Skip to main content

Advertisement

SpringerLink
Log in

Anti-inflammatory Effects of Oleanolic Acid on LPS-Induced Inflammation In Vitro and In Vivo

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Oleanolic acid (OA) is a triterpenoid known for its anti-inflammatory and anti-cancer properties; however, the anti-inflammatory effects of OA on lipopolysaccharide (LPS)-mediated pro-inflammatory responses have not been studied. Here, we first investigated the possible anti-inflammatory effects of OA against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) induced by LPS and the associated signaling pathways. We found that OA inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of monocytes to HUVECs. OA also suppressed acetic acid-induced hyperpermeability and carboxymethylcellulose-induced leukocyte migration in vivo. Further studies revealed that OA suppressed the production of tumor necrosis factor-α and activation of nuclear factor-κB by LPS. Collectively, these results suggest that OA has anti-inflammatory effects by inhibiting hyperpermeability, the expression of CAMs, and the adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapeutic agent for vascular inflammatory diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Luscher, T.F., and M. Barton. 1997. Biology of the endothelium. Clinical Cardiology 20: II-3–II-10.

    Google Scholar 

  2. Ley, K., C. Laudanna, M.I. Cybulsky, and S. Nourshargh. 2007. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Reviews Immunology 7: 678–689.

    Article  PubMed  CAS  Google Scholar 

  3. Frijns, C.J., and L.J. Kappelle. 2002. Inflammatory cell adhesion molecules in ischemic cerebrovascular disease. Stroke 33: 2115–2122.

    Article  PubMed  CAS  Google Scholar 

  4. Ulbrich, H., E.E. Eriksson, and L. Lindbom. 2003. Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease. Trends in Pharmacological Sciences 24: 640–647.

    Article  PubMed  CAS  Google Scholar 

  5. Lockyer, J.M., J.S. Colladay, W.L. Alperin-Lea, T. Hammond, and A.J. Buda. 1998. Inhibition of nuclear factor-kappaB-mediated adhesion molecule expression in human endothelial cells. Circulation Research 82: 314–320.

    Article  PubMed  CAS  Google Scholar 

  6. Marui, N., M.K. Offermann, R. Swerlick, et al. 1993. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. The Journal of Clinical Investigation 92: 1866–1874.

    Article  PubMed  CAS  Google Scholar 

  7. Spiecker, M., H. Darius, and J.K. Liao. 2000. A functional role of I kappa B-epsilon in endothelial cell activation. Journal of Immunology 164: 3316–3322.

    CAS  Google Scholar 

  8. Branen, L., L. Hovgaard, M. Nitulescu, E. Bengtsson, J. Nilsson, and S. Jovinge. 2004. Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arteriosclerosis, Thrombosis, and Vascular Biology 24: 2137–2142.

    Article  PubMed  CAS  Google Scholar 

  9. Takeda, R., E. Suzuki, H. Satonaka, et al. 2005. Blockade of endogenous cytokines mitigates neointimal formation in obese Zucker rats. Circulation 111: 1398–1406.

    Article  PubMed  CAS  Google Scholar 

  10. Li, S.S. 2002. Mistletoe lectins: telomerase inhibitors in alternative cancer therapy. Drug Discovery Today 7: 896–897.

    Article  PubMed  Google Scholar 

  11. Kim, B.K., M.J. Choi, K.Y. Park, and E.J. Cho. 2010. Protective effects of Korean mistletoe lectin on radical-induced oxidative stress. Biological and Pharmaceutical Bulletin 33: 1152–1158.

    Article  PubMed  CAS  Google Scholar 

  12. Yoon, T.J., Y.C. Yoo, T.B. Kang, et al. 1999. Lectins isolated from Korean mistletoe (Viscum album coloratum) induce apoptosis in tumor cells. Cancer Letters 136: 33–40.

    Article  PubMed  CAS  Google Scholar 

  13. Yoon, T.J., Y.C. Yoo, T.B. Kang, et al. 2001. Cellular and humoral adjuvant activity of lectins isolated from Korean mistletoe (Viscum album coloratum). International Immunopharmacology 1: 881–889.

    Article  PubMed  CAS  Google Scholar 

  14. Yoon, T.J., Y.C. Yoo, T.B. Kang, et al. 2003. Antitumor activity of the Korean mistletoe lectin is attributed to activation of macrophages and NK cells. Archives of Pharmacal Research 26: 861–867.

