Skip to main content

Advertisement

SpringerLink
Log in

Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective and design

High mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. Rutin (RT), an active flavonoid compound, is well known to possess potent antiplatelet, antiviral and antihypertensive properties. In this study, we investigated the anti-inflammatory effects of RT against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) induced by HMGB1 and the associated signaling pathways.

Methods

The anti-inflammatory activities of RT were determined by measuring permeability, monocytes adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice.

Results

We found that RT potently inhibited HMGB1 release, down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with RT resulted in reduced cecal ligation and puncture-induced release of HMGB1 and sepsis-related mortality. Further studies revealed that RT suppressed the production of tumor necrosis factor-α and interleukin 6 and the activation of nuclear factor-κB and extracellular regulated kinases 1/2 by HMGB1.

Conclusion

Collectively, these results indicate that RT could be a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011;29:139–62.

    Article  CAS  PubMed  Google Scholar 

  2. Bae JS. Role of high mobility group box 1 in inflammatory disease: focus on sepsis. Arch Pharm Res. 2012;35:1511–23.

    Article  CAS  PubMed  Google Scholar 

  3. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem. 1995;270:25752–61.

    Article  CAS  PubMed  Google Scholar 

  4. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. 2004;279:7370–7.

    Article  CAS  PubMed  Google Scholar 

  5. Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, et al. Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med. 2005;33:564–73.

    Article  CAS  PubMed  Google Scholar 

  6. Gibot S, Massin F, Cravoisy A, Barraud D, Nace L, Levy B, et al. High-mobility group box 1 protein plasma concentrations during septic shock. Intensive Care Med. 2007;33:1347–53.

    Article  CAS  PubMed  Google Scholar 

  7. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296–327.

    Article  PubMed  Google Scholar 

  8. Wang X, Feuerstein GZ, Gu JL, Lysko PG, Yue TL. Interleukin-1 beta induces expression of adhesion molecules in human vascular smooth muscle cells and enhances adhesion of leukocytes to smooth muscle cells. Atherosclerosis. 1995;115:89–98.

    Article  CAS  PubMed  Google Scholar 

  9. Sluiter W, Pietersma A, Lamers JM, Koster JF. Leukocyte adhesion molecules on the vascular endothelium: their role in the pathogenesis of cardiovascular disease and the mechanisms underlying their expression. J Cardiovasc Pharmacol. 1993;22(Suppl 4):S37–44.

    Article  CAS  PubMed  Google Scholar 

  10. Lockyer JM, Colladay JS, Alperin-Lea WL, Hammond T, Buda AJ. Inhibition of nuclear factor-kappaB-mediated adhesion molecule expression in human endothelial cells. Circ Res. 1998;82:314–20.

    Article  CAS  PubMed  Google Scholar 

  11. Marui N, Offermann MK, Swerlick R, Kunsch C, Rosen CA, Ahmad M, et al. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest. 1993;92:1866–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Spiecker M, Darius H, Liao JK. A functional role of I kappa B-epsilon in endothelial cell activation. J Immunol. 2000;164:3316–22.

    CAS  PubMed  Google Scholar 

  13. Branen L, Hovgaard L, Nitulescu M, Bengtsson E, Nilsson J, Jovinge S. Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2004;24:2137–42.

    Article  CAS  PubMed  Google Scholar 

  14. Takeda R, Suzuki E, Satonaka H, Oba S, Nishimatsu H, Omata M, et al. Blockade of endogenous cytokines mitigates neointimal formation in obese Zucker rats. Circulation. 2005;111:1398–406.

    Article  CAS  PubMed  Google Scholar 

  15. Ushida Y, Matsui T, Tanaka M, Matsumoto K, Hosoyama H, Mitomi A, et al. Endothelium-dependent vasorelaxation effect of rutin-free tartary buckwheat extract in isolated rat thoracic aorta. J Nutr Biochem. 2008;19:700–7.

    Article  CAS  PubMed  Google Scholar 

  16. Knekt P, Kumpulainen J, Jarvinen R, Rissanen H, Heliovaara M, Reunanen A, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr. 2002;76:560–8.

