DOI QR코드

DOI QR Code

Luteolin and luteolin-7-O-glucoside inhibit lipopolysaccharide-induced inflammatory responses through modulation of NF-${\kappa}B$/AP-1/PI3K-Akt signaling cascades in RAW 264.7 cells

  • Park, Chung Mu ;
  • Song, Young-Sun
  • Received : 2013.04.09
  • Accepted : 2013.09.02
  • Published : 2013.12.01

Abstract

Luteolin is a flavonoid found in abundance in celery, green pepper, and dandelions. Previous studies have shown that luteolin is an anti-inflammatory and anti-oxidative agent. In this study, the anti-inflammatory capacity of luteolin and one of its glycosidic forms, luteolin-7-O-glucoside, were compared and their molecular mechanisms of action were analyzed. In lipopolysaccharide (LPS)-activated RAW 264.7 cells, luteolin more potently inhibited the production of nitric oxide (NO) and prostaglandin E2 as well as the expression of their corresponding enzymes (inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) than luteolin-7-O-glucoside. The molecular mechanisms underlying these effects were investigated to determine whether the inflammatory response was related to the transcription factors, nuclear factor (NF)-${\kappa}B$ and activator protein (AP)-1, or their upstream signaling molecules, mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K). Luteolin attenuated the activation of both transcription factors, NF-${\kappa}B$ and AP-1, while luteolin-7-O-glucoside only impeded NF-${\kappa}B$ activation. However, both flavonoids inhibited Akt phosphorylation in a dose-dependent manner. Consequently, luteolin more potently ameliorated LPS-induced inflammation than luteolin-7-O-glucoside, which might be attributed to the differentially activated NF-${\kappa}B$/AP-1/PI3K-Akt pathway in RAW 264.7 cells.

