Skip to main content
SpringerLink
Log in

Activation of the transcription factor Nrf2 in macrophages, Caco-2 cells and intact human gut tissue by Maillard reaction products and coffee

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

In addition to direct antioxidative effects, Maillard reaction products (MRPs) could increase the antioxidative capacity of cells through the induction of cytoprotective enzymes. Since many of those enzymes are regulated by the transcription factor Nrf2, the effect of MRPs on nuclear translocation of Nrf2 in macrophages and Caco-2 cells was investigated. Stimulation of both cell types by MRPs showed a concentration-dependent significant increase in nuclear translocation of Nrf2 up to fivefold after short-term (2 h) and up to 50-fold after long-term treatment (24 h). In intact human gut tissue, nuclear translocation of Nrf2 was significantly twofold increased after short-term incubation. To study the activation mechanisms, macrophages and Caco-2 cells were stimulated with MRPs in the presence of catalase, which significantly suppressed Nrf2 activation. Thus, activation was related to extracellular H2O2 continuously formed from MRPs. Short-term incubation with coffee, a MRP-rich beverage, led to a trend towards Nrf2 activation in macrophages, but not in Caco-2 cells or intact human gut tissue. Long-term incubation with coffee (1–4 mg/mL) significantly increased nuclear Nrf2 up to 17-fold. Since raw coffee was inactive under the tested conditions, the effect was related to roasting products. Coffee-induced Nrf2 translocation was, however, only slightly reversed by catalase. Therefore, the Nrf2 activity of coffee can only partially be explained by MRP-induced, H2O2-dependent mechanisms. Thus, it can be concluded that MRPs may increase the antioxidative capacity inside the cell by inducing Nrf2-regulated signalling pathways not only in different cell types, but also in intact gut tissue.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Andrews NC, Faller DV (1991) A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res 19(9):2499

    Article  PubMed  CAS  Google Scholar 

  • Bellezza I, Mierla AL, Minelli A (2010) Nrf2 and NF-kB and their concerted modulation in cancer pathogenesis and progression. Cancers 2:483–497

    Article  CAS  Google Scholar 

  • Boettler U, Sommerfeld K, Volz N, Pahlke G, Teller N, Somoza V, Lang R, Hofmann T, Marko D (2010) Coffee constituents as modulators of Nrf2 nuclear translocation and ARE (EpRE)-dependent gene expression. J Nutr Biochem. doi:10.1016/j.jnutbio.2010.03.011

  • Borelli RC, Visconti A, Mennella C, Anese M, Fogliano V (2002) Chemical characterization and antioxidant properties of coffee melanoidins. J Agric Food Chem 50(22):6527–6533

    Article  Google Scholar 

  • Cavin C, Marin-Kuan M, Langouet S, Bezencon C, Guignard G, Verguet C, Piguet D, Holzhauser D, Cornaz R, Schilter B (2008) Induction of Nrf2-mediated cellular defenses and alteration of phase I activities as mechanisms of chemoprotective effects of coffee in the liver. Food Chem Toxicol 46(4):1239–1248. doi:10.1016/j.fct.2007.09.099

    Article  PubMed  CAS  Google Scholar 

  • Cheng X, Siow RC, Mann GE (2011) Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: a role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway. Antioxid Redox Signal 14(3):469–487. doi:10.1089/ars.2010.3283

    Article  PubMed  CAS  Google Scholar 

  • Cheung KL, Yu S, Pan Z, Ma J, Wu TY, Kong AN (2011) tBHQ-induced HO-1 expression is mediated by calcium through regulation of Nrf2 binding to enhancer and polymerase II to promoter region of HO-1. Chem Res Toxicol 24(5):670–676. doi:10.1021/tx1004369

    Article  PubMed  CAS  Google Scholar 

  • Clarke JD, Dashwood RH, Ho E (2008) Multi-targeted prevention of cancer by sulforaphane. Cancer Lett 269(2):291–304. doi:10.1016/j.canlet.2008.04.018

