Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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The Anti-Inflammatory Activity of Eucommia ulmoides Oliv. Bark. Involves NF-κB Suppression and Nrf2-Dependent HO-1 Induction in BV-2 Microglial Cells

  • Kwon, Seung-Hwan (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Ma, Shi-Xun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Hwang, Ji-Young (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Ko, Yong-Hyun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Seo, Ji-Yeon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Bo-Ram (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Seok-Yong (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Jang, Choon-Gon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
  • Received : 2015.09.14
  • Accepted : 2015.12.02
  • Published : 2016.05.01
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Abstract

In the present study, we investigated the anti-inflammatory properties of Eucommia ulmoides Oliv. Bark. (EUE) in lipopolysaccharide (LPS)-stimulated microglial BV-2 cells and found that EUE inhibited LPS-mediated up-regulation of pro-inflammatory response factors. In addition, EUE inhibited the elevated production of pro-inflammatory cytokines, mediators, and reactive oxygen species (ROS) in LPS-stimulated BV-2 microglial cells. Subsequent mechanistic studies revealed that EUE suppressed LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs), phosphoinositide-3-kinase (PI3K)/Akt, glycogen synthase $kinase-3{\beta}$ ($GSK-3{\beta}$), and their downstream transcription factor, nuclear factor-kappa B ($NF-{\kappa}B$). EUE also blocked the nuclear translocation of $NF-{\kappa}B$ and inhibited its binding to DNA. We next demonstrated that EUE induced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated heme oxygenase-1 (HO-1) expression. We determined that the significant up-regulation of HO-1 expression by EUE was a consequence of Nrf2 nuclear translocation; furthermore, EUE increased the DNA binding of Nrf2. In contrast, zinc protoporphyrin (ZnPP), a specific HO-1 inhibitor, blocked the ability of EUE to inhibit NO and $PGE_2$ production, indicating the vital role of HO-1. Overall, our results indicate that EUE inhibits pro-inflammatory responses by modulating MAPKs, PI3K/Akt, and $GSK-3{\beta}$, consequently suppressing $NF-{\kappa}B$ activation and inducing Nrf2-dependent HO-1 activation.

Keywords

References

  1. Amor, S., Puentes, F., Baker, D. and van der Valk, P. (2010) Inflammation in neurodegenerative diseases. Immunology 129, 154-169. https://doi.org/10.1111/j.1365-2567.2009.03225.x
  2. Baima, E. T., Guzova, J. A., Mathialagan, S., Nagiec, E. E., Hardy, M. M., Song, L. R., Bonar, S. L., Weinberg, R. A., Selness, S. R., Woodard, S. S., Chrencik, J., Hood, W. F., Schindler, J. F., Kishore, N. and Mbalaviele, G. (2010) Novel insights into the cellular mechanisms of the anti-inflammatory effects of NF-kB essential modulator binding domain peptides. J. Biol. Chem. 285, 13498-13506. https://doi.org/10.1074/jbc.M109.099895
  3. Bauer, M. and Bauer, I. (2002) Heme oxygenase-1: redox regulation and role in the hepatic response to oxidative stress. Antioxid. Redox Signal. 4, 749-758. https://doi.org/10.1089/152308602760598891
  4. Block, M. L. and Hong, J. S. (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog. Neurobiol. 76, 77-98. https://doi.org/10.1016/j.pneurobio.2005.06.004
  5. Block, M. L., Zecca, L. and Hong, J. S. (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57-69. https://doi.org/10.1038/nrn2038
  6. Boje, K. M. and Arora, P. K. (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res. 587, 250-256. https://doi.org/10.1016/0006-8993(92)91004-X
  7. Botchkina, G. I., Meistrell, M. E., 3rd, Botchkina, I. L. and Tracey, K. J. (1997) Expression of TNF and TNF receptors (p55 and p75) in the rat brain after focal cerebral ischemia. Mol. Med. 3, 765-781.
