities of licorice extract and its active compounds, glycyrrhizic acid, liquiritin and liquiritigenin, in BV2 cells and mice liver. Molecules. 2015; 20: 13041–13054. doi: 10.3390/molecules200713041 26205049

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