Skip to main content

Advertisement

SpringerLink
Log in

Involvement of Heme Oxygenase-1 in Kaempferol-Induced Anti-Allergic Actions in RBL-2H3 Cells

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Kaempferol is one of the most commonly found dietary flavonoids. The exposure to kaempferol is known to inhibit degranulation from mast cells, but the inhibitory mechanism of degranulation has not been clarified yet. In this study, we investigated the involvement of heme oxygenase (HO)-1 in the anti-allergic action of kaempferol against degranulation in rat basophilic leukemia (RBL-2H3) cells. Our results demonstrate upregulation of HO enzymatic activity after short (15 min) exposure to kaempferol, followed by the induction of HO-1 expression in protein. The involvement of HO-1 in the kaempferol-induced inhibition of degranulation was confirmed using tin protoporphyrin IX (SnPP), a HO-1 inhibitor. These findings strongly suggest that kaempferol exerts anti-allergic actions via activation of the HO-1.

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

Similar content being viewed by others

Abbreviations

ARE:

antioxidant response element

Nrf2:

NF-E2-related factor-2

SnPP:

tin protoporphyrin IX

HO:

heme oxygenase

CO:

carbon monoxide

References

  1. Cho, S., S. Park, M. Kwon, T. Jeong, S. Bok, W. Choi, W. Jeong, S. Ryu, S. Do, C. Lee, J. Song, and K. Jeong. 2003. Quercetin suppresses proinflammatory cytokines production through map kinases and NF-kappaB pathway in lipopolysaccharide-stimulated macrophage. Mol. Cell. Biochem. 243:153–160. doi:10.1023/A:1021624520740.

    Article  PubMed  CAS  Google Scholar 

  2. Huxley, R., M. Lean, A. Crozier, J. John, and H. Neil. 2004. Effect of dietary advice to increase fruit and vegetable consumption on plasma flavonol concentrations: Results from a randomised controlled intervention trial. J. Epidemiol. Community Health 58:288–289. doi:10.1136/jech.2003.014274.

    Article  PubMed  CAS  Google Scholar 

  3. Middleton, E. J., C. Kandaswami, and T. Theoharides. 2000. The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol. Rev. 52:673–751.

    PubMed  CAS  Google Scholar 

  4. Wedemeyer, J., and S. Galli. 2000. Mast cells and basophils in acquired immunity. Br. Med. Bull. 56:936–955. doi:10.1258/0007142001903616.

    Article  PubMed  CAS  Google Scholar 

  5. Theoharides, T. 1996. The mast cell: A neuroimmunoendocrine master player. Int. J. Tissue React. 18:1–21.

    PubMed  CAS  Google Scholar 

  6. Morse, D., S. Pischke, Z. Zhou, R. Davis, R. Flavell, T. Loop, S. Otterbein, L. Otterbein, and A. Choi. 2003. Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. J. Biol. Chem. 278:36993–36998. doi:10.1074/jbc.M302942200.

    Article  PubMed  CAS  Google Scholar 

  7. Wagener, F., H. Volk, D. Willis, N. Abraham, M. Soares, G. Adema, and C. Figdor. 2003. Different faces of the heme-heme oxygenase system in inflammation. Pharmacol. Rev. 55:551–571. doi:10.1124/pr.55.3.5.

    Article  PubMed  CAS  Google Scholar 

  8. Takamiya, R., M. Murakami, M. Kajimura, N. Goda, N. Makino, Y. Takamiya, T. Yamaguchi, Y. Ishimura, N. Hozumi, and M. Suematsu. 2002. Stabilization of mast cells by heme oxygenase-1: An anti-inflammatory role. Am. J. Physiol. Heart Circ. Physiol. 283:H861–H870.

    PubMed  CAS  Google Scholar 

  9. García-Mediavilla, V., I. Crespo, P. Collado, A. Esteller, S. Sánchez-Campos, M. Tuñón, and J. González-Gallego. 2007. The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive c-protein, and down-regulation of the nuclear factor kappaB pathway in chang liver cells. Eur. J. Pharmacol. 557:221–229. doi:10.1016/j.ejphar.2006.11.014.

    Article  PubMed  Google Scholar 

  10. Kempuraj, D., B. Madhappan, S. Christodoulou, W. Boucher, J. Cao, N. Papadopoulou, C. Cetrulo, and T. Theoharides. 2005. Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells. Br. J. Pharmacol. 145:934–944. doi:10.1038/sj.bjp.0706246.

    Article  PubMed  CAS  Google Scholar 

  11. Lin, H., S. Juan, S. Shen, F. Hsu, and Y. Chen. 2003. Inhibition of lipopolysaccharide-induced nitric oxide production by flavonoids in RAW264.7 macrophages involves heme oxygenase-1. Biochem. Pharmacol. 66:1821–1832. doi:10.1016/S0006-2952(03)00422-2.

    Article  PubMed  CAS  Google Scholar 

  12. Suzuki, R., T. Kimura, K. Kitaichi, Y. Tatsumi, M. Matsushima, Y. Zhao, E. Shibata, K. Baba, T. Hasegawa, and K. Takagi. 2002. Platelet factor 4 fragment induces histamine release from rat peritoneal mast cells. Peptides 23:1713–1717. doi:10.1016/S0196-9781(02)00143-2.