  8. Floyd, R. A. and Hensley, K. (2002) Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol. Aging 23, 795-807. https://doi.org/10.1016/S0197-4580(02)00019-2
  9. Fremond, C. M., Togbe, D., Doz, E., Rose, S., Vasseur, V., Maillet, I., Jacobs, M., Ryffel, B. and Quesniaux, V. F. (2007) IL-1 receptormediated signal is an essential component of MyD88-dependent innate response to Mycobacterium tuberculosis infection. J. Immunol. 179, 1178-1189. https://doi.org/10.4049/jimmunol.179.2.1178
  10. Gao, H. M. and Hong, J. S. (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol. 29, 357-365. https://doi.org/10.1016/j.it.2008.05.002
  11. Guo, Y. J., Luo, T., Wu, F., Mei, Y. W., Peng J., Liu, H., Li, H. R., Zhang, S. L., Dong, J. H., Fang, Y., Zhao, L. (2015) Involvement of TLR2 and TLR9 in the anti-inflammatory effects of chlorogenic acid in HSV-1-infected microglia. Life Sci. 127, 12-18. https://doi.org/10.1016/j.lfs.2015.01.036
  12. Heneka, M. T. and O'Banion, M. K. (2007) Inflammatory processes in Alzheimer's disease. J. Neuroimmunol. 184, 69-91. https://doi.org/10.1016/j.jneuroim.2006.11.017
  13. Hsieh, H. L., Wang, H. H., Wu, W. B., Chu, P. J. and Yang, C. M. (2010) Transforming growth factor-b1 induces matrix metalloproteinase-9 and cell migration in astrocytes: roles of ROS-dependent ERK- and JNK-NF-kB pathways. J. Neuroinflammation 7, 88. https://doi.org/10.1186/1742-2094-7-88
  14. Innamorato, N. G., Rojo, A. I., García-Yagüe, A. J., Yamamoto, M., de Ceballos, M. L. and Cuadrado, A. (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. J. Immunol. 181, 680-689. https://doi.org/10.4049/jimmunol.181.1.680
  15. Jiang, L., Wang, Z., Zhu, H. W., Di, H. Y., Li, H., Zhang, Y. Y. and Chen, D. F. (2011) Beneficial effect of Eucommia polysaccharides on systemic lupus erythematosus-like syndrome induced by Campylobacter jejuni in BALB/c mice. Inflammation 34, 402-411. https://doi.org/10.1007/s10753-010-9247-7
  16. Kaminska, B. (2005) MAPK signalling pathways as molecular targets for anti-inflammatory therapy--from molecular mechanisms to therapeutic benefits. Biochim. Biophys. Acta 1754, 253-262. https://doi.org/10.1016/j.bbapap.2005.08.017
  17. Kang, C. H., Kim, M. J., Seo, M. J., Choi, Y. H., Jo, W. S., Lee, K. T., Jeong, Y. K. and Kim, G. Y. (2013) 5-Hydroxy-3,6,7,8,3'4'-hexamethoxyflavone inhibits nitric oxide production in lipopolysaccharidestimulated BV2 microglia via NF-kB suppression and Nrf-2-dependent heme oxygenase-1 induction. Food Chem. Toxicol. 57, 119-125. https://doi.org/10.1016/j.fct.2013.03.019
  18. Kensler, T. W., Wakabayashi, N. and Biswal, S. (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol. 47, 89-116. https://doi.org/10.1146/annurev.pharmtox.46.120604.141046
  19. Kim, B. H., Park, K. S. and Chang, I. M. (2009) Elucidation of antiinflammatory potencies of Eucommia ulmoides bark and Plantago asiatica seeds. J. Med. Food 12, 764-769. https://doi.org/10.1089/jmf.2008.1239
  20. Kim, J., Cha, Y. N. and Surh, Y. J. (2010) A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat. Res. 690, 12-23. https://doi.org/10.1016/j.mrfmmm.2009.09.007
  21. Kim, M. C., Kim, D. S., Kim, S. J., Park, J., Kim, H. L., Kim, S. Y., Ahn, K. S., Jang, H. J., Lee, S. G., Lee, K. M., Hong, S. H. and Um, J. Y. (2012) Eucommiae cortex inhibits TNF-a and IL-6 through the suppression of caspase-1 in lipopolysaccharide-stimulated mouse peritoneal macrophages. Am. J. Chin. Med. 40, 135-149. https://doi.org/10.1142/S0192415X12500115
  22. Koistinaho, J., Malm, T. and Goldsteins, G. (2011) Glycogen synthase kinase-3b: a mediator of inflammation in Alzheimer's disease? Int. J. Alzheimers Dis. 2011, 129753.
