Download PDF
Thromb Haemost 1997; 77(04): 772-782
DOI: 10.1055/s-0038-1656049
Vessel Wall
Schattauer GmbH Stuttgart

The Dietary Pigment Curcumin Reduces Endothelial Tissue Factor Gene Expression by Inhibiting Binding of AP-1 to the DNA and Activation of NF-κB

Angelika Bierhaus
1   The Department of Internal Medicine I, University of Heidelberg, Germany
,
Youming Zhang
1   The Department of Internal Medicine I, University of Heidelberg, Germany
,
Peter Quehenberger
2   The Allgemeines Krankenhaus Wien, Austria
,
Thomas Luther
3   The Institute for Pathology, Technical University Dresden, Germany
,
Michael Haase
3   The Institute for Pathology, Technical University Dresden, Germany
,
Martin Müller
3   The Institute for Pathology, Technical University Dresden, Germany
,
Nigel Mackman
4   The Department of Immunology, Scripps Institute, La Jolla, USA
,
Reinhard Ziegler
1   The Department of Internal Medicine I, University of Heidelberg, Germany
,
Peter P Nawroth
1   The Department of Internal Medicine I, University of Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Received 25 June 1996

Accepted after resubmission 19 December 1996

Publication Date:
11 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

The natural occurring pigment curcumin, a major component of the spice tumeric, has been described to have antioxidative, antitumorpro moting, anti-thrombotic and anti-inflammatory properties. It appears, that the pleiotropic effects of curcumin are at least partly due to inhibi tion of the transcription factors NF-κB and AP-1. This study investi gates the effect of curcumin on the TNFa induced expression of endo thelial Tissue Factor (TF), the central mediator of coagulation known to be controlled by AP-1 and NF-κ When bovine aortic endothelial cells (B AEC) were preincubated in the presence of curcumin, TNFα induced TF gene transcription and expression were reduced. Transient transfec tion studies with TF-promoter plasmids revealed that both, NF-κ and AP-1 dependent TF expression, were reduced by curcumin action. The observed inhibitions were due to distinct mechanisms. Curcumininhib ited TNFa induced kBa degradation and the nuclear import of NF-κB. In contrast, inhibition of AP-1 was due to a direct interaction of curcu min with AP-1-binding to its DNA binding motif. Thus, curcumin inhibits NF-κB and AP-1 by two different mechanisms and reduces expression of endothelial genes controlled by both transcription factors in vitro.

 

  • References

  • 1 Collins T. Endothelial nuclear factor-kappa B and the initiation of the athe rosclerotic lesion. Lab Invest 1993; 68: 499-508
    PubMedGoogle Scholar
  • 2 Liao F, Andalibi A, deBeer FC, Fogelman AM, Lusis AJ. Genetic control of inflammatory gene induction and NF-kappa B-like transcription factor acti vation in response to an atherogenic diet in mice. J Clin Invest 1993; 91: 2572-2579
    CrossrefPubMedGoogle Scholar
  • 3 Henning B, Diana JN, Toborek M, Me ClainCJ. Influence of nutrients and cytokines on endothelial cell metabolism. J Am Coll Nutr 1994; 13: 224-231
    CrossrefPubMedGoogle Scholar
  • 4 Read MA, Whitley MZ, Williams AJ, Collins T. NF-kappa B and I kappa B alpha: an inducible regulatory system in endothelial activation. J Exp Med 1994; 179: 503-512
    CrossrefPubMedGoogle Scholar
  • 5 Semau T, Bierhaus A, Tritschler T, Ziegler R, Wahl P, Nawroth PP. Thioc tic acid prevents AGE mediated Tissue Factor induction by blocking trans location of(NF-κB) in vitro and in vivo. Ann of Hematol 1995; 70: 305
    PubMedGoogle Scholar
  • 6 Wautier JL, Wautier MP, Schmidt AM, Anderson GM, Hori O, Zoukourian C, Capron L, Chappey O, Yan SD, Brett J. et al. Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications. Proc Natl Acad Sci USA 1994; 91: 7742-7746
    CrossrefPubMedGoogle Scholar