    Article  PubMed  CAS  Google Scholar 

  13. Gomi, K., F. Zhu, and J. Marshall. 2000. Prostaglandin E2 selectively enhances the IgE-mediated production of IL-6 and granulocyte-macrophage colony-stimulating factor by mast cells through an EP1/EP3-dependent mechanism. J. Immunol. 165:6545–6552.

    PubMed  CAS  Google Scholar 

  14. Foresti, R., J. Clark, C. Green, and R. Motterlini. 1997. Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells. Involvement of superoxide and peroxynitrite anions. J. Biol. Chem. 272:18411–18417. doi:10.1074/jbc.272.29.18411.

    Article  PubMed  CAS  Google Scholar 

  15. Blonska, M., Z. Czuba, and W. Krol. 2003. Effect of flavone derivatives on interleukin-1beta (IL-1beta) mRNA expression and IL-1beta protein synthesis in stimulated RAW 264.7 macrophages. Scand. J. Immunol. 57:162–166. doi:10.1046/j.1365-3083.2003.01213.x.

    Article  PubMed  CAS  Google Scholar 

  16. Yokomizo, A., and M. Moriwaki. 2006. Effects of uptake of flavonoids on oxidative stress induced by hydrogen peroxide in human intestinal Caco-2 cells. Biosci. Biotechnol. Biochem. 70:1317–1324. doi:10.1271/bbb.50604.

    Article  PubMed  CAS  Google Scholar 

  17. Comalada, M., I. Ballester, E. Bailón, S. Sierra, J. Xaus, J. Gálvez, F. de Medina, and A. Zarzuelo. 2006. Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: Analysis of the structure-activity relationship. Biochem. Pharmacol. 72:1010–1021. doi:10.1016/j.bcp.2006.07.016.

    Article  PubMed  CAS  Google Scholar 

  18. Ichimatsu, D., M. Nomura, S. Nakamura, S. Moritani, K. Yokogawa, S. Kobayashi, T. Nishioka, and K. Miyamoto. 2007. Structure-activity relationship of flavonoids for inhibition of epidermal growth factor-induced transformation of JB6 Cl 41 cells. Mol. Carcinog. 46:436–445. doi:10.1002/mc.20292.

    Article  PubMed  CAS  Google Scholar 

  19. Kawai, M., T. Hirano, S. Higa, J. Arimitsu, M. Maruta, Y. Kuwahara, T. Ohkawara, K. Hagihara, T. Yamadori, Y. Shima, A. Ogata, I. Kawase, and T. Tanaka. 2007. Flavonoids and related compounds as anti-allergic substances. Allergol. Int. 56:113–123. doi:10.2332/allergolint.R-06-135.

    Article  PubMed  CAS  Google Scholar 

  20. Sadeghipour, M., R. Terreux, and J. Phipps. 2005. Flavonoids and tyrosine nitration: Structure-activity relationship correlation with enthalpy of formation. Toxicol. In Vitro 19:155–165. doi:10.1016/j.tiv.2004.06.009.

    Article  PubMed  CAS  Google Scholar 

  21. Wang, L., Y. Tu, T. Lian, J. Hung, J. Yen, and M. Wu. 2006. Distinctive antioxidant and antiinflammatory effects of flavonols. J. Agric. Food Chem. 54:9798–9804. doi:10.1021/jf0620719.

    Article  PubMed  CAS  Google Scholar 

  22. Overhaus, M., B. Moore, J. Barbato, F. Behrendt, J. Doering, and A. Bauer. 2006. Biliverdin protects against polymicrobial sepsis by modulating inflammatory mediators. Am. J. Physiol. Gastrointest. Liver Physiol. 290:G695–G703. doi:10.1152/ajpgi.00152.2005.

    Article  PubMed  CAS  Google Scholar 

  23. Otterbein, L., F. Bach, J. Alam, M. Soares, H. Tao Lu, M. Wysk, R. Davis, R. Flavell, and A. Choi. 2000. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat. Med. 6:422–428. doi:10.1038/74680.

    Article  PubMed  CAS  Google Scholar 

  24. Ryter, S., L. Otterbein, D. Morse, and A. Choi. 2002. Heme oxygenase/carbon monoxide signaling pathways: Regulation and functional significance. Mol. Cell Biochem. 234–235:249–263. doi:10.1023/A:1015957026924.

    Article  PubMed  Google Scholar 

  25. Belcher, J., H. Mahaseth, T. Welch, L. Otterbein, R. Hebbel, and G. Vercellotti. 2006. Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. J. Clin. Invest. 116:808–816. doi:10.1172/JCI26857.

    Article  PubMed  CAS  Google Scholar 

  26. Kitada, O., T. Kodama, K. Kuribayashi, D. Ihaku, M. Fujita, T. Matsuyama, and M. Sugita. 2001. Heme oxygenase-1 (HO-1) protein induction in a mouse model of asthma. Clin. Exp. Allergy 31:1470–1477. doi:10.1046/j.1365-2222.2001.01179.x.

