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Journal of Neuroinflammation

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Open Access 01-12-2008 | Research

Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression

Authors: Kavon Rezai-Zadeh, Jared Ehrhart, Yun Bai, Paul R Sanberg, Paula Bickford, Jun Tan, R Douglas Shytle

Published in: Journal of Neuroinflammation | Issue 1/2008

Abstract

Background

It is well known that most neurodegenerative diseases are associated with microglia-mediated inflammation. Our previous research demonstrates that the CD40 signaling is critically involved in microglia-related immune responses in the brain. For example, it is well known that the activation of the signal transducer and activator of transcription (STAT) signaling pathway plays a central role in interferon-gamma (IFN-γ)-induced microglial CD40 expression. We and others have previously reported that microglial CD40 expression is significantly induced by IFN-γ and amyloid-β (Aβ) peptide. Recent studies have shown that certain flavonoids possess anti-inflammatory and neuroprotective properties distinct from their well-known anti-oxidant effects. In particular, flavonoids, apigenin and luteolin have been found to be effective CD40 immunomodulators.

Methods

Cultured microglia, both N9 and primary derived lines, were treated with flavonoids in the presence of IFN-γ and/or CD40 ligation to assess any anti-inflammatory effects and/or mechanisms. CD40 expression on microglia was analyzed by fluorescence activated cell sorting (FACS). Anti-inflammatory effects and mechanisms were confirmed by ELISA for interlekin-6 (IL-6) and TNF-α, lactate dehydrogenase (LDH) assay, and STAT1 Western blotting.

Results

Apigenin and luteolin concentration-dependently suppressed IFN-γ-induced CD40 expression. Apigenin and luteolin also suppressed microglial TNF-α and IL-6 production stimulated by IFN-gamma challenge in the presence of CD40 ligation. In addition, apigenin and luteolin markedly inhibited IFN-γ-induced phosphorylation of STAT1 with little impact on cell survival.

Conclusion

Our findings provide further support for apigenin and luteolin's anti-inflammatory effects and suggest that these flavonoids may have neuroprotective/disease-modifying properties in various neurodegenerative disorders, including Alzheimer's disease (AD).

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Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams A: Neuroinflammation in Alzheimer's disease and prion disease. Glia. 2002, 40: 232-239. 10.1002/glia.10146.CrossRefPubMed

Garden GA: Microglia in human immunodeficiency virus-associated neurodegeneration. Glia. 2002, 40: 240-251. 10.1002/glia.10155.CrossRefPubMed

Schubert P, Morino T, Miyazaki H, Ogata T, Nakamura Y, Marchini C, Ferroni S: Cascading glia reactions: a common pathomechanism and its differentiated control by cyclic nucleotide signaling. Ann N Y Acad Sci. 2000, 903: 24-33. 10.1111/j.1749-6632.2000.tb06346.x.CrossRefPubMed

Tan J, Town T, Paris D, Placzek A, Parker T, Crawford F, Yu H, Humphrey J, Mullan M: Activation of microglial cells by the CD40 pathway: relevance to multiple sclerosis. Neuroimmunol. 1999, 97: 77-85. 10.1016/S0165-5728(99)00053-3.CrossRef

Hall ED, Oostveen JA, Gurney ME: Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia. 1998, 23: 249-256. 10.1002/(SICI)1098-1136(199807)23:3<249::AID-GLIA7>3.0.CO;2-#.CrossRefPubMed

Barger SW, Harmon AD: Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature. 1997, 388: 878-881. 10.1038/42257.CrossRefPubMed

Raine C: Multiple sclerosis: immune system molecule expression in the central nervous system. J Neuropathol Exp Neurol. 1994, 53: 328-337. 10.1097/00005072-199407000-00002.CrossRefPubMed

Dickson DW, Lee SC, Mattiace LA, Yen SH, Brosnan C: Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease. Glia. 1993, 7: 75-83. 10.1002/glia.440070113.CrossRefPubMed

Kawamata T, Akiyama H, Yamada T, McGeer PL: Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992, 140: 691-707.PubMedCentralPubMed

10.

