DOI QR코드

DOI QR Code

Donggwaja Suppresses Inflammatory Reaction Via Tumor Necrosis Factor α-induced Protein3 and NF-κB

Tumor necrosis factor α - induced protein3의 발현과 NF-κB 활성 억제를 통한 동과자의 염증반응 억제 효과

  • Kim, Kyun Ha (Department of Internal Medicine, Pusan National University Korean Medicine Hospital) ;
  • Choi, Jun-Yong (Department of Internal Medicine, Pusan National University Korean Medicine Hospital) ;
  • Joo, Myungsoo (School of Korean Medicine, Pusan National University)
  • 김균하 (부산대학교 한방병원 한방내과) ;
  • 최준용 (부산대학교 한방병원 한방내과) ;
  • 주명수 (부산대학교 한의학전문대학원)
  • Received : 2021.01.04
  • Accepted : 2021.02.25
  • Published : 2021.02.25

Abstract

Donggwaja (Benincasae Semen), the seed of Benincasa hispida (Thunb.) Cogn., has been used in Korean traditional medicine to control the body heat and water retention caused by various diseases. Both the symptoms targeted by the herbal medicine in clinic and studies with disease mouse models support the potential anti-inflammatory effect of Donggwaja. However, it is less understood how Donggwaja exerts its possible anti-inflammatory effect. Here, we present evidence that Donggwaja suppresses macrophage inflammatory reactions via expressing tumor necrosis factor a-induced protein 3 (TNFAIP3 or A20) and suppressing NF-kB activity. The ethanol extract of Donggwaja (EED) showed no toxicity when added to RAW 264.7 cells less than 100mg/ml. When treating the cells for 16 h, EED significantly suppressed the nuclear localization of NF-kB, suggesting that EED suppresses NF-kB activity. Concordantly, a semi-quantitative RT-PCR analysis showed that EED decreased the expression of prototypic pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-a, IL(interleukin)-6, and IL-1b. EED induced in RAW 264.7 cells the expression of A20, a ubiquitin modulator that suppresses inflammatory signaling cascades initiated from TLR4 and TNF and IL-1 receptors, while not affecting the induction of Nrf2, an anti-inflammatory factor that could suppress the effect of NF-kB. These results suggest that EED exerts its suppressive effect on inflammation, at least in part, by expressing anti-inflammatory factor A20 and suppressing pro-inflammatory factor NF-kB activity.