    Article  PubMed  CAS  Google Scholar 

  27. Almolki, A., C. Taillé, G. Martin, P. Jose, C. Zedda, M. Conti, J. Megret, D. Henin, M. Aubier, and J. Boczkowski. 2004. Heme oxygenase attenuates allergen-induced airway inflammation and hyperreactivity in guinea pigs. Am. J. Physiol. Lung Cell. Mol. Physiol. 287:L26–L34. doi:10.1152/ajplung.00237.2003.

    Article  PubMed  CAS  Google Scholar 

  28. Prestera, T., W. Holtzclaw, Y. Zhang, and P. Talalay. 1993. Chemical and molecular regulation of enzymes that detoxify carcinogens. Proc. Natl. Acad. Sci. USA 90:2965–2969. doi:10.1073/pnas.90.7.2965.

    Article  PubMed  CAS  Google Scholar 

  29. Dhakshinamoorthy, S., and A. Jaiswal. 2001. Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:Quinone oxidoreductase1 gene. Oncogene 20:3906–3917. doi:10.1038/sj.onc.1204506.

    Article  PubMed  CAS  Google Scholar 

  30. Itoh, K., N. Wakabayashi, Y. Katoh, T. Ishii, K. Igarashi, J. Engel, and M. Yamamoto. 1999. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13:76–86. doi:10.1101/gad.13.1.76.

    Article  PubMed  CAS  Google Scholar 

  31. Kim, M., J. Lee, H. Lee, D. Aryal, Y. Kim, S. Kim, E. Woo, and K. Kang. 2006. Antioxidative effects of quercetin-glycosides isolated from the flower buds of Tussilago Farfara L. Food Chem. Toxicol. 44:1299–1307. doi:10.1016/j.fct.2006.02.007.

    Article  PubMed  CAS  Google Scholar 

  32. Hanneken, A., F. Lin, J. Johnson, and P. Maher. 2006. Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Invest. Ophthalmol. Vis. Sci. 47:3164–3177. doi:10.1167/iovs.04-1369.

    Article  PubMed  Google Scholar 

  33. Novotny, V., E. Prieschl, R. Csonga, G. Fabjani, and T. Baumruker. 1998. Nrf1 in a complex with fosB, c-jun, junD and ATF2 forms the AP1 component at the TNF alpha promoter in stimulated mast cells. Nucleic. Acids Res. 26:5480–5485. doi:10.1093/nar/26.23.5480.

    Article  PubMed  CAS  Google Scholar 

  34. Morse, D., and A. Choi. 2005. Heme oxygenase-1: From bench to bedside. Am. J. Respir. Crit. Care Med. 172:660–670. doi:10.1164/rccm.200404-465SO.

    Article  PubMed  Google Scholar 

  35. Alexandrakis, M., R. Letourneau, D. Kempuraj, K. Kandere-Grzybowska, M. Huang, S. Christodoulou, W. Boucher, D. Seretakis, and T. Theoharides. 2003. Flavones inhibit proliferation and increase mediator content in human leukemic mast cells (HMC-1). Eur. J. Haematol. 71:448–454. doi:10.1046/j.0902-4441.2003.00167.x.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Grant-in-Aid for the Scientific Research from the Japan Society for the Promotion of Science, and Grant-in-Aid of Nagono Medical Foundation (Nagoya, Japan), and Ichihara International Scholarship Foundation (Nagoya, Japan).

Author information

Authors and Affiliations

  1. Department of Medical Technology, Nagoya University School of Health Science, 1-1-20 Daikou-minami, Higashi-ku, Nagoya, 461-8673, Japan

    Etsuko Hirose, Miyoko Matsushima, Kenzo Takagi, Yui Ota, Keiko Ishigami, Tatsuya Hirayama & Tsutomu Kawabe

  2. MEXT Innovative Research Center for Preventive Medical Engineering, Nagoya University, Furou-cho, Chikusa-ku, Nagoya, 464-8603, Japan

    Miyoko Matsushima & Tsutomu Kawabe

  3. Department of Respiratory Medicine, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi, 480-1195, Japan

    Kenji Baba

  4. Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Yuta Hayashi, Toshinobu Nakamura, Naozumi Hashimoto, Kazuyoshi Imaizumi & Yoshinori Hasegawa

Authors
  1. Etsuko Hirose
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miyoko Matsushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenzo Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yui Ota
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keiko Ishigami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tatsuya Hirayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuta Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Toshinobu Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Naozumi Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kazuyoshi Imaizumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kenji Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoshinori Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tsutomu Kawabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsutomu Kawabe.

Additional information

Etsuko Hirose and Miyoko Matsushima have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hirose, E., Matsushima, M., Takagi, K. et al. Involvement of Heme Oxygenase-1 in Kaempferol-Induced Anti-Allergic Actions in RBL-2H3 Cells. Inflammation 32, 99–108 (2009). https://doi.org/10.1007/s10753-009-9108-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-009-9108-4

KEY WORDS

Search

Navigation