Yamada T, McGeer PL, McGeer EG: Relationship of complement-activated oligodendrocytes to reactive microglia and neuronal pathology in neurodegenerative disease. Dementia. 1991, 2: 71-77. 10.1159/000107179.

11.

McGeer PL, Itagaki S, Boyes BE, McGeer EG: Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology. 1988, 38: 1285-1291.CrossRefPubMed

12.

Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD: Peroxynitrite mediates neurotoxicity of amyloid β-peptide1-42-and lipopolysaccharide-activated microglia. J Neurosci. 2002, 22: 3484-3492.PubMed

13.

McGuire SO, Ling ZD, Lipton JW, Sortwell CE, Collier TJ, Carvey PM: Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons. Exp Neurol. 2001, 169: 219-230. 10.1006/exnr.2001.7688.CrossRefPubMed

14.

Jeohn G-H, Kong L-Y, Wilson B, Hudson P, Hong J-S: Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures. J Neuroimmuno. 1998, 85: 1-10. 10.1016/S0165-5728(97)00204-X.CrossRef

15.

Chao CC, Hu S, Ehrlich L, Peterson PK: Interleukin-1 and tumor necrosis factor-α synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behav Immun. 1995, 9: 355-365. 10.1006/brbi.1995.1033.CrossRefPubMed

16.

Boje KM, Arora PK: Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res. 1992, 587: 250-6. 10.1016/0006-8993(92)91004-X.CrossRefPubMed

17.

Chao CC, Hu S, Molitor TW, Shaskan EG, Peterson PK: Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol. 1992, 149: 2736-2741.PubMed

18.

Streit WJ: Microglia and neuroprotection: implications for Alzheimer's disease. Brain Res Brain Res Rev. 2005, 48: 234-9. 10.1016/j.brainresrev.2004.12.013.CrossRefPubMed

19.

Alderson MR, Armitage RJ, Tough TW, Strockbine L, Fanslow WC, Spriggs MK: CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40. J Exp Med. 1993, 178: 669-74. 10.1084/jem.178.2.669.CrossRefPubMed

20.

van Kooten C, Banchereau J: CD40-CD40 ligand. J Leukoc Biol. 2000, 67: 2-17.PubMed

21.

Grewal IS, Flavell RA: CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol. 1998, 16: 111-135. 10.1146/annurev.immunol.16.1.111.CrossRefPubMed

22.

Nguyen VT, Walker WS: Benveniste EN, Post-transcriptional inhibition of CD40 gene expression in microglia by transforming growth factor-beta. Eur J Immunol. 1998, 28: 2537-2548. 10.1002/(SICI)1521-4141(199808)28:08<2537::AID-IMMU2537>3.0.CO;2-1.CrossRefPubMed

23.

Boehm U, Klamp T, Groot M, Howard JC: Cellular responses to interferon-gamma. Annu Rev Immunol. 1997, 15: 749-795. 10.1146/annurev.immunol.15.1.749.CrossRefPubMed

24.

Seder , Paul RA, Seder , Paul WE: Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994, 12: 635-673. 10.1146/annurev.iy.12.040194.003223.CrossRefPubMed

25.

Nguyen VT, Benveniste EN: Involvement of STAT-1 and ets family members in interferon-gamma induction of CD40 transcription in microglia/macrophages. J Biol Chem. 2000, 275: 23674-84. 10.1074/jbc.M002482200.CrossRefPubMed

26.

Leonard WJ, O'Shea JJ: Jaks and STATs: biological implications. Annu Rev Immunol. 1998, 16: 293-322. 10.1146/annurev.immunol.16.1.293.CrossRefPubMed

27.

Townsend KP, Town T, Mori T, Lue LF, Shytle D, Sanberg PR, Morgan D, Fernandez F, Flavell RA, Tan J: CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid beta-peptide. Eur J Immunol. 2005, 35: 901-10. 10.1002/eji.200425585.CrossRefPubMed

28.