  23. Kronke, G., Bochkov, V. N., Huber, J., Gruber, F., Blüml, S., Fürnkranz, A., Kadl, A., Binder, B. R. and Leitinger, N. (2003) Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive element-binding protein. J. Biol. Chem. 278, 51006-51014. https://doi.org/10.1074/jbc.M304103200
  24. Kwan, C. Y., Chen, C. X., Deyama, T. and Nishibe, S. (2003) Endothelium- dependent vasorelaxant effects of the aqueous extracts of the Eucommia ulmoides Oliv. leaf and bark: implications on their antihypertensive action. Vascul. Pharmacol. 40, 229-235. https://doi.org/10.1016/j.vph.2003.09.001
  25. Kwon, S. H., Ma, S. X., Hong, S. I., Kim, S. Y., Lee, S. Y. and Jang, C. G. (2014) Eucommia ulmoides Oliv. bark. attenuates 6-hydroxydopamine- induced neuronal cell death through inhibition of oxidative stress in SH-SY5Y cells. J. Ethnopharmacol. 152, 173-182. https://doi.org/10.1016/j.jep.2013.12.048
  26. Kwon, S. H., Kim, M. J., Ma, S. X., You, I. J., Hwang, J. Y., Oh, J. H., Kim, S. Y., Kim, H. C., Lee, S. Y. and Jang, C. G. (2012) Eucommia ulmoides Oliv. Bark. protects against hydrogen peroxide-induced neuronal cell death in SH-SY5Y cells. J. Ethnopharmacol. 142, 337-345. https://doi.org/10.1016/j.jep.2012.04.010
  27. Kwon, S. H., Lee, H. K., Kim, J. A., Hong, S. I., Kim, S. Y., Jo, T. H., Park, Y. I., Lee, C. K., Kim, Y. B., Lee, S. Y. and Jang, C. G. (2011) Neuroprotective effects of Eucommia ulmoides Oliv. Bark on amyloid beta25-35-induced learning and memory impairments in mice. Neurosci. Lett. 487, 123-127. https://doi.org/10.1016/j.neulet.2010.10.042
  28. Lee, I. S., Lim, J., Gal, J., Kang, J. C., Kim, H. J., Kang, B. Y. and Choi, H. J. (2011) Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells. Neurochem. Int. 58, 153-160. https://doi.org/10.1016/j.neuint.2010.11.008
  29. Lee, J., Ryu, H., Ferrante, R. J., Morris, S. M., Jr. and Ratan, R. R. (2003) Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc. Natl. Acad. Sci. U.S.A. 100, 4843-4848. https://doi.org/10.1073/pnas.0735876100
  30. Lee, M. K., Cho, S. Y., Kim, D. J., Jang, J. Y., Shin, K. H., Park, S. A., Park, E. M., Lee, J. S., Choi, M. S., Lee, J. S. and Kim, M. J. (2005) Du-zhong (Eucommia ulmoides Oliv.) cortex water extract alters heme biosynthesis and erythrocyte antioxidant defense system in lead-administered rats. J. Med. Food 8, 86-92. https://doi.org/10.1089/jmf.2005.8.86
  31. Li, F., Chong, Z. Z. and Maiese, K. (2006) Microglial integrity is maintained by erythropoietin through integration of Akt and its substrates of glycogen synthase kinase-3b, b-catenin, and nuclear factor-kB. Curr. Neurovasc. Res. 3, 187-201. https://doi.org/10.2174/156720206778018758
  32. Lin, J., Fan, Y. J., Mehl, C., Zhu, J. J., Chen, H., Jin, L. Y., Xu, J. H. and Wang, H. M. (2011) Eucommia ulmoides Oliv. antagonizes $H_2O_2$- induced rat osteoblastic MC3T3-E1 apoptosis by inhibiting expressions of caspases 3, 6, 7, and 9. J. Zhejiang Univ. Sci. B 12, 47-54. https://doi.org/10.1631/jzus.B1000057
  33. Liu, E., Han, L., Wang, J., He, W., Shang, H., Gao, X. and Wang, T. (2012) Eucommia ulmoides bark protects against renal injury in cadmium-challenged rats. J. Med. Food 15, 307-314. https://doi.org/10.1089/jmf.2011.1756
  34. Lucas, S. M., Rothwell, N. J. and Gibson, R. M. (2006) The role of inflammation in CNS injury and disease. Br. J. Pharmacol. 147, S232-S240.