  • 7 Bierhaus A, Hemmer C, Mackman N, Kutob R, Ziegler R, Dietrich M, Nawroth PP. Antiparasitic treatment of patients with p. falciparum malaria reduces the ability of patients serum to induce tissue factor by decreasing (NF-κB) activation. Thromb Haemost 1995; 73: 39-48
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Bierman EL. George Lyman Duff Memorial Lecture. Atherogenesis in diabetes. Arterioscler Thromb 1992; 12: 647-656
    CrossrefPubMedGoogle Scholar
  • 9 Mohanty S, Mishra SK, Das BS, Satpathy SK, Mohanty D, Patnaik JK, Bose TK. Altered plasma lipid pattern in falciparum malaria. Ann Trop Med Parasitol 1992; 86: 601-606
    CrossrefPubMedGoogle Scholar
  • 10 Gey KF, Moser UK, Jordan P, Stahelin HB, Eichholzer M, Ludin E. Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: an epidemiological update with special attention to carotene and vitamin C. Am J Clin Nutr 1993; 57: 787-797
    CrossrefPubMedGoogle Scholar
  • 11 Gaziano JM, Manson JE, Buring JE, Hennekens CH. Dietary antioxidants and cardiovascular disease. Ann N Y Acad Sci 1992; 669: 249-258
    CrossrefPubMedGoogle Scholar
  • 12 Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men [see comments]. N Engl J Med 1993; 328: 1450-1456
    CrossrefPubMedGoogle Scholar
  • 13 Steinberg D. Antioxidant vitamins and coronary heart disease [editorial; comment]. N Engl J Med 1993; 328: 1487-1489
    CrossrefPubMedGoogle Scholar
  • 14 Meyer M, Schreck R, Baeuerle PA. H202 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. Embo J 1993; 12: 2005-2015
    PubMedGoogle Scholar
  • 15 Meyer M, Pahl H, Baeuerle PA. Regulation of the transcription factors (NF-κB) and AP-1 by redox changes. Chem Biol Interact 1994; 91: 94-100
    PubMedGoogle Scholar
  • 16 Schenk H, Klein M, Erdbrugger W, Droge W, Schulze-Osthoff K. Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-kappa B and AP-1. Proc Natl Acad Sci USA 1994; 91: 1672-1676
    CrossrefPubMedGoogle Scholar
  • 17 Bierhaus A, Zhang Y, Deng Y, Mackman N, Quehenberger P, Haase M, Luther T, Muller M, Bohrer H, Greten J, Martin E, Baeuerle PA, Waldherr R, Kisiel W, Ziegler R, Stem DM, Nawroth PP. Mechanism of the TNFa mediated induction of endothelial tissue factor. J Biol Chem 1995; 270: 26419-26432
    CrossrefPubMedGoogle Scholar
  • 18 Mackman N, Fowler BJ, Edgington TS, Morrissey JH. Functional analysis of the human tissue factor promoter and induction by serum. Proc Natl Acad Sci USA 1990; 87: 2254-2258
    CrossrefPubMedGoogle Scholar
  • 19 Mackman N. Protease inhibitors block lipopolysaccharide induction of tissue factor gene expression in human monocytic cells by preventing activation of c-Rel/p65 heterodimers. J Biol Chem 1994; 269: 26363-26367
    PubMedGoogle Scholar
  • 20 Oeth PA, Parry GC, Kunsch C, Nantermet P, Rosen CA, Mackman N. Lipopolysaccharide induction of tissue factor gene expression in monocytic cells is mediated by binding of c-Rel/p65 heterodimers to a kappa B-like site. Mol Cell Biol 1994; 14: 3772-3781
    CrossrefPubMedGoogle Scholar
  • 21 Parry GC, Mackman N. A set of inducible genes expressed by activated human monocytic and endothelial cells contain kappa B-like sites that specifically bind c-Rel-p65 heterodimers. J Biol Chem 1994; 269: 20823-20825
    PubMedGoogle Scholar
  • 22 Mackman N. Regulation of the tissue factor gene. FASEB J 1995; 9: 883-889
    CrossrefPubMedGoogle Scholar
  • 23 Parry GCN, Mackman N. Transcriptional regulation of Tissue Factor expression in human endothelial cells. Arterioscl Thromb Vase Biol 1995; 15: 612-621
    PubMedGoogle Scholar
  • 24 Moll T, Czyz M, Holzmiiller H, Hofer-Warbinek R, Wagner E, Winkler H, Bach FH, Hofer E. Regulation of the Tissue Factor promotor in endothelial cells. J Biol Chem 1995; 270: 3849-3857
    CrossrefPubMedGoogle Scholar
  • 25 Quehenberger P, Greten J, v-Riedesel J, Ziegler R, Wahl P, Speiser W, Bierhaus A, Nawroth PP. Endothelin-1 is under the control of the transcription factors p50/p65 (NF-κB) and AP-1. Ann of Hematol 1995; 70 A53, 211 (abstract).