    Article  PubMed  CAS  Google Scholar 

  • Cuadrado A, Moreno-Murciano P, Pedraza-Chaverri J (2009) The transcription factor Nrf2 as a new therapeutic target in Parkinson’s disease. Expert Opin Ther Targets 13(3):319–329. doi:10.1517/13543780802716501

    Article  PubMed  CAS  Google Scholar 

  • Dittrich R, El-Massry F, Kunz K, Rinaldi F, Peich CC, Beckmann MW, Pischetsrieder M (2003) Maillard reaction products inhibit oxidation of human low-density lipoproteins in vitro. J Agric Food Chem 51(13):3900–3904. doi:10.1021/jf026172s

    Article  PubMed  CAS  Google Scholar 

  • Dittrich R, Dragonas C, Kannenkeril D, Hoffmann I, Mueller A, Beckmann MW, Pischetsrieder M (2009) A diet rich in Maillard reaction products protects LDL against copper-induced oxidation ex vivo, a human intervention trial. Food Res Int 42:1315–1322

    Article  CAS  Google Scholar 

  • Fogliano V, Morales FJ (2011) Estimation of dietary intake of melanoidins from coffee and bread. Food Funct 2:117–123

    Article  PubMed  CAS  Google Scholar 

  • Goya L, Delgado-Andrade C, Rufian-Henares JA, Bravo L, Morales FJ (2007) Effect of coffee melanoidin on human hepatoma HepG2 cells. Protection against oxidative stress induced by tert-butylhydroperoxide. Mol Nutr Food Res 51(5):536–545. doi:10.1002/mnfr.200600228

    Article  PubMed  CAS  Google Scholar 

  • He M, Siow RC, Sugden D, Gao L, Cheng X, Mann GE (2011) Induction of HO-1 and redox signaling in endothelial cells by advanced glycation end products: a role for Nrf2 in vascular protection in diabetes. Nutr Metab Cardiovasc Dis 21(4):277–285. doi:10.1016/j.numecd.2009.12.008

    PubMed  CAS  Google Scholar 

  • Hegele J, Munch G, Pischetsrieder M (2009) Identification of hydrogen peroxide as a major cytotoxic component in Maillard reaction mixtures and coffee. Mol Nutr Food Res 53(6):760–769. doi:10.1002/mnfr.200800221

    Article  PubMed  CAS  Google Scholar 

  • Higgins LG, Cavin C, Itoh K, Yamamoto M, Hayes JD (2008) Induction of cancer chemopreventive enzymes by coffee is mediated by transcription factor Nrf2. Evidence that the coffee-specific diterpenes cafestol and kahweol confer protection against acrolein. Toxicol Appl Pharmacol 226(3):328–337. doi:10.1016/j.taap.2007.09.018

    Article  PubMed  CAS  Google Scholar 

  • Iida T, Yoshiki Y, Someya S, Okubo K (2002) Generation of reactive oxygen species and photon emission from a browned product. Biosci Biotechnol Biochem 66(8):1641–1645

    Article  PubMed  CAS  Google Scholar 

  • Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236(2):313–322

    Article  PubMed  CAS  Google Scholar 

  • Jin W, Wang H, Ji Y, Hu Q, Yan W, Chen G, Yin H (2008) Increased intestinal inflammatory response and gut barrier dysfunction in Nrf2-deficient mice after traumatic brain injury. Cytokine 44(1):135–140. doi:10.1016/j.cyto.2008.07.005

    Article  PubMed  CAS  Google Scholar 

  • Jin W, Wang HD, Hu ZG, Yan W, Chen G, Yin HX (2009) Transcription factor Nrf2 plays a pivotal role in protection against traumatic brain injury-induced acute intestinal mucosal injury in mice. J Surg Res 157(2):251–260. doi:10.1016/j.jss.2008.08.003

    Article  PubMed  CAS  Google Scholar 

  • Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN (2006) Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 66(24):11580–11584. doi:10.1158/0008-5472.CAN-06-3562

    Article  PubMed  CAS  Google Scholar 

  • Kruidenier L, Kuiper I, Van Duijn W, Mieremet-Ooms MA, van Hogezand RA, Lamers CB, Verspaget HW (2003) Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease. J Pathol 201(1):17–27. doi:10.1002/path.1408