    Article  PubMed  CAS  Google Scholar 

  15. Giner-Larza, E.M., S. Manez, M.C. Recio, et al. 2001. Oleanonic acid, a 3-oxotriterpene from Pistacia, inhibits leukotriene synthesis and has anti-inflammatory activity. European Journal of Pharmacology 428: 137–143.

    Article  PubMed  CAS  Google Scholar 

  16. Hsu, H.Y., J.J. Yang, S.Y. Lin, and C.C. Lin. 1997. Comparisons of geniposidic acid and geniposide on antitumor and radioprotection after sublethal irradiation. Cancer Letters 113: 31–37.

    Article  PubMed  CAS  Google Scholar 

  17. Zhu, Y.M., J.K. Shen, H.K. Wang, L.M. Cosentino, and K.H. Lee. 2001. Synthesis and anti-HIV activity of oleanolic acid derivatives. Bioorganic & Medicinal Chemistry Letters 11: 3115–3118.

    Article  CAS  Google Scholar 

  18. Jeong, H.G. 1999. Inhibition of cytochrome P450 2E1 expression by oleanolic acid: hepatoprotective effects against carbon tetrachloride-induced hepatic injury. Toxicology Letters 105: 215–222.

    Article  PubMed  CAS  Google Scholar 

  19. Bae, J.S., and A.R. Rezaie. 2011. Activated protein C inhibits high mobility group box 1 signaling in endothelial cells. Blood 118: 3952–3959.

    Article  PubMed  CAS  Google Scholar 

  20. Bae, J.S., and A.R. Rezaie. 2008. Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand. Thrombosis and Haemostasis 100: 101–109.

    PubMed  CAS  Google Scholar 

  21. Che, W., N. Lerner-Marmarosh, Q. Huang, et al. 2002. Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression. Circulation Research 90: 1222–1230.

    Article  PubMed  CAS  Google Scholar 

  22. Bae, J.W., and J.S. Bae. 2011. Barrier protective effects of lycopene in human endothelial cells. Inflammation Research 60: 751–758.

    Article  PubMed  CAS  Google Scholar 

  23. Akeson, A.L., and C.W. Woods. 1993. A fluorometric assay for the quantitation of cell adherence to endothelial cells. Journal of Immunological Methods 163: 181–185.

    Article  PubMed  CAS  Google Scholar 

  24. Kim, I., S.O. Moon, S.H. Kim, H.J. Kim, Y.S. Koh, and G.Y. Koh. 2001. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. Journal of Biological Chemistry 276: 7614–7620.

    Article  PubMed  CAS  Google Scholar 

  25. Sun, J., S. Wang, D. Zhao, F.H. Hun, L. Weng, and H. Liu. 2011. Cytotoxicity, permeability, and inflammation of metal oxide nanoparticles in human cardiac microvascular endothelial cells: cytotoxicity, permeability, and inflammation of metal oxide nanoparticles. Cell Biology and Toxicology 27: 333–342.

    Article  PubMed  Google Scholar 

  26. Campbell, W.N., M. Fitzpatrick, X. Ding, M. Jett, P. Gemski, and S.E. Goldblum. 1997. SEB is cytotoxic and alters EC barrier function through protein tyrosine phosphorylation in vitro. American Journal of Physiology 273: L31–L39.

    PubMed  CAS  Google Scholar 

  27. Chen, B.C., C.F. Chou, and W.W. Lin. 1998. Pyrimidinoceptor-mediated potentiation of inducible nitric-oxide synthase induction in J774 macrophages. Role of intracellular calcium. Journal of Biological Chemistry 273: 29754–29763.

    Article  PubMed  CAS  Google Scholar 

  28. Thompson, J.E., R.J. Phillips, H. Erdjument-Bromage, P. Tempst, and S. Ghosh. 1995. I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B. Cell 80: 573–582.

    Article  PubMed  CAS  Google Scholar 

  29. Komarova, Y.A., D. Mehta, and A.B. Malik. 2007. Dual regulation of endothelial junctional permeability. Science’s STKE: Signal Transduction knowledge Environment 2007: re8.

