Skip to main content

Imperatorin Attenuates LPS-Induced Inflammation by Suppressing NF-κB and MAPKs Activation in RAW 264.7 Macrophages

Inflammation volume 35, pages 1764–1772 (2012)Cite this article

Abstract

Imperatorin is a type of coumarin compound with antibacterial and antiviral activities. In the present study, we examined the anti-inflammatory effects of imperatorin in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages by investigating its impact on the production and expression of cytokines and the major signal-transduction pathways. We found that imperatorin downregulated LPS-induced levels of TNF-α, IL-1β, and IL-6 in RAW 264.7 macrophages in a concentration-dependent manner, and it significantly inhibited expression of TNF-α and IL-6 (P < 0.05 or P < 0.01). The phosphorylation of mitogen-activated protein kinases and nuclear factor-kappaB (NF-κB) p65 protein were analyzed by western blotting. In RAW 264.7 macrophages treated with 1 mg/L of LPS, imperatorin significantly inhibited p38 and Jun N-terminal kinase phosphorylation protein expression. However, there was no significant change in p-ERK. Furthermore, imperatorin also inhibited NF-κB translocation into the nucleus through blockage of IκBα phosphorylation and degradation.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

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

References

  1. Lawrence, T., D.A. Willoughby, and D.W. Gilroy. 2002. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nature Reviews Immunology 2: 787–795.

    PubMed  Article  CAS  Google Scholar 

  2. Lu, Y.C., W.C. Yeh, and P.S. Ohashi. 2008. LPS/TLR4 signal transduction pathway. Cytokine 42: 145–51.

    PubMed  Article  CAS  Google Scholar 

  3. McGettrick, A.F., and L.A. O'Neill. 2010. Localisation and trafficking of Toll-like receptors: an important mode of regulation. Current Opinion in Immunology 22: 20–7.

    PubMed  Article  CAS  Google Scholar 

  4. Wang, Z.M., C. Liu, and R. Dziarski. 2000. Chemokines are the main proinflammatory mediators in human monocytes activated by Staphylococcus aureus, peptidoglycan, and endotoxin. The Journal of Biological Chemistry 275(27): 20260–20267.

    PubMed  Article  CAS  Google Scholar 

  5. Shimazu, R., S. Akashi, H. Ogata, Y. Nagai, K. Fukudome, K. Miyake, et al. 1999. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. The Journal of Experimental Medicine 189: 1777–1782.

    PubMed  Article  CAS  Google Scholar 

  6. Karin, M., and M. Delhase. 2000. The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling, Semin. Immunol 12: 85–98.

    CAS  Google Scholar 

  7. Collins, T., M.A. Read, A.S. Neish, M.Z. Whitley, D. Thanos, and T. Maniatis. 1995. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine inducible enhancers. The FASEB Journal 9: 899–909.

    CAS  Google Scholar 

  8. Baldwin Jr., A.S. 1996. The NF-κB and IκB proteins: new discoveries and insights. Annual Review of Immunology 14: 649–681.

    PubMed  Article  CAS  Google Scholar 

  9. Mendis, E., M.M. Kim, N. Rajapakse, and S.K. Kim. 2008. Suppression of cytokine production in lipopolysaccharide-stimulated mouse macrophages by novel cationic glucosamine derivative involves downregulation of NF-κB and MAPK expressions. Bioorganic & Medicinal Chemistry 16: 8390–8396.

    Article  CAS  Google Scholar 

  10. López-Neblina, F., and L.H. Toledo-Pereyra. 2006. Phosphoregulation of signal transduction pathways in ischemia and reperfusion. The Journal of Surgical Research 134: 292–299.

    PubMed  Article  Google Scholar 

  11. Sironi, L., C. Banfi, M. Brioschi, P. Gelosa, U. Guerrini, E. Nobili, et al. 2006. Activation of NF-κB and ERK1/2 after permanent focal ischemia is abolished by simvastatin treatment. Neurobiology of Disease 22(2): 445–451.

    PubMed  Article  CAS  Google Scholar 

  12. He, J.Y., W. Zhang, L.C. He, and Y.X. Cao. 2007. Imperatorin induces vasodilatation possibly via inhibiting voltage dependent calcium channel and receptor-mediated Ca2+ influx and release. European Journal of Pharmacology 573: 170–175.

    PubMed  Article  CAS  Google Scholar 

  13. Raja SB, Murali MR, Roopa K, Devaraj SN. 2011. Imperatorin a furocoumarin inhibits periplasmic Cu-Zn SOD of Shigella dysenteriae their by modulates its resistance towards phagocytosis during host pathogen interaction. Biomedicine and Pharmacotherapy 65(8): 560–568.

    Google Scholar 

  14. Sancho, R., N. Márquez, M. Gómez-Gonzalo, M.A. Calzado, G. Bettoni, M.T. Coiras, et al. 2004. Imperatorin Inhibits HIV-1 Replication through an Sp1-dependent Pathway. The Journal of Biological Chemistry 279(36): 37349–37359.

    PubMed  Article  CAS  Google Scholar 

  15. Wang, C.C., L.G. Chen, and L.L. Yang. 1999. Inducible nitric oxide synthase inhibitor of the Chinese herb I. Saposhnikovia divaricata (Turcz.) Schischk. Cancer Letters 145(1–2): 151–157.

    PubMed  Article  CAS  Google Scholar 

  16. Ban, H.S., S.S. Lim, K. Suzuki, S.H. Jung, S. Lee, Y.S. Lee, et al. 2003. Inhibitory effects of furanocoumarins isolated from the roots of Angelica dahurica on prostaglandin E2 production. Planta Medica 69(5): 408–412.

    PubMed  Article  CAS  Google Scholar 

  17. Lin, W.J., and W.C. Yeh. 2005. Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock. Shock 24(3): 