    CAS  PubMed  Google Scholar 

  17. Korkmaz A, Kolankaya D. Protective effect of rutin on the ischemia/reperfusion induced damage in rat kidney. J Surg Res. 2010;164:309–15.

    Article  CAS  PubMed  Google Scholar 

  18. Milde J, Elstner EF, Grassmann J. Synergistic inhibition of low-density lipoprotein oxidation by rutin, gamma-terpinene, and ascorbic acid. Phytomedicine. 2004;11:105–13.

    Article  CAS  PubMed  Google Scholar 

  19. Lee W, Ku SK, Kim TH, Bae JS. Emodin-6-O-beta-d-glucoside inhibits HMGB1-induced inflammatory responses in vitro and in vivo. Food Chem Toxicol. 2013;52:97–104.

    Article  CAS  PubMed  Google Scholar 

  20. Bae JS, Rezaie AR. 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. Thromb Haemost. 2008;100:101–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;10:1216–21.

    Article  CAS  PubMed  Google Scholar 

  22. Lee W, Kim TH, Ku SK, Min KJ, Lee HS, Kwon TK, et al. Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models. Toxicol Appl Pharmacol. 2012;262:91–8.

    Article  CAS  PubMed  Google Scholar 

  23. Yang EJ, Lee W, Ku SK, Song KS, Bae JS. Anti-inflammatory activities of oleanolic acid on HMGB1 activated HUVECs. Food Chem Toxicol. 2012;50:1288–94.

    Article  CAS  PubMed  Google Scholar 

  24. Bae JS, Yang L, Manithody C, Rezaie AR. The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood. 2007;110:3909–16.

    Article  CAS  PubMed  Google Scholar 

  25. Che W, Lerner-Marmarosh N, Huang Q, Osawa M, Ohta S, Yoshizumi M, et al. 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. Circ Res. 2002;90:1222–30.

    Article  CAS  PubMed  Google Scholar 

  26. Bae JW, Bae JS. Barrier protective effects of lycopene in human endothelial cells. Inflamm Res. 2011;60:751–8.

    Article  CAS  PubMed  Google Scholar 

  27. Akeson AL, Woods CW. A fluorometric assay for the quantitation of cell adherence to endothelial cells. J Immunol Methods. 1993;163:181–5.

    Article  CAS  PubMed  Google Scholar 

  28. Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY. 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. J Biol Chem. 2001;276:7614–20.

    Article  CAS  PubMed  Google Scholar 

  29. El Gazzar M. HMGB1 modulates inflammatory responses in LPS-activated macrophages. Inflamm Res. 2007;56:162–7.

    Article  PubMed  Google Scholar 

  30. Mullins GE, Sunden-Cullberg J, Johansson AS, Rouhiainen A, Erlandsson-Harris H, Yang H, et al. Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1. Scand J Immunol. 2004;60:566–73.

    Article  CAS  PubMed  Google Scholar 

  31. Bae JS, Rezaie AR. Activated protein C inhibits high mobility group box 1 signaling in endothelial cells. Blood. 2011;118:3952–9.

    Article  CAS  PubMed  Google Scholar 

  32. Chen G, Li J, Ochani M, Rendon-Mitchell B, Qiang X, Susarla S, et al. Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms. J Leukoc Biol. 2004;76:994–1001.

    Article  CAS  PubMed  Google Scholar 

  33. Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nat Rev Drug Discov. 2005;4:854–65.

    Article  CAS  PubMed  Google Scholar 

  34. Tsung A, Klune JR, Zhang X, Jeyabalan G, Cao Z, Peng X, et al. HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp Med. 2007;204:2913–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Bell CW, Jiang W, Reich CF 3rd, Pisetsky DS. The extracellular release of HMGB1 during apoptotic cell death. Am J Physiol Cell Physiol. 2006;291:C1318–25.

    Article  CAS  PubMed  Google Scholar 

  36. Kikuchi K, Kawahara K, Biswas KK, Ito T, Tancharoen S, Morimoto Y, et al. Minocycline attenuates both OGD-induced HMGB1 release and HMGB1-induced cell death in ischemic neuronal injury in PC12 cells. Biochem Biophys Res Commun. 2009;385:132–6.