Townsend KP, Shytle DR, Bai Y, San N, Zeng J, Freeman M, Mori T, Fernandez F, Morgan D, Sanberg P, Tan J: Lovastatin modulation of microglial activation via suppression of functional CD40 expression. J Neurosci Res. 2004, 78: 167-76. 10.1002/jnr.20234.CrossRefPubMed

29.

Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB: Fruit and vegetable juices and Alzheimer's disease: the Kame Project. Am J Med. 2006, 119: 751-9. 10.1016/j.amjmed.2006.03.045.PubMedCentralCrossRefPubMed

30.

Genkinger JM, Platz EA, Hoffman SC, Comstock GW, Helzlsouer KJ: Fruit, vegetable, and antioxidant intake and all-cause, cancer, and cardiovascular disease mortality in a community-dwelling population in Washington County, Maryland. Am J Epidemiol. 2004, 160: 1223-33.CrossRefPubMed

31.

Laurin D, Masaki KH, Foley DJ, White LR, Launer LJ: Midlife Dietary Intake of Antioxidants and Risk of Late-Life Incident Dementia: The Honolulu-Asia Aging Study. Am J Epidemiol. 2004, 159: 959-967. 10.1093/aje/kwh124.CrossRefPubMed

32.

Bastianetto S: Red wine consumption and brain aging. Nutrition. 2002, 18: 432-3. 10.1016/S0899-9007(01)00745-6.CrossRefPubMed

33.

Sun AY, Simonyi A, Sun GY: The "French Paradox" and beyond: neuroprotective effects of polyphenols. Free Radic Biol Med. 2002, 32: 314-8. 10.1016/S0891-5849(01)00803-6.CrossRefPubMed

34.

Sampson L, Rimm E, Hollman PC, de Vries JH, Katan MB: Flavonol and flavone intakes in US health professionals. J Am Diet Assoc. 2002, 102: 1414-20. 10.1016/S0002-8223(02)90314-7.CrossRefPubMed

35.

Nielsen SE, Young JF, Daneshvar B, Lauridsen ST, Knuthsen P, Sandstrom B, Dragsted LO: Effect of parsley (Petroselinum crispum) intake on urinary apigenin excretion, blood antioxidant enzymes and biomarkers for oxidative stress in human subjects. Br J Nutr. 1999, 81: 447-55.PubMed

36.

van Acker SA, Berg van den DJ, Tromp MN: Structural aspects of antioxidant activity of flavonoids. Free Rad Biol Med. 1996, 20: 331-342. 10.1016/0891-5849(95)02047-0.CrossRefPubMed

37.

Saija A, Scalese M, Lanza M, Marzullo D, Bonina F: Flavonoids as antioxidant agents: importance of their interaction with biomembranes. Free Rad Biol Med. 1995, 19: 481-486. 10.1016/0891-5849(94)00240-K.CrossRefPubMed

38.

Kanadaswami C, Lee LT, Lee PP, Hwang JJ, Ke FC, Huang YT, Lee MT: The antitumor activities of flavonoids. In Vivo. 2005, 19: 895-909.PubMed

39.

Ren W, Qiao Z, Wang H, Zhu L, Zhang L: Flavonoids: promising anticancer agents. Med Res Rev. 2003, 23: 519-34. 10.1002/med.10033.CrossRefPubMed

40.

Ferrandiz ML, Gil B, Sanz MJ: Effect of bakuchiol on leukocyte functions and some inflammatory responses in mice. J Pharm Pharmacol. 1996, 48: 975-80.CrossRefPubMed

41.

Friesenecker B, Tsai AG, Allegra C, Intaglietta M: Oral administration of purified micronized flavonoid fraction suppresses leukocyte adhesion in ischemia-reperfusion injury: in vivo observations in the hamster skin fold. Int J Microcirc Clin Exp. 1994, 14: 50-5.CrossRefPubMed

42.