Keywords

References

  1. Fujiwara N, Kobayashi K. Macrophages in Inflammation. Curr Drug Targets Inflamm Allergy. 2005;4(3):281-6, https://doi.org/10.2174/1568010054022024
  2. Kimbrell DA, Beutler B. The evolution and Genetics of Innate Immunity. Nat Rev Genet. 2001;2(4):256-67. https://doi.org/10.1038/35066006
  3. Zhang H, Wu ZM, Yang YP, Shaukat A, Yang J, Guo YF, Zhang T, Zhu XY, Qiu JX, Deng GZ, Shi DM. Catalpol Ameliorates LPS-induced Endometritis by Inhibiting Inflammation and TLR4/NF-kappaB Signaling. J Zhejiang Univ Sci B. 2019;20(10):816-27. https://doi.org/10.1631/jzus.b1900071
  4. Israel A. The IKK Complex, a Central Regulator of NF-kappaB Activation. Cold Spring Harb Perspect Biol. 2010;2(3):a000158. https://doi.org/10.1101/cshperspect.a000158
  5. Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL, Ma A, Koonin EV, Dixit VM. De-ubiquitination and Ubiquitin Ligase Domains of A20 Downregulate NF-kappaB Signalling. Nature. 2004;430(7000):694-9. https://doi.org/10.1038/nature02794
  6. Catrysse L, Vereecke L, Beyaert R, van Loo G. A20 in Inflammation and Autoimmunity. Trends Immunol. 2014;35(1):22-31. https://doi.org/10.1016/j.it.2013.10.005
  7. Lin SC, Chung JY, Lamothe B, Rajashankar K, Lu M, Lo YC, Lam AY, Darnay BG, Wu H. Molecular Basis for the Unique Deubiquitinating Activity of the NF-kappaB Inhibitor A20. J Mol Biol. 2008;376(2):526-40. https://doi.org/10.1016/j.jmb.2007.11.092
  8. Robledinos-Anton N, Fernandez-Gines R, Manda G, Cuadrado A. Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development. Oxid Med Cell Longev. 2019;2019:9372182.
  9. Yan C, Zhang X, Miao J, Yuan H, Liu E, Liang T, Li Q. Farrerol Directly Targets GSK-3beta to Activate Nrf2-ARE Pathway and Protect EA.hy926 Cells against Oxidative Stress-Induced Injuries. Oxid Med Cell Longev. 2020;2020:5967434.
  10. Hwang DY. Banyakhapeon. Seoul:Yonglim Books, 2010. p. 548-9.
  11. Ministry of Food and Drug Safety. The Korean Herbal Pharmacopoeia. Republic of Korea:Ministry of Food and Drug Safety; 2020.
  12. Al-Snafi AE. The Pharmacological Importance of Benincasa hispida. A review. International Journal of Pharma Sciences and Research (IJPSR). 2013;4(12):165-70.
  13. Lee KH, Choi HR, Kim CH. Anti-angiogenic Effect of the Seed Extract of Benincasa Hispida Cogniaux. J Ethnopharmacol. 2005;97(3):509-13. https://doi.org/10.1016/j.jep.2004.12.008
  14. Choi JY KS, Kwun MJ, Kim K.H., Joo M, Han C. Effects of Ethanol Extract of Benincasa Seeds on the Experimental Cellular Model of Nonalcholic Fatty Liver Disease. Korean J Orinet Int Med. 2012;33(4):438-47.
  15. An SM, Kim HG, Choi EJ, Hwang HH, Lee E, Baek JH, Boo YC, Koh JS. Screening for Anti-inflammatory Activities in Extracts from Korean Herb Medicines. J Soc Cosmet Scientists Korea. 2014;40(1);95-108. https://doi.org/10.15230/SCSK.2014.40.1.95
  16. Park Gi, Lee JA. Anti-oxidant, Anti-inflammatory and Whitening Effect of Benincasa hispida Seed Extract. Journal of Convergence for Information Technology. 2020;10(7):249-56. https://doi.org/10.22156/CS4SMB.2020.10.07.249
  17. Park SK, Kim JJ, Sung SMi, Lee MY. Suppressive Effects of Benincasae hispida on Allergic Inflammation. Molecular & Cellular Toxicology 2009;5(4):304-9.
  18. Kim KH, Kim DH, Jeong N, Kim KI, Kim YH, Lee M, Choi JY, Jung HJ, Jung SK, Joo M.: Therapeutic Effect of Chung-Pae, an Experimental Herbal Formula, on Acute Lung Inflammation Is Associated with Suppression of NF-κB and Activation of Nrf2, Evid Based Complement Alternat Med. 2013;2013:659459.
  19. Zhang Q, Lenardo MJ, Baltimore D.30 Years of NF-kappaB: A Blossoming of Relevance to Human Pathobiology. Cell. 2017;168(1):37-57. https://doi.org/10.1016/j.cell.2016.12.012
  20. Sinnongbonchogyeong. Seoul: Euisungdang; 2012.
  21. Kumazawa Y, Nakatsuru Y, Yamada A, Yadomae T, Nishimura C, Otsuka Y, Nomoto K. Immunopotentiator Separated from Hot Water Extract of the Seed of Benincasa cerifera Savi (Tohgashi). Cancer Immunol Immunother. 1985;19(2):79-84. https://doi.org/10.1007/BF00199713
  22. Broad A, Jones DE, Kirby JA. Toll-like Receptor (TLR) Response Tolerance: a Key Physiological "Damage Limitation" Effect and an Important Potential Opportunity for Therapy. Curr Med Chem. 2006;13(21):2487-502. https://doi.org/10.2174/092986706778201675
  23. Miller SI, Ernst RK, Bader MW. LPS, TLR4 and Infectious Disease Diversity. Nat Rev Microbiol. 2005;3(1):36-46. https://doi.org/10.1038/nrmicro1068
  24. M Bhatia, S Moochhala. Role of Inflammatory Mediators in the Pathophysiology of Acute Respiratory Distress Syndrome. J Pathol. 2004;202:145-56. https://doi.org/10.1002/path.1491