    Article  CAS  PubMed  Google Scholar 

  37. Sama AE, D’Amore J, Ward MF, Chen G, Wang H. Bench to bedside: HMGB1-a novel proinflammatory cytokine and potential therapeutic target for septic patients in the emergency department. Acad Emerg Med. 2004;11:867–73.

    PubMed  Google Scholar 

  38. Wolfson RK, Chiang ET, Garcia JG. HMGB1 induces human lung endothelial cell cytoskeletal rearrangement and barrier disruption. Microvasc Res. 2011;81:189–97.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Yang H, Wang H, Czura CJ, Tracey KJ. The cytokine activity of HMGB1. J Leukoc Biol. 2005;78:1–8.

    Article  CAS  PubMed  Google Scholar 

  40. Qin YH, Dai SM, Tang GS, Zhang J, Ren D, Wang ZW, et al. HMGB1 enhances the proinflammatory activity of lipopolysaccharide by promoting the phosphorylation of MAPK p38 through receptor for advanced glycation end products. J Immunol. 2009;183:6244–50.

    Article  CAS  PubMed  Google Scholar 

  41. Sun C, Liang C, Ren Y, Zhen Y, He Z, Wang H, et al. Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways. Basic Res Cardiol. 2009;104:42–9.

    Article  CAS  PubMed  Google Scholar 

  42. Treutiger CJ, Mullins GE, Johansson AS, Rouhiainen A, Rauvala HM, Erlandsson-Harris H, et al. High mobility group 1 B-box mediates activation of human endothelium. J Intern Med. 2003;254:375–85.

    Article  CAS  PubMed  Google Scholar 

  43. Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood. 2003;101:2652–60.

    Article  CAS  PubMed  Google Scholar 

  44. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med. 2000;192:565–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Park JS, Arcaroli J, Yum HK, Yang H, Wang H, Yang KY, et al. Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol. 2003;284:C870–9.

    Article  CAS  PubMed  Google Scholar 

  46. Lin WN, Luo SF, Wu CB, Lin CC, Yang CM. Lipopolysaccharide induces VCAM-1 expression and neutrophil adhesion to human tracheal smooth muscle cells: involvement of Src/EGFR/PI3-K/Akt pathway. Toxicol Appl Pharmacol. 2008;228:256–68.

    Article  CAS  PubMed  Google Scholar 

  47. Ruiz-Torres MP, Perez-Rivero G, Rodriguez-Puyol M, Rodriguez-Puyol D, Diez-Marques ML. The leukocyte-endothelial cell interactions are modulated by extracellular matrix proteins. Cell Physiol Biochem. 2006;17:221–32.

    Article  CAS  PubMed  Google Scholar 

  48. Rose BA, Force T, Wang Y. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev. 2010;90:1507–46.

    Article  CAS  PubMed  Google Scholar 

  49. Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, et al. High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol. 2006;290:C917–24.

    Article  CAS  PubMed  Google Scholar 

  50. Yang H, Tracey KJ. Targeting HMGB1 in inflammation. Biochim Biophys Acta. 2010;1799:149–56.

    Article  CAS  PubMed  Google Scholar 

  51. Palumbo R, Galvez BG, Pusterla T, De Marchis F, Cossu G, Marcu KB, et al. Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-kappaB activation. J Cell Biol. 2007;179:33–40.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF) funded by the Korea government [MEST] (Grant No. 2012-0009400).

Conflict of interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

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

    Hayoung Yoo & Jong-Sup Bae

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

    Sae-Kwang Ku

  3. Department of Clinical Pathology, Daegu Health College, Daegu, 702-722, Republic of Korea

    Young-Doo Baek

Authors
  1. Hayoung Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sae-Kwang Ku
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Young-Doo Baek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. 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

Responsible Editor: Mauro Teixeira.

H. Yoo and S.-K. Ku contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoo, H., Ku, SK., Baek, YD. et al. Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo. Inflamm. Res. 63, 197–206 (2014). https://doi.org/10.1007/s00011-013-0689-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-013-0689-x

Keywords

Search

Navigation