DOI QR코드

DOI QR Code

Inhibitory Effects of Lycopene on the Expression of Pro-inflammatory Genes in Human Vascular Endothelial Cells

혈관내피세포에서 라이코펜이 염증유전자 발현에 미치는 영향

  • Kim, Tae-Hoon (Department of Herbal Medicinal Pharmacology, Daegu Haany University) ;
  • Bae, Jong-Sup (College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University)
  • 김태훈 (대구한의대학교 한약재약리학과) ;
  • 배종섭 (경북대학교 약학과, 약학연구소)
  • Received : 2011.11.26
  • Accepted : 2012.02.17
  • Published : 2012.04.30

Abstract

Lycopene, found in tomatoes and tomato products, has antioxidant, anticancer, and anti-inflammatory effects. High-mobility-group box 1 (HMGB1) mediates the pro-inflammatory responses in several inflammatory diseases. In this study, the potential roles of lycopene in the HMGB1-mediated pro-inflammatory gene expressions in the primary human-umbilical-vein endothelial cells (HUVECs) were investigated. The data showed that HMGB1 upregulated the expressions of monocyte chemotactic protein 1 (MCP-1), interleukin-6 (IL-6), secretory phospholipase A2 (sPLA2)-IIA, and prostaglandin E2 (PGE2). Lycopene pre-incubation for 6 h decreased the HMGB1-mediated induction of MCP-1, IL-6, sPLA2-IIA, and PGE2. Further study revealed that the inhibitory effects of lycopene on the HMGB-1 induced expression of pro-inflammatory genes were mediated by the inhibition of two important inflammatory cytokines: tumor necrosis factor (TNF)-${\alpha}$ and nuclear factor (NF)-${\kappa}B$. These results suggest that HMGB1 upregulated the expression of pro-inflammatory genes and lycopene inhibited HMGB-1-induced pro-inflammatory genes by inhibiting TNF-${\alpha}$ and NF-${\kappa}B$. This finding will serve as an important evidence in the development of a new medicine for the treatment of inflammatory diseases.

본 연구에서는 HMGB1 의해 증가되는 각종 염증관련물질에 대해 라이코펜이 가지는 저해 역할을 규명하고 하였다. 라이코펜은 HMGB1에 의해 증가되는 MCP-1, IL-8, sPLA2-IIA, PGE2의 발현을 NF-${\kappa}B$ 그리고 TNF-${\alpha}$의 활성를 저해함으로써 감소시켰다. 특히, 1 mM에서 그 효능이 통계적으로 유효하였다. 결론적으로 HMGB1에 의해서 발생하는 각종 혈관염증질환에서 라이코펜은 증가하는 각종 염증관련물질을 저해하였고, 결국 라이코펜이 패혈증을 포함하는 염증질환을 효과적으로 치료할 수 있는 방법에 있어 많은 방향성을 제시할 것으로 기대한다.

Keywords

References

  1. Heber D, Lu QY (2002) Overview of mechanisms of action of lycopene. Exp Biol Med (Maywood), 227, 920-923 https://doi.org/10.1177/153537020222701013
  2. Bae JW, Bae JS (2011) Barrier protective effects of lycopene in human endothelial cells. Inflamm Res, 60, 751-758 https://doi.org/10.1007/s00011-011-0330-9
  3. Goodwin GH, Sanders C, Johns EW (1973) A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem, 38, 14-19 https://doi.org/10.1111/j.1432-1033.1973.tb03026.x
  4. Bustin M, Reeves R (1996) High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog Nucleic Acid Res Mol Biol, 54, 35-100 https://doi.org/10.1016/S0079-6603(08)60360-8
  5. Boonyaratanakornkit V, Melvin V, Prendergast P, Altmann M, Ronfani L, Bianchi ME, Taraseviciene L, Nordeen SK, Allegretto EA, Edwards DP (1998) High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells. Mol Cell Biol, 18, 4471-4487 https://doi.org/10.1128/MCB.18.8.4471
  6. Mosevitsky MI, Novitskaya VA, Iogannsen MG, Zabezhinsky MA (1989) Tissue specificity of nucleo-cytoplasmic distribution of HMG1 and HMG2 proteins and their probable functions. Eur J Biochem, 185, 303-310 https://doi.org/10.1111/j.1432-1033.1989.tb15116.x
  7. Andersson U, Tracey KJ (2011) HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immuno, 129, 139-162
  8. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E,Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science, 285, 248-251 https://doi.org/10.1126/science.285.5425.248
  9. Esmon CT, Fukudome K, Mather T, Bode W, Regan LM, Stearns-Kurosawa DJ, Kurosawa S (1999) Inflammation, sepsis, and coagulation. Haematologica, 84, 254-259
  10. Alon R, Shulman Z (2011) Chemokine triggered integrin activation and actin remodeling events guiding lymphocyte migration across vascular barriers. Exp Cell Res, 317, 632-641 https://doi.org/10.1016/j.yexcr.2010.12.007
  11. Castellani ML, De Lutiis MA, Toniato E, Conti F, Felaco P, Fulcheri M, Theoharides T C, Caraffa A, Antinolfi P, Conti P, Cuccurullo C, Ciampoli C, Felaco M, Orso C, Salini V, Cerulli G, Kempuraj D, Tete S, Shaik B (2010) Impact of RANTES, MCP-1 and IL-8 in mast cells. J Biol Regu lHomeost Agents, 24, 1-6
  12. Bradle JR (2008) TNF-mediated inflammatory disease. J Pathol, 214, 149-160 https://doi.org/10.1002/path.2287
  13. Javaid K, Rahman A, Anwar KN, Frey RS, Minshall RD, Malik AB (2003) Tumor necrosis factor-alpha induces early-onset endothelial adhesivity by protein kinase Czeta-dependent activation of intercellular adhesion molecule-1. Circ Res, 92, 1089-1097. https://doi.org/10.1161/01.RES.0000072971.88704.CB
  14. Lockyer JM, Colladay JS, Alperin-Lea WL, Hammond T, Buda AJ (1998) Inhibition of nuclear factor-kappaB-mediated adhesion molecule expression in human endothelial cells. Circ Res, 82, 314-320 https://doi.org/10.1161/01.RES.82.3.314
  15. Marui N, Offermann MK, Swerlick R, Kunsch C, Rosen CA, Ahmad M, Alexander R W, Medford RM (1993) 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, 92, 1866-1874 https://doi.org/10.1172/JCI116778
  16. Jaulmes A, Thierry S, Janvier B, Raymondjean M, Marechal V (2006) Activation of sPLA2-IIA and PGE2 production by high mobility group protein B1 in vascular smooth muscle cells sensitized by IL-1beta. FASEB J, 20, 1727-1729 https://doi.org/10.1096/fj.05-5514fje
  17. Vadas P, Pruzanski W (1986) Role of secretory phospholipases A2 in the pathobiology of disease. Lab Invest, 55, 391-404
  18. Bae JS, Rezaie AR (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. Thromb Haemost, 100, 101-109 https://doi.org/10.1160/TH08-02-0127
  19. Dennis EA (1997) The growing phospholipase A2 superfamily of signal transduction enzymes. Trends Biochem Sci, 22, 1-2 https://doi.org/10.1016/S0968-0004(96)20031-3
  20. Nakano T, Ohara O, Teraoka H, Arita H (1990) Group II phospholipase A2 mRNA synthesis is stimulated by two distinct mechanisms in rat vascular smooth muscle cells. FEBS Lett, 261, 171-174 https://doi.org/10.1016/0014-5793(90)80663-4
  21. Oka S, Arita H (1991) Inflammatory factors stimulate expression of group II phospholipase A2 in rat cultured astrocytes. Two distinct pathways of the gene expression. J Biol Chem, 266, 9956-9960
  22. Menschikowski M, Hagelgans A, Siegert G (2006) Secretory phospholipase A2 of group IIA: is it an offensive or a defensive player during atherosclerosis and other inflammatory diseases? Prostaglandins Other Lipid Mediat, 79, 1-33 https://doi.org/10.1016/j.prostaglandins.2005.10.005
  23. Hajjar DP, Pomerantz KB (1992) Signal transduction in atherosclerosis: integration of cytokines and the eicosanoid network. FASEB J, 6, 2933-2941 https://doi.org/10.1096/fasebj.6.11.1644257
  24. Branen L, Hovgaard L, Nitulescu M, Bengtsson E, Nilsson J, Jovinge S (2004) Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol, 24, 2137-2142 https://doi.org/10.1161/01.ATV.0000143933.20616.1b
  25. Li Y, Schwabe RF, DeVries-Seimon T, Yao PM, Gerbod-Giannone MC., Tall AR, Davis RJ, Flavell R, Brenner DA, Tabas I (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. J Biol Chem, 280, 21763-21772 https://doi.org/10.1074/jbc.M501759200
  26. Stoll LL, Denning GM, Weintraub NL (2006) Endotoxin, TLR4 signaling and vascular inflammation: potential therapeutic targets in cardiovascular disease. Curr Pharm Des, 12, 4229-4245 https://doi.org/10.2174/138161206778743501
  27. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A, Bianchi ME (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J, 22, 5551-5560 https://doi.org/10.1093/emboj/cdg516
  28. Par, JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham, E (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem, 279, 7370-7377 https://doi.org/10.1074/jbc.M306793200
  29. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ (2000) High mobility group1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med, 192, 565-570 https://doi.org/10.1084/jem.192.4.565
  30. Wang H, Yang H, Czura CJ, Sama AE, Tracey KJ (2001) HMGB1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med, 164, 1768-1773 https://doi.org/10.1164/ajrccm.164.10.2106117