    PubMed  Google Scholar 

  30. Dudek, S.M., and J.G. Garcia. 2001. Cytoskeletal regulation of pulmonary vascular permeability. Journal of Applied Physiology 91: 1487–1500.

    PubMed  CAS  Google Scholar 

  31. Chen, C.C., C.L. Rosenbloom, D.C. Anderson, and A.M. Manning. 1995. Selective inhibition of E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 expression by inhibitors of I kappa B-alpha phosphorylation. Journal of Immunology 155: 3538–3545.

    CAS  Google Scholar 

  32. Jersmann, H.P., C.S. Hii, J.V. Ferrante, and A. Ferrante. 2001. Bacterial lipopolysaccharide and tumor necrosis factor alpha synergistically increase expression of human endothelial adhesion molecules through activation of NF-kappaB and p38 mitogen-activated protein kinase signaling pathways. Infection and Immunity 69: 1273–1279.

    Article  PubMed  CAS  Google Scholar 

  33. Lin, W.N., S.F. Luo, C.B. Wu, C.C. Lin, and C.M. Yang. 2008. Lipopolysaccharide induces VCAM-1 expression and neutrophil adhesion to human tracheal smooth muscle cells: involvement of Src/EGFR/PI3-K/Akt pathway. Toxicology and Applied Pharmacology 228: 256–268.

    Article  PubMed  CAS  Google Scholar 

  34. Ruiz-Torres, M.P., G. Perez-Rivero, M. Rodriguez-Puyol, D. Rodriguez-Puyol, and M.L. Diez-Marques. 2006. The leukocyte–endothelial cell interactions are modulated by extracellular matrix proteins. Cellular Physiology and Biochemistry 17: 221–232.

    Article  PubMed  CAS  Google Scholar 

  35. Langer, H.F., and T. Chavakis. 2009. Leukocyte–endothelial interactions in inflammation. Journal of Cellular and Molecular Medicine 13: 1211–1220.

    Article  PubMed  CAS  Google Scholar 

  36. Pardi, R., L. Inverardi, and J.R. Bender. 1992. Regulatory mechanisms in leukocyte adhesion: flexible receptors for sophisticated travelers. Immunology Today 13: 224–230.

    Article  PubMed  CAS  Google Scholar 

  37. Cantor, J.M., M.H. Ginsberg, and D.M. Rose. 2008. Integrin-associated proteins as potential therapeutic targets. Immunology Reviews 223: 236–251.

    Article  CAS  Google Scholar 

  38. Lacasse, C., S. Turcotte, D. Gingras, J. Stankova, and M. Rola-Pleszczynski. 1997. Platelet-activating factor stimulates interleukin-6 production by human endothelial cells and synergizes with tumor necrosis factor for enhanced production of granulocyte-macrophage colony stimulating factor. Inflammation 21: 145–158.

    Article  PubMed  CAS  Google Scholar 

  39. Li, Y., R.F. Schwabe, T. DeVries-Seimon, et al. 2005. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. Journal of Biological Chemistry 280: 21763–21772.

    Article  PubMed  CAS  Google Scholar 

  40. Ghosh, S., M.J. May, and E.B. Kopp. 1998. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annual Review of Immunology 16: 225–260.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0026695, 2011-0030124).

Conflict of Interest Statement

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea

    Wonhwa Lee, Kyung-Sik Song & Jong-Sup Bae

  2. Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, 702-701, Republic of Korea

    Wonhwa Lee

  3. BK21 Research Team for Developing Functional Health Food Materials, Kyungpook National University, Daegu, 702-701, Republic of Korea

    Eun-Ju Yang

  4. Department of Anatomy and Histology, College of Oriental Medicine, Daegu Haany University, Gyeongsan, 712-715, Republic of Korea

    Sae-Kwang Ku

Authors
  1. Wonhwa Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eun-Ju Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sae-Kwang Ku
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyung-Sik Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jong-Sup Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jong-Sup Bae.

Additional information

Wonhwa Lee, Eun-Ju Yang, and Sae-Kwang Ku contributed equally to this work.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 40 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, W., Yang, EJ., Ku, SK. et al. Anti-inflammatory Effects of Oleanolic Acid on LPS-Induced Inflammation In Vitro and In Vivo . Inflammation 36, 94–102 (2013). https://doi.org/10.1007/s10753-012-9523-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-012-9523-9

KEY WORDS

Search

Navigation