Bennett JP, Gomperts BD, Wollenweber E: Inhibitory effects of natural flavonoids on secretion from mast cells and neutrophils. Arzneimittelforschung. 1981, 31: 433-7.PubMed

43.

Yoon MS, Lee JS, Choi BM, Jeong YI, Lee CM, Park JH, Moon Y, Sung SC, Lee SK, Chang YH, Chung HY, Park YM: Apigenin inhibits immunostimulatory function of dendritic cells: Implication of immunotherapeutic adjuvant. Mol Pharmacol. 2006, 70 (3): 1033-1044. 10.1124/mol.106.024547.CrossRefPubMed

44.

Hirano T, Arimitsu J, Higa S, Naka T, Ogata A, Shima Y, Fujimoto M, Yamadori T, Ohkawara T, Kuwabara Y, Kawai M, Kawase I, Tanaka T: Luteolin, a flavonoid, inhibits CD40 ligand expression by activated human basophils. Int Arch Allergy Immunol. 2006, 40: 150-6. 10.1159/000092554.CrossRef

45.

Ueda H, Yamazaki C, Yamazaki M: A hydroxyl group of flavonoids affects oral anti-inflammatory activity and inhibition of systemic tumor necrosis factor-alpha production. Biosci Biotechnol Biochem. 2004, 68: 119-25. 10.1271/bbb.68.119.CrossRefPubMed

46.

Smolinski AT, Pestka JJ: Modulation of lipopolysaccharide-induced proinflammatory cytokine production in vitro and in vivo by the herbal constituents apigenin (chamomile), ginsenoside Rb(1) (ginseng) and parthenolide (feverfew). Food Chem Toxicol. 2003, 41: 1381-90. 10.1016/S0278-6915(03)00146-7.CrossRefPubMed

47.

Raso GM, Meli R, Di Carlo G, Pacilio M, Di Carlo R: Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1. Life Sci. 2001, 68: 921-31. 10.1016/S0024-3205(00)00999-1.CrossRefPubMed

48.

Liang YC, Tsai SH, Tsai DC, Lin-Shiau SY, Lin JK: Suppression of inducible cyclooxygenase and nitric oxide synthase through activation of peroxisome proliferator-activated receptor-gamma by flavonoids in mouse macrophages. FEBS Lett. 2001, 496: 12-8. 10.1016/S0014-5793(01)02393-6.CrossRefPubMed

49.

Gerritsen ME, Carley WW, Ranges GE, Shen CP, Phan SA, Ligon GF, Perry CA: Flavonoids inhibit cytokine-induced endothelial cell adhesion protein gene expression. Am J Pathol. 1995, 147: 278-92.PubMedCentralPubMed

50.

Tan J, Town T, Saxe M, Paris D, Wu Y: Mullan M, Ligation of microglial CD40 results in p44/42 mitogen-activated protein kinase-dependent TNF-alpha production that is opposed by TGF-beta 1 and IL-10. J Immunol. 1999, 163: 6614-21.PubMed

51.

Corradin SB, Mauël J, Donini SD, Quattrocchi E, Ricciardi-Castagnoli P: Inducible nitric oxide synthase activity of cloned murine microglial cells. Glia. 1993, 7: 255-62. 10.1002/glia.440070309.CrossRefPubMed

52.

Matsuo M, Sasaki N, Saga K, Kaneko T: Cytotoxicity of flavonoids toward cultured normal human cells. Biol Pharm Bull. 2005, 28: 253-9. 10.1248/bpb.28.253.CrossRefPubMed

53.

Kovarik P, Mangold M, Ramsauer K: Specificity of signaling by STAT1 depends on SH2 and C-terminal domains that regulate Ser727 phosphorylation, differentially affecting specific target gene expression. EMBO J. 2001, 20: 91-100. 10.1093/emboj/20.1.91.PubMedCentralCrossRefPubMed

54.