  35. Lull, M. E. and Block, M. L. (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7, 354-365. https://doi.org/10.1016/j.nurt.2010.05.014
  36. Luo, L. F., Wu, W. H., Zhou, Y. J., Yan, J., Yang, G. P. and Ouyang, D. S. (2010) Antihypertensive effect of Eucommia ulmoides Oliv. extracts in spontaneously hypertensive rats. J. Ethnopharmacol. 129, 238-243. https://doi.org/10.1016/j.jep.2010.03.019
  37. Maines, M. D. (1988) Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J. 2, 2557-2568. https://doi.org/10.1096/fasebj.2.10.3290025
  38. Marchetti, B. and Abbracchio, M. P. (2005) To be or not to be (inflamed)--is that the question in anti-inflammatory drug therapy of neurodegenerative disorders? Trends Pharmacol. Sci. 26, 517-525. https://doi.org/10.1016/j.tips.2005.08.007
  39. Mattson, M. P. (2005) NF-kB in the survival and plasticity of neurons. Neurochem. Res. 30, 883-893. https://doi.org/10.1007/s11064-005-6961-x
  40. Mattson, M. P. and Camandola, S. (2001) NF-kB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest. 107, 247-254. https://doi.org/10.1172/JCI11916
  41. Minghetti, L. (2004) Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J. Neuropathol. Exp. Neurol. 63, 901-910. https://doi.org/10.1093/jnen/63.9.901
  42. Minghetti, L. and Levi, G. (1998) Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog. Neurobiol. 54, 99-125. https://doi.org/10.1016/S0301-0082(97)00052-X
  43. Minghetti, L., Walsh, D. T., Levi, G. and Perry, V. H. (1999) In vivo expression of cyclooxygenase-2 in rat brain following intraparenchymal injection of bacterial endotoxin and inflammatory cytokines. J. Neuropathol. Exp. Neurol. 58, 1184-1191. https://doi.org/10.1097/00005072-199911000-00008
  44. Nomura, Y. (2001) NF-kB activation and IkBa dynamism involved in iNOS and chemokine induction in astroglial cells. Life Sci. 68, 1695-1701. https://doi.org/10.1016/S0024-3205(01)00967-5
  45. O'Neill, L. A. and Kaltschmidt, C. (1997) NF-kB: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci. 20, 252-258. https://doi.org/10.1016/S0166-2236(96)01035-1
  46. Park, S. Y., Kim, J. H., Lee, S. J. and Kim, Y. (2013) Involvement of PKA and HO-1 signaling in anti-inflammatory effects of surfactin in BV-2 microglial cells. Toxicol. Appl. Pharmacol. 268, 68-78. https://doi.org/10.1016/j.taap.2013.01.017
  47. Rock, R. B., Gekker, G., Hu, S., Sheng, W. S., Cheeran, M., Lokensgard, J. R. and Peterson, P. K. (2004) Role of microglia in central nervous system infections. Clin. Microbiol. Rev. 17, 942-964. https://doi.org/10.1128/CMR.17.4.942-964.2004
  48. Rothwell, N., Allan, S. and Toulmond, S. (1997) The role of interleukin 1 in acute neurodegeneration and stroke: pathophysiological and therapeutic implications. J. Clin. Invest. 100, 2648-2652. https://doi.org/10.1172/JCI119808
  49. Salminen, A., Huuskonen, J., Ojala, J., Kauppinen, A., Kaarniranta, K. and Suuronen, T. (2008) Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflammaging. Ageing Res. Rev. 7, 83-105. https://doi.org/10.1016/j.arr.2007.09.002
  50. Smith, J. A., Das, A., Ray, S. K. and Banik, N. L. (2012) Role of proinflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res. Bull. 87, 10-20. https://doi.org/10.1016/j.brainresbull.2011.10.004
  51. Sriram, K., Matheson, J. M., Benkovic, S. A., Miller, D. B., Luster, M. I. and O'Callaghan, J. P. (2002) Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson's disease. FASEB J. 16, 1474-1476. https://doi.org/10.1096/fj.02-0216fje
  52. Surh, Y. J., Chun, K. S., Cha, H. H., Han, S. S., Keum, Y. S., Park, K. K. and Lee, S. S. (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NFkB activation. Mutat. Res. 480-481, 243-268. https://doi.org/10.1016/S0027-5107(01)00183-X
  53. Takagi, T., Naito, Y., Uchiyama, K. and Yoshikawa, T. (2010) The role of heme oxygenase and carbon monoxide in inflammatory bowel disease. Redox Rep. 15, 193-201. https://doi.org/10.1179/174329210X12650506623889
  54. Wang, M. J., Lin, S. Z., Kuo, J. S., Huang, H. Y., Tzeng, S. F., Liao, C. H., Chen, D. C. and Chen, W. F. (2007) Urocortin modulates inflammatory response and neurotoxicity induced by microglial activation. J. Immunol. 179, 6204-6214. https://doi.org/10.4049/jimmunol.179.9.6204
  55. Yang, J., Kato, K., Noguchi, K., Dairaku, N., Koike, T., Iijima, K., Imatani, A., Sekine, H., Ohara, S., Sasano, H. and Shimosegawa, T. (2003) Tochu (Eucommia ulmoides) leaf extract prevents ammonia and vitamin C deficiency induced gastric mucosal injury. Life Sci. 73, 3245-3256. https://doi.org/10.1016/j.lfs.2003.06.011
  56. Yuskaitis, C. J. and Jope, R. S. (2009) Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammationinduced neurotoxicity. Cell. Signal. 21, 264-273. https://doi.org/10.1016/j.cellsig.2008.10.014

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