    Article  PubMed  CAS  Google Scholar 

  • Li J, Ichikawa T, Janicki JS, Cui T (2009) Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets 13(7):785–794. doi:10.1517/14728220903025762

    Article  PubMed  CAS  Google Scholar 

  • Martin MA, Ramos S, Mateos R, Rufian-Henares JA, Morales FJ, Bravo L, Goya L (2009) Biscuit melanoidins of different molecular masses protect human HepG2 cells against oxidative stress. J Agric Food Chem 57(16):7250–7258. doi:10.1021/jf9006032

    Article  PubMed  CAS  Google Scholar 

  • McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, Wolf CR, Cavin C, Hayes JD (2001) The Cap’n’Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res 61(8):3299–3307

    PubMed  CAS  Google Scholar 

  • Moi P, Chan K, Asunis I, Cao A, Kan YW (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA 91(21):9926–9930

    Article  PubMed  CAS  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63

    Article  PubMed  CAS  Google Scholar 

  • Mueller U, Sauer T, Weigel I, Pichner R, Pischetsrieder M (2011) Identification of H2O2 as a major antimicrobial component in coffee. Food Funct 2(5):265–272. doi:10.1039/c0fo00180e

    Article  PubMed  CAS  Google Scholar 

  • Muscat S, Pelka J, Hegele J, Weigle B, Munch G, Pischetsrieder M (2007) Coffee and Maillard products activate NF-kappaB in macrophages via H2O2 production. Mol Nutr Food Res 51(5):525–535. doi:10.1002/mnfr.200600254

    Article  PubMed  CAS  Google Scholar 

  • Ning JL, Mo LW, Lai XN (2010) Low- and high-dose hydrogen peroxide regulation of transcription factor NF-E2-related factor 2. Chin Med J (Engl) 123(8):1063–1069

    CAS  Google Scholar 

  • Paur I, Austenaa LM, Blomhoff R (2008) Extracts of dietary plants are efficient modulators of nuclear factor kappa B. Food Chem Toxicol 46(4):1288–1297. doi:10.1016/j.fct.2007.09.103

    Article  PubMed  CAS  Google Scholar 

  • Paur I, Balstad TR, Blomhoff R (2010) Degree of roasting is the main determinant of the effects of coffee on NF-kappaB and EpRE. Free Radic Biol Med 48(9):1218–1227. doi:10.1016/j.freeradbiomed.2010.02.005

    Article  PubMed  CAS  Google Scholar 

  • Petry A, Weitnauer M, Gorlach A (2010) Receptor activation of NADPH oxidases. Antioxid Redox Signal 13(4):467–487. doi:10.1089/ars.2009.3026

    Article  PubMed  CAS  Google Scholar 

  • Pool-Zobel B, Veeriah S, Bohmer FD (2005) Modulation of xenobiotic metabolising enzymes by anticarcinogens—focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis. Mutat Res 591(1–2):74–92. doi:10.1016/j.mrfmmm.2005.04.020

    PubMed  CAS  Google Scholar 

  • Raithel M, Weidenhiller M, Shaban M, Abel R, Tuchbreiter H, Backhaus B, Donhauser N, Baenkler HW, Hahn EG (2003) Diagnostic use of mucosa oxygenation and histamine release experiments in patients with gastrointestinally mediated allergy (GMA). Inflamm Res 52(Suppl 1):13–14

    Article  Google Scholar 

  • Raithel M, Weidenhiller M, Abel R, Baenkler HW, Hahn EG (2006) Colorectal mucosal histamine release by mucosa oxygenation in comparison with other established clinical tests in patients with gastrointestinally mediated allergy. World J Gastroenterol 12(29):4699–4705

    PubMed  CAS  Google Scholar 

  • Rousseau EJ, Davison AJ, Dunn B (1992) Protection by beta-carotene and related compounds against oxygen-mediated cytotoxicity and genotoxicity: implications for carcinogenesis and anticarcinogenesis. Free Radic Biol Med 13(4):407–433