Goh KC, Haque SJ, Williams BR: p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. EMBO J. 1999, 18: 5601-8. 10.1093/emboj/18.20.5601.PubMedCentralCrossRefPubMed

55.

Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP: Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem Pharmacol. 2005, 69: 1421-32. 10.1016/j.bcp.2005.02.022.CrossRefPubMed

56.

Zheng PW, Chiang LC, Lin CC: Apigenin induced apoptosis through p53-dependent pathway in human cervical carcinoma cells. Life Sci. 2005, 76: 1367-79. 10.1016/j.lfs.2004.08.023.CrossRefPubMed

57.

Elsisi NS, Darling-Reed S, Lee EY, Oriaku ET, Soliman KF: Ibuprofen and apigenin induce apoptosis and cell cycle arrest in activated microglia. Neurosci Lett. 2005, 375: 91-6. 10.1016/j.neulet.2004.10.087.CrossRefPubMed

58.

Townsend PA, Scarabelli TM, Davidson SM, Knight RA, Latchman DS, Stephanou A: STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis. J Biol Chem. 2004, 279: 5811-20. 10.1074/jbc.M302637200.CrossRefPubMed

59.

Stephanou A, Scarabelli TM, Brar BK, Nakanishi Y, Matsumura M, Knight RA, Latchman DS: Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701. J Biol Chem. 2001, 276: 28340-7. 10.1074/jbc.M101177200.CrossRefPubMed

60.

Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR: Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science. 1997, 278: 1630-2. 10.1126/science.278.5343.1630.CrossRefPubMed

61.

Tan J, Town T, Mori T, Obregon D, Wu Y, DelleDonne A, Rojiani A, Crawford F, Flavell RA, Mullan M: CD40 is expressed and functional on neuronal cells. EMBO J. 2002, 21: 643-52. 10.1093/emboj/21.4.643.PubMedCentralCrossRefPubMed

62.

Nguyen H, Ramana CV, Bayes J, Stark GR: Roles of phosphatidylinositol 3-kinase in interferon-gamma-dependent phosphorylation of STAT1 on serine 727 and activation of gene expression. J Biol Chem. 2001, 276: 33361-8. 10.1074/jbc.M105070200.CrossRefPubMed

63.

Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, Griffiths E, Krawczyk C, Richardson CD, Aitken K, Iscove N, Koretzky G, Johnson P, Liu P, Rothstein DM, Penninger JM: CD45 is a JAK phosphatase and negatively regulates cytokine receptor signaling. Nature. 2001, 409: 349-54. 10.1038/35053086.CrossRefPubMed

64.

Manach C, Williamson G, Morand C, Scalbert A, Remesy C: Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr. 2005, 81: 230S-42S.PubMed

65.

Gradolatto A, Basly JP, Berges R, Teyssier C, Chagnon MC, Siess MH, Canivenc-Lavier MC: Pharmacokinetics and metabolism of apigenin in female and male rats after a single oral administration. Drug Metab Dispos. 2005, 33: 49-54. 10.1124/dmd.104.000893.CrossRefPubMed

66.

Gradolatto A, Canivenc-Lavier MC, Basly JP, Siess MH, Teyssier C: Metabolism of apigenin by rat liver phase I and phase ii enzymes and by isolated perfused rat liver. Drug Metab Dispos. 2004, 32: 58-65. 10.1124/dmd.32.1.58.CrossRefPubMed

67.

Li LP, Jiang HD: Determination and assay validation of luteolin and apigenin in human urine after oral administration of tablet of Chrysanthemum morifolium extract by HPLC. J Pharm Biomed Anal. 2006, 41: 261-5. 10.1016/j.jpba.2005.10.019.CrossRefPubMed

Title: Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression
Authors: Kavon Rezai-Zadeh
Jared Ehrhart
Yun Bai
Paul R Sanberg
Paula Bickford
Jun Tan
R Douglas Shytle
Publication date: 01-12-2008
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2008
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-5-41

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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