Journal Mobile Options
Table of Contents
Vol. 7, No. 2, 2000
Issue release date: February 1999
Neuroimmunomodulation 2000;7:99–105

Caffeic Acid Phenethyl Ester Induces Leukocyte Apoptosis, Modulates Nuclear Factor-Kappa B and Suppresses Acute Inflammation

Orban Z. · Mitsiades N. · Burke Jr. T.R. · Tsokos M. · Chrousos G.P.
aDevelopmental Endocrinology Branch, National Institute of Child Health and Human Development, and Laboratories of bPathology and cMedicinal Chemistry, National Cancer Institute, Bethesda, Md., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Nuclear factor kappa-B (NF-κB) is a heterodimeric transcription factor with a pivotal role in orchestrating immune and inflammatory processes. Inflammatory cytokines and prostanoids activate NF-κB, which, in turn, stimulates expression of cytokines, proteases, adhesion molecules and other inflammatory mediators. Caffeic acid phenethyl ester (CAPE) is a compound that modulates nuclear binding of the NF-κB p65 subunit (RelA). To determine whether CAPE decreases the viability of cells participating in host defense, we first tested its in vitro effect on a glucocorticoid-sensitive and -resistant cell line of lymphoid origin. CAPE induced apoptotic cell death in a dose-dependent fashion and to a similar extent in both cell lines. Furthermore, a low concentration of CAPE decreased the LD50 of dexamethasone by 3- to 5-fold. Since therapeutic induction of apoptosis of activated inflammatory cells holds the attraction of destroying effector cells safely without secondary tissue damage, we examined the effects of CAPE in a rat model of carrageenin-induced subcutaneous inflammation. Local administration of CAPE resulted in increased leukocyte apoptosis and marked reduction in exudate leukocyte, neutrophil and monocyte concentrations at the inflammatory site. CAPE decreased expression of cytosolic IκBα and increased nuclear translocation of p65. These findings may suggest that novel anti-inflammatory therapies can be based upon activation of NF-κB-mediated transcription of genes curbing the inflammatory response and that CAPE or its analogs hold therapeutic promise.

Copyright © 2000 S. Karger AG, Basel

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Barnes PJ, Karin M: Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336:1066–1071.
  2. Baeuerle PA: Pro-inflammatory signaling: Last pieces in the NF-kappaB puzzle? Curr Biol 1998;8:R19–R22.

    External Resources

  3. Gerondakis S, Grumont R, Rourke I, Grossmann M: The regulation and roles of Rel/NF-kappa B transcription factors during lymphocyte activation. Curr Opin Immunol 1998;10:353–359.
  4. Blackwell TS, Christman JW: The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell Mol Biol 1997;17:3–9.
  5. Ghiorzo P, Musso M, Mantelli M, Garre C, Ravazzolo R, Bianchi-Scarra G: c-Rel and p65 subunits bind to an upstream NF-kappaB site in human granulocyte macrophage-colony stimulating factor promoter involved in phorbol ester response in 5,637 cells. FEBS Lett 1997;418:215–218.

    External Resources

  6. Manning AM, Bell FP, Rosenbloom CL, Chosay JG, Simmons CA, Northrup JL, Shebuski RJ, Dunn CJ, Anderson DC: NF-kappa B is activated during acute inflammation in vivo in association with elevated endothelial cell adhesion molecule gene expression and leukocyte recruitment. J Inflamm 1995;45:283–296.

    External Resources

  7. Dirsch VM, Gerbes AL, Vollmar AM: Ajoene, a compound of garlic, induces apoptosis in human promyeloleukemic cells, accompanied by generation of reactive oxygen species and activation of nuclear factor kappa B. Mol Pharmacol 1998;53:402–407.
  8. Li Y, Zhang W, Mantell LL, Kazzaz JA, Fein AM, Horowitz S: Nuclear factor-kappa B is activated by hyperoxia but does not protect from cell death. J Biol Chem 1997;272:20646–20649.
  9. Rudin CM, Thompson CB: Apoptosis and disease: Regulation and clinical relevance of programmed cell death. Annu Rev Med 1997;48:267–281.
  10. Attar RM, Caamano J, Carrasco D, Iotsova V, Ishikawa H, Ryseck RP, Weih F, Bravo R: Genetic approaches to study Rel/NF-kappa B/I kappa B function in mice. Semin Cancer Biol 1997;8:93–101.

    External Resources

  11. Franzoso G, Carlson L, Poljak L, Shores EW, Epstein S, Leonardi A, Grinberg A, Tran T, Scharton-Kersten T, Anver M, Love P, Brown K, Siebenlist U: Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J Exp Med 1998;187:147–159.
  12. Caamano JH, Rizzo CA, Durham SK, Barton DS, Raventos-Suarez C, Snapper CM, Bravo R: Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J Exp Med 1998;187:185–196.
  13. McDonald PP, Bald A, Cassatella MA: Activation of the NF-kappa B pathway by inflammatory stimuli in human neutrophils. Blood 1997;89:3421–3433.
  14. Natarajan K, Singh S, Burke TRJ, Grunberger D, Aggarwal BB: Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA 1996;93:9090–9095.
  15. Burke TRJ, Fesen MR, Mazumder A, Wang J, Carothers AM, Grunberger D, Driscoll J, Kohn K, Pommier Y: Hydroxylated aromatic inhibitors of HIV-1 integrase. J Med Chem 1995;38:4171–4178.
  16. Geley S, Hartmann BL, Hala M, Strasser-Wozak EM, Kapelari LK, Kofler R: Resistance to glucocorticoid-induced apoptosis in human T-cell acute lymphoblastic leukemia CEM-C1 cells is due to insufficient glucocorticoid receptor expression. Cancer Res 1996;56:5033–5038.