    PubMedGoogle Scholar
  • 26 van-de-Stolpe A, Caldenhoven E, Stade BG, Koenderman L, Raaijmakers JA, Johnson JP, van-der-Saag PT. 12 120 J Biol Chem 1994; 269: 6185-6192
    PubMed
  • 27 Brach MA, Gruss HJ, Kaisho T, Asano Y, Hirano T, Herrmann F. Ionizing radiation induces expression of interleukin 6 by human fibroblasts involving activation of nuclear factor-kappa B. J Biol Chem 1993; 268: 8466-8472
    PubMedGoogle Scholar
  • 28 Yasumoto K, Okamoto S, Mukaida N, Murakami S, Mai M, Matsushima K. Tumor necrosis factor alpha and interferon gamma synergistically induce interleukin 8 production in a human gastric cancer cell line through acting concurrently on AP-1 and NF-kB-like binding sites of the interleukin 8 gene. J Biol Chem 1992; 267: 22506-22511
    PubMedGoogle Scholar
  • 29 Descheemaeker KA, Wyns S, Nelles L, Auwerx J, Ny T, Collen D. Interaction of AP-1-, AP-2-, and Spl-like proteins with two distinct sites in the upstream regulatory region of the plasminogen activator inhibitor-1 gene mediates the phorbol 12-myristate 13-acetate response. J Biol Chem 1992; 267: 15086-15091
    PubMedGoogle Scholar
  • 30 Joe B, Lokesh BR. Role of capsaicin, curcumin and dietary n-3 fatty acids in lowering the generation of reactive oxygen species in rat peritoneal macophages. Biochim Biophys Acta 1994; 1224: 255-263
    CrossrefPubMedGoogle Scholar
  • 31 Venkatesan N, Chandrakasan G. Modulation of cyclophosphamide-induced early lung injury by curcumin, an antiinflammatory antioxidant. Mol Cell Biochem 1995; 142: 79-87
    CrossrefPubMedGoogle Scholar
  • 32 Chan MM. Inhibition of tumor necrosis factor by curcumin, a phytochemical. Biochem Pharmacol 1995; 49: 1551-1556
    CrossrefPubMedGoogle Scholar
  • 33 Singh S, Aggarwal BB. Activation of trancription factor NF-kappa B is suppressed by curcumin (diferulolmethane). J Biol Chem 1995; 270: 24995-25000
    CrossrefPubMedGoogle Scholar
  • 34 Huang TS, Lee SC, Lin JK. Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. Proc Natl Acad Sci USA 1991; 88: 5292-5296
    CrossrefPubMedGoogle Scholar
  • 35 Huang T, Kuo M, Lin J, Hsieh J. A labile hyperphosphorylated c-Fos protein is induced in mouse fibroblast cells treated with a combination of phorbol ester and anti-tumor promotor curcumin. Cancer Lett 1995; 96: 1-7
    CrossrefPubMedGoogle Scholar
  • 36 Takeshita A, Chen Y, Watanabe A, Kitano S, Hanazawa S. TGF-beta induces expression of monocyte chemoattractant JE/monocyte chemo-attractant protein 1 via transcriptional factor AP-1 induced by protein kinase in osteoblastic cells. J Immunol 1995; 155: 419-426
    PubMedGoogle Scholar
  • 37 Hanazawa S, Takeshita A, Amano S, Semba T, Nirazuka T, Katoh H, Kitano S. Tumor necrosis factor-alpha induces expression of monocyte chemoattractant JE via fos and jun genes in clonal osteoblastic MC3T3-E1 cells. J Biol Chem 1993; 268: 9526-9532
    PubMedGoogle Scholar
  • 38 Lu Y-P, Chang RL, Lou Y-R, Huang M-T, Newmark HL, Reuhl K, Conney AH. Effect of curcumin on 12-O-tetradecanoylphorbol-13-acetate and ultraviolet B light-induced expression of c-Jun and c-Fos in JB6 cells and in mouse epidermis. Carcinogenesis 1994; 15: 2362-2370
    PubMedGoogle Scholar
  • 39 Dixit VM, Marks RM, Sarnia V, Prochownik EV. The antimitogenic action of tumor necrosis factor is associated with increased AP-l/c-jun protooncogene transcription. J Biol Chem 1989; 264: 16905-16909
    PubMedGoogle Scholar
  • 40 Collins T, Read AM, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: (NF-κB) and cytokine-inducible enhancers. FASEB J 1995; 9: 899-909
    CrossrefPubMedGoogle Scholar
  • 41 Schutze S, Potthoff K, Machleidt T, Berkovic D, Wiegmann K, Kronke M. TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 1992; 71: 765-776
    CrossrefPubMedGoogle Scholar
  • 42 Collins T, Palmer HJ, Whitley M, Neish AS, Willims A. A common theme in endothelial activation. TCM 1993; 03: 92-97
    PubMedGoogle Scholar
  • 43 Bach R. Initiation of coagulation by tissue factor. CRC Crit Rev Biochem 1988; 23: 339-368
    PubMedGoogle Scholar
  • 44 Sassone-Corsi P, Ransone LJ, Lamph WW, Verma IM. Direct interaction between fos and jun nuclear oncoproteins: role of the leucine zipper domain. Nature 1988; 36: 692-695
    PubMedGoogle Scholar
  • 45 Lamph WW, Dwarki VJ, Ofir R, Montminy M, Verma IM. Negative and positive regulation by transcription factor cAMP response element-binding protein is modulated by phosphorylation. Proc Natl Acad Sci USA 1990; 87: 4320-4324
    CrossrefPubMedGoogle Scholar
  • 46 Bohmann D, Tjian R. Biochemical analysis of transcriptional activation by Jun: differential activity of c-and v-Jun. Cell 1989; 59: 709-717
    CrossrefPubMedGoogle Scholar
  • 47 Scarpati EM, Wen D, Broze G, Miletich JP, Flandermayer RR, Siegel NR, Sadler E. Human Tissue Factor: c-DNA-sequence and chromosome localisation of the gene. Biochemistry 1987; 26: 5234-5238
    CrossrefPubMedGoogle Scholar
  • 48 Schwartz SM. Selection and characterization of bovine aortic endothelial cells. In vitro 1978; 14: 966-970
    CrossrefPubMedGoogle Scholar
  • 49 Nawroth PP, Stern DM, Kaplan KL, Nossel HL. Prostacyclin production by perturbed bovine aortic endothelial cells in culture. Blood 1984; 64: 801-806
    PubMedGoogle Scholar
  • 50 Nawroth PP, Stern DM, Kisiel W, Bach R. Cellular requirements for tissue factor generation by bovine aortic endothelial cells in culture. Thromb Res 1985; 40: 677-691
    CrossrefPubMedGoogle Scholar
  • 51 Greenberg NE, Ziff ME. Stimulation of 3T3 cells induce transcription of c-fos protooncogene. Nature 1984; 311: 433-438
    CrossrefPubMedGoogle Scholar
  • 52 Andrews NC, Faller DV. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucl Acids Res 1991; 19: 2499
    CrossrefPubMedGoogle Scholar
  • 53 Melton DA, Krieg PA, Rabdaliati MR, Maniatis T, Zinn K, Green MR. Efficient synthesis of biologically active RNA and RNA hybridisation probes from plasmids containing a bacteriophage SP6 promotor. Nucl Acids Res 1984; 12: 7035-7056
    CrossrefPubMedGoogle Scholar
  • 54 Schreiber E, Matthias P, Muller MM, Schaffner W. Rapid detection of octamer binding proteins with ‘mini-extracts’, prepared from a small number of cells. Nucleic Acids Res 1989; 17: 6419
    CrossrefPubMedGoogle Scholar
  • 55 Srimal RC, Dhawan BN. Pharmacology of diferuloyl methane (curcumin)a non-steroidal antiinflammatory agent. J Pharm Pharmac 1973; 25: 447-452
    CrossrefPubMedGoogle Scholar
  • 56 Yasni S, Imaizumi K, Nakamura M, Aimoto J, Sugano M. Effects of Curcuma xanthorrhiza Roxb. and curcuminoids on the level of serum and liver lipids, serum apolipoprotein A-I and lipogenic enzymes in rats. Food Chem Toxicol 1993; 31: 213-218
    CrossrefPubMedGoogle Scholar
  • 57 Nagabhushan M, Bhide SV. Curcumin as an inhibitor of cancer. J Am Coll Nutr 1992; 11: 192-198
    PubMedGoogle Scholar
  • 58 Srivatava R, Diksit M, Srimal RC, Dhawan BN. Anti-thrombotic effects of curcumin. Thromb Res 1985; 40: 413-417
    CrossrefPubMedGoogle Scholar
  • 59 Nagabhushan M, Amokar AJ, D’Souza AV, Bhide SV. Antimutagenicity of curcumins and related compounds: the structural requirements for the antimutagenicity of curcumins. Indian Drugs 1987; 25: 91-95
    PubMedGoogle Scholar
  • 60 Ammon HP, Safayhi H, Mack T, Sabieraj J. Mechanism of antiinflammatory actions of curcumine and boswellic acids. J Ethnopharmacol 1993; 38: 113-119
    CrossrefPubMedGoogle Scholar
  • 61 Huang MT, Lou YR, Ma W, Newmark HL, Reuhl KR, Conney AH. Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res 1994; 54: 5841-5847
    PubMedGoogle Scholar
  • 62 Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants and the degenerative diseases of aging. Proc Natl Acad Sci USA 1993; 90: 7915-722
    CrossrefPubMedGoogle Scholar
  • 63 Karin M. Signal transduction and gene control. Curr Opin Cell Biol 1991; 03: 467-473
    CrossrefPubMedGoogle Scholar
  • 64 Baeuerle PA, Henkel T. Function and activation of (NF-κB) in the immune system. Annu Rev Immun 1994; 12: 141-179
    PubMedGoogle Scholar
  • 65 Liu J-Y, Lin SJ, Lin J-K. Inhibitory effects of curcumin on protein kinase C activity induced by 12-O-tetradecanoylphorbol-13-acetate in NIH3T3 cells. Carcinogenesis 1993; 14: 857-861
    CrossrefPubMedGoogle Scholar
  • 66 Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M, Hunter T. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA binding activity. Celt 1991; 64: 573-584
    CrossrefPubMedGoogle Scholar
  • 67 Brenner DA, O’Hara M, Angel P, Chojkier M, Karin M. Prolonged activation of jun and collagenase genes by tumor necrosis factor-alpha. Nature 1989; 337: 661-663
    CrossrefPubMedGoogle Scholar
  • 68 de-Pater S, Katagiri F, Kijne J, Chua NH. bZIP proteins bind to a palindromic sequence without an ACGT core located in a seed-specific element of the pea lectin promoter. Plant J 1994; 06: 133-140
    CrossrefPubMedGoogle Scholar
  • 69 Herrlich P, Ponta H, Rahmsdorf HJ. DNA damage-induced gene expression: signal transduction and relation to growth factor signaling. Rev Physiol Biochem Pharmacol 1992; 119: 187-223
    PubMedGoogle Scholar