    Article  PubMed  CAS  Google Scholar 

  • Samaras TS, Gordon MH, Ames JM (2005) Antioxidant properties of malt model systems. J Agric Food Chem 53(12):4938–4945. doi:10.1021/jf0501600

    Article  PubMed  CAS  Google Scholar 

  • Sauer T, Raithel M, Kressel J, Muscat S, Munch G, Pischetsrieder M (2011) Nuclear translocation of NF-kappaB in intact human gut tissue upon stimulation with coffee and roasting products. Food Funct 2(9):529–540. doi:10.1039/c1fo10055f

    Article  PubMed  CAS  Google Scholar 

  • Saw CL, Kong AN (2011) Nuclear factor-erythroid 2-related factor 2 as a chemopreventive target in colorectal cancer. Expert Opin Ther Targets 15(3):281–295. doi:10.1517/14728222.2011.553602

    Article  PubMed  CAS  Google Scholar 

  • Seiquer I, Ruiz-Roca B, Mesias M, Munoz-Hoyos A, Galdo G, Ochoa JJ, Navarro MP (2008) The antioxidant effect of a diet rich in Maillard reaction products is attenuated after consumption by healthy male adolescents. In vitro and in vivo comparative study. J Sci Food Agr 88(7):1245–1252. doi:10.1002/Jsfa.3213

    Google Scholar 

  • Surh YJ, Kundu JK, Na HK (2008) Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 74(13):1526–1539. doi:10.1055/s-0028-1088302

    Article  PubMed  CAS  Google Scholar 

  • Theiss AL, Vijay-Kumar M, Obertone TS, Jones DP, Hansen JM, Gewirtz AT, Merlin D, Sitaraman SV (2009) Prohibitin is a novel regulator of antioxidant response that attenuates colonic inflammation in mice. Gastroenterology 137(1):199–208, 208 e191–196. doi:10.1053/j.gastro.2009.03.033

    Google Scholar 

  • Thiele K, Bierhaus A, Autschbach F, Hofmann M, Stremmel W, Thiele H, Ziegler R, Nawroth PP (1999) Cell-specific effects of glucocorticoid treatment on the NF-kappaBp65/IkappaBalpha system in patients with Crohn’s disease. Gut 45(5):693–704

    Article  PubMed  CAS  Google Scholar 

  • Urquiaga I, Leighton F (2000) Plant polyphenol antioxidants and oxidative stress. Biol Res 33(2):55–64

    Article  PubMed  CAS  Google Scholar 

  • van Boekel M, Fogliano V, Pellegrini N, Stanton C, Scholz G, Lalljie S, Somoza V, Knorr D, Jasti PR, Eisenbrand G (2010) A review on the beneficial aspects of food processing. Mol Nutr Food Res 54(9):1215–1247. doi:10.1002/mnfr.200900608

    Article  PubMed  Google Scholar 

  • Xue M, Qian Q, Adaikalakoteswari A, Rabbani N, Babaei-Jadidi R, Thornalley PJ (2008) Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes 57(10):2809–2817. doi:10.2337/db06-1003

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Chemistry and Pharmacy, Food Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstr. 19, 91052, Erlangen, Germany

    Tanja Sauer & Monika Pischetsrieder

  2. Functional Tissue Diagnostics, Gastroenterology, Department of Medicine I, Friedrich-Alexander University, Ulmenweg 18, 91054, Erlangen, Germany

    Martin Raithel & Jürgen Kressel

  3. Department of Pharmacology, School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith, NSW, 2751, Australia

    Gerald Münch

Authors
  1. Tanja Sauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Raithel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jürgen Kressel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gerald Münch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Monika Pischetsrieder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monika Pischetsrieder.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sauer, T., Raithel, M., Kressel, J. et al. Activation of the transcription factor Nrf2 in macrophages, Caco-2 cells and intact human gut tissue by Maillard reaction products and coffee. Amino Acids 44, 1427–1439 (2013). https://doi.org/10.1007/s00726-012-1222-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-012-1222-1

Keywords

Search

Navigation