    External Resources

  17. Mitsiades N, Poulaki V, Kotoula V, Leone A, Tsokos M: Fas ligand is present in tumors of the Ewing’s sarcoma family and is cleaved into a soluble form by a metalloproteinase. Am J Pathol 1998;153:1947–1956.
  18. Bornstein SR, Webster EL, Torpy DJ, Richman SJ, Mitsiades N, Igel M, Lewis DB, Rice KC, Joost HG, Tsokos M, Chrousos GP: Chronic effects of a nonpeptide corticotropin-releasing hormone type I receptor antagonist on pituitary-adrenal function, body weight, and metabolic regulation. Endocrinology 1998;139:1546–1555.
  19. Webster EL, Lewis DB, Torpy DJ, Zachman EK, Rice KC, Chrousos GP: In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: Suppression of pituitary ACTH release and peripheral inflammation. Endocrinology 1996;137:5747–5750.
  20. de Wit H, Dokter WH, Koopmans SB, Lummen C, van der Leij M, Smit JW, Vellenga E: Regulation of p100 (NFKB2) expression in human monocytes in response to inflammatory mediators and lymphokines. Leukemia 1998;12:363–370.
  21. Beauparlant P, Hiscott J: Biological and biochemical inhibitors of the NF-kappa B/Rel proteins and cytokine synthesis. Cytokine Growth Factor Rev 1996;7:175–190.
  22. Li Z, Nabel GJ: A new member of the I kappaB protein family, I kappaB epsilon, inhibits RelA (p65)-mediated NF-kappaB transcription. Mol Cell Biol 1997;17:6184–6190.

    External Resources

  23. Grumont RJ, Rourke IJ, O’Reilly LA, Strasser A, Miyake K, Sha W, Gerondakis S: B lymphocytes differentially use the Rel and nuclear factor kappa B1 (NF-kappaB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J Exp Med 1998;187:663–674.
  24. Snapper CM, Zelazowski P, Rosas FR, Kehry MR, Tian M, Baltimore D, Sha WC: B cells from p50/NF-kappa B knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching. J Immunol 1996;156:183–191.
  25. Yaron A, Gonen H, Alkalay I, Hatzubai A, Jung S, Beyth S, Mercurio F, Manning AM, Ciechanover A, Ben-Neriah Y: Inhibition of NF-kappa-B cellular function via specific targeting of the I-kappa-B-ubiquitin ligase. EMBO J. 1997;16:6486–6494.
  26. Makarov SS, Johnston WN, Olsen JC, Watson JM, Mondal K, Rinehart C, Haskill JS: NF-kappa B as a target for anti-inflammatory gene therapy: Suppression of inflammatory responses in monocytic and stromal cells by stable gene transfer of I kappa B alpha cDNA. Gene Ther 1997;4:846–852.

    External Resources

  27. Neurath MF, Pettersson S: Predominant role of NF-kappa B p65 in the pathogenesis of chronic intestinal inflammation. Immunobiology 1997;198:91–98.

    External Resources

  28. Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W, Royer HD, Grinstein E, Greiner A, Scheidereit C, Dorken B: Constitutive nuclear factor-kappa B-RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells. J Clin Invest 1997;100:2961–2969.
  29. Grunberger D, Banerjee R, Eisinger K, Oltz EM, Efros L, Caldwell M, Estevez V, Nakanishi K: Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia 1988;44:230–232.
  30. Chiao C, Carothers AM, Grunberger D, Solomon G, Preston GA, Barrett JC: Apoptosis and altered redox state induced by caffeic acid phenethyl ester (CAPE) in transformed rat fibroblast cells. Cancer Res 1995;55:3576–3583.
  31. Gilston V, Jones HW, Soo CC, Coumbe A, Blades S, Kaltschmidt C, Baeuerle PA, Morris CJ, Blake DR, Winyard PG: NF-kappa B activation in human knee-joint synovial tissue during the early stage of joint inflammation. Biochem Soc Trans 1997;25:518S.
  32. Keates S, Hitti YS, Upton M, Kelly CP: Helicobacter pylori infection activates NF-kappa B in gastric epithelial cells. Gastroenterology 1997;113:1099–1109.
  33. Schwartz MD, Moore EE, Moore FA, Shenkar R, Moine P, Haenel JB, Abraham E: Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Crit Care Med 1996;24:1285–1292.
  34. Valle BM, Luque I, Collantes E, Aranda E, Solana R, Pena J, Munoz E: Cellular redox status influences both cytotoxic and NF-kappa B activation in natural killer cells. Immunology 1997;90:455–460.

    External Resources

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50