Keywords

Luteolin;luteolin-7-O-glucoside;NF-${\kappa}B$;AP-1;PI3K;RAW

References

  1. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 2001;480-481:243-68. https://doi.org/10.1016/S0027-5107(01)00183-X
  2. Fujioka S, Niu J, Schmidt C, Sclabas GM, Peng B, Uwagawa T, Li Z, Evans DB, Abbruzzese JL, Chiao PJ. NF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity. Mol Cell Biol 2004;24:7806-19. https://doi.org/10.1128/MCB.24.17.7806-7819.2004
  3. Kim YW, West XZ, Byzova TV. Inflammation and oxidative stress in angiogenesis and vascular disease. J Mol Med (Berl) 2013;91:323-8. https://doi.org/10.1007/s00109-013-1007-3
  4. Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003;3:768-80. https://doi.org/10.1038/nrc1189
  5. Biesalski HK. Polyphenols and inflammation: basic interactions. Curr Opin Clin Nutr Metab Care 2007;10:724-8. https://doi.org/10.1097/MCO.0b013e3282f0cef2
  6. Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000;52:673-751.
  7. Richelle M, Pridmore-Merten S, Bodenstab S, Enslen M, Offord EA. Hydrolysis of isoflavone glycosides to aglycones by ss-glycosidase does not alter plasma and urine isoflavone pharmacokinetics in postmenopausal women. J Nutr 2002;132:2587-92. https://doi.org/10.1093/jn/132.9.2587
  8. Kano M, Takayanagi T, Harada K, Sawada S, Ishikawa F. Bioavailability of isoflavones after ingestion of soy beverages in healthy adults. J Nutr 2006;136:2291-6. https://doi.org/10.1093/jn/136.9.2291
  9. Murota K, Shimizu S, Miyamoto S, Izumi T, Obata A, Kikuchi M, Terao J. Unique uptake and transport of isoflavone aglycones by human intestinal Caco-2 cells: comparison of isoflavonoids and flavonoids. J Nutr 2002;132:1956-61. https://doi.org/10.1093/jn/132.7.1956
  10. Zhou P, Li LP, Luo SQ, Jiang HD, Zeng S. Intestinal absorption of luteolin from peanut hull extract is more efficient than that from individual pure luteolin. J Agric Food Chem 2008;56: 296-300. https://doi.org/10.1021/jf072612+
  11. Izumi T, Piskula MK, Osawa S, Obata A, Tobe K, Saito M, Kataoka S, Kubota Y, Kikuchi M. Soy isoflavone aglycones are absorbed faster and in higher amounts than their glucosides in humans. J Nutr 2000;130:1695-9. https://doi.org/10.1093/jn/130.7.1695
  12. Andlauer W, Kolb J, Fürst P. Isoflavones from tofu are absorbed and metabolized in the isolated rat small intestine. J Nutr 2000;130:3021-7. https://doi.org/10.1093/jn/130.12.3021
  13. Piskula MK. Factors affecting flavonoids absorption. Biofactors 2000;12:175-80. https://doi.org/10.1002/biof.5520120128
  14. Zubik L, Meydani M. Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women. Am J Clin Nutr 2003;77:1459-65. https://doi.org/10.1093/ajcn/77.6.1459
  15. Seelinger G, Merfort I, Schempp CM. Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med 2008;74: 1667-77. https://doi.org/10.1055/s-0028-1088314
  16. Rowland I, Faughnan M, Hoey L, Wähälä K, Williamson G, Cassidy A. Bioavailability of phyto-oestrogens. Br J Nutr 2003;89 Suppl 1:S45-58.
  17. Park CM, Park JY, Noh KH, Shin JH, Song YS. Taraxacum officinale Weber extracts inhibit LPS-induced oxidative stress and nitric oxide production via the NF-$\kappa$B modulation in RAW 264.7 cells. J Ethnopharmacol 2011;133:834-42. https://doi.org/10.1016/j.jep.2010.11.015
  18. Chen CY, Peng WH, Tsai KD, Hsu SL. Luteolin suppresses inflammation-associated gene expression by blocking NF-kappaB and AP-1 activation pathway in mouse alveolar macrophages. Life Sci 2007;81:1602-14. https://doi.org/10.1016/j.lfs.2007.09.028
  19. Hu C, Kitts DD. Luteolin and luteolin-7-O-glucoside from dandelion flower suppress iNOS and COX-2 in RAW264.7 cells. Mol Cell Biochem 2004;265:107-13. https://doi.org/10.1023/B:MCBI.0000044364.73144.fe
  20. Hwang JT, Park OJ, Lee YK, Sung MJ, Hur HJ, Kim MS, Ha JH, Kwon DY. Anti-tumor effect of luteolin is accompanied by AMP-activated protein kinase and nuclear factor-κB modulation in HepG2 hepatocarcinoma cells. Int J Mol Med 2011;28:25-31.
  21. Park CM, Jin KS, Lee YW, Song YS. Luteolin and chicoric acid synergistically inhibited inflammatory responses via inactivation of PI3K-Akt pathway and impairment of NF-${\kappa}B$ translocation in LPS stimulated RAW 264.7 cells. Eur J Pharmacol 2011;660: 454-9. https://doi.org/10.1016/j.ejphar.2011.04.007
  22. Schutz K, Kammerer DR, Carle R, Schieber A. Characterization of phenolic acids and flavonoids in dandelion (Taraxacum officinale WEB. ex WIGG.) root and herb by high-performance liquid chromatography/electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom 2005;19:179-86. https://doi.org/10.1002/rcm.1767
  23. Jin M, Yang JH, Lee E, Lu Y, Kwon S, Son KH, Son JK, Chang HW. Antiasthmatic activity of luteolin-7-O-glucoside from Ailanthus altissima through the downregulation of T helper 2 cytokine expression and inhibition of prostaglandin E2 production in an ovalbumin-induced asthma model. Biol Pharm Bull 2009;32: 1500-3. https://doi.org/10.1248/bpb.32.1500
  24. Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 2002;22:19-34. https://doi.org/10.1146/annurev.nutr.22.111401.144957
  25. Verschooten L, Smaers K, Van Kelst S, Proby C, Maes D, Declercq L, Agostinis P, Garmyn M. The flavonoid luteolin increases the resistance of normal, but not malignant keratinocytes, against UVB-induced apoptosis. J Invest Dermatol 2010;130:2277-85. https://doi.org/10.1038/jid.2010.124
  26. Baskar AA, Ignacimuthu S, Michael GP, Al Numair KS. Cancer chemopreventive potential of luteolin-7-O-glucoside isolated from Ophiorrhiza mungos Linn. Nutr Cancer 2011;63:130-8.
  27. Jung HA, Jin SE, Min BS, Kim BW, Choi JS. Anti-inflammatory activity of Korean thistle Cirsium maackii and its major flavonoid, luteolin 5-O-glucoside. Food Chem Toxicol 2012;50:2171-9. https://doi.org/10.1016/j.fct.2012.04.011
  28. Hollman PC, Katan MB. Health effects and bioavailability of dietary flavonols. Free Radic Res 1999;31 Suppl:S75-80. https://doi.org/10.1080/10715769900301351
  29. Lee JP, Li YC, Chen HY, Lin RH, Huang SS, Chen HL, Kuan PC, Liao MF, Chen CJ, Kuan YH. Protective effects of luteolin against lipopolysaccharide-induced acute lung injury involves inhibition of MEK/ERK and PI3K/Akt pathways in neutrophils. Acta Pharmacol Sin 2010;31:831-8. https://doi.org/10.1038/aps.2010.62
  30. Jang S, Kelley KW, Johnson RW. Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci U S A 2008;105:7534-9. https://doi.org/10.1073/pnas.0802865105
  31. Park CM, Jin KS, Cho CW, Lee YW, Huh GH, Cha YS, Song YS. Luteolin inhibits inflammatory responses by down-regulating the JNK-NF$\kappa$B and AP-1 pathways in TNF-$\alpha$ activated HepG2 cells. Food Sci Biotechnol 2012;21:279-83. https://doi.org/10.1007/s10068-012-0037-x
  32. Oh J, Kim JH, Park JG, Yi YS, Park KW, Rho HS, Lee MS, Yoo JW, Kang SH, Hong YD, Shin SS, Cho JY. Radical scavenging activity-based and AP-1-targeted anti-inflammatory effects of lutein in macrophage-like and skin keratinocytic cells. Mediators Inflamm 2013;2013:787042.

Cited by

  1. Anti-Inflammatory Potential of Newly Synthesized 4-[(Butylsulfinyl)methyl]-1,2-benzenediol in Lipopolysaccharide-Stimulated BV2 Microglia vol.19, pp.10, 2014, https://doi.org/10.3390/molecules191016609
  2. Anti-Inflammatory Action of Isorhamnetin vol.37, pp.4, 2014, https://doi.org/10.1007/s10753-014-9846-9
  3. vol.8, pp.3, 2014, https://doi.org/10.4162/nrp.2014.8.3.267
  4. Comparative study of anti-angiogenic activities of luteolin, lectin and lupeol biomolecules vol.13, pp.1, 2015, https://doi.org/10.1186/s12967-015-0665-z
  5. B-Mediated Inflammatory Response vol.2015, pp.1466-1861, 2015, https://doi.org/10.1155/2015/143025
  6. Modulation of Insulin Sensitivity of Hepatocytes by the Pharmacological Downregulation of Phospholipase D vol.2015, pp.1687-8345, 2015, https://doi.org/10.1155/2015/794838
  7. Biological evaluation of synthetic chalcone and flavone derivatives as anti-inflammatory agents vol.24, pp.4, 2015, https://doi.org/10.1007/s00044-014-1214-7
  8. Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin vol.36, pp.7, 2015, https://doi.org/10.1002/bdd.1956
  9. Anti-atherogenic effect of Humulus japonicus in apolipoprotein E-deficient mice vol.38, pp.4, 2016, https://doi.org/10.3892/ijmm.2016.2727
  10. Luteolin attenuates endotoxin-induced uveitis in Lewis rats vol.78, pp.8, 2016, https://doi.org/10.1292/jvms.16-0118
  11. Enhanced Anti-Inflammatory Activities by the Combination of Luteolin and Tangeretin vol.81, pp.5, 2016, https://doi.org/10.1111/1750-3841.13300
  12. -D-glucopyranosyloxy)-3-phenylpropenoic acid in prevention of metabolic syndrome pp.1549-7852, 2016, https://doi.org/10.1080/10408398.2016.1157568
  13. Effects of luteolin and luteolin-morphine co-administration on acute and chronic pain and sciatic nerve ligated-induced neuropathy in mice vol.14, pp.1, 2017, https://doi.org/10.1515/jcim-2016-0066
  14. . vol.14, pp.9, 2017, https://doi.org/10.1002/cbdv.201700150
  15. Thermal treatment of luteolin-7-O-β-glucoside improves its immunomodulatory and antioxidant potencies vol.22, pp.6, 2017, https://doi.org/10.1007/s12192-017-0808-7
  16. Inhibitory effect of the Pseudobrickellia brasiliensis (Spreng) R.M. King & H. Rob. aqueous extract on human lymphocyte proliferation and IFN-γ and TNF-α production in vitro vol.50, pp.8, 2017, https://doi.org/10.1590/1414-431x20175163
  17. Luteolin suppresses the JAK/STAT pathway in a cellular model of intestinal inflammation vol.8, pp.1, 2017, https://doi.org/10.1039/C6FO01529H
  18. and Their Comparative Anti-Inflammatory Activity in Lipopolysaccharide-Stimulated RAW 264.7 Cells vol.18, pp.1, 2015, https://doi.org/10.1089/jmf.2014.3205
  19. B Activation and Induction of Heme Oxygenase-1 vol.18, pp.5, 2015, https://doi.org/10.1089/jmf.2014.3262
  20. Development of a Cell-Based High-Throughput Screening Assay to Identify Porcine Host Defense Peptide-Inducing Compounds vol.2018, pp.2314-7156, 2018, https://doi.org/10.1155/2018/5492941
  21. Aspalathus linearis (Rooibos) – a functional food targeting cardiovascular disease vol.9, pp.10, 2018, https://doi.org/10.1039/C8FO01010B
  22. Luteoloside Protects the Uterus from Staphylococcus aureus-Induced Inflammation, Apoptosis, and Injury vol.41, pp.5, 2018, https://doi.org/10.1007/s10753-018-0814-7
  23. The Flavone Luteolin Improves Central Nervous System Disorders by Different Mechanisms: A Review vol.65, pp.4, 2018, https://doi.org/10.1007/s12031-018-1094-2
  24. vol.34, pp.2, 2018, https://doi.org/10.5487/TR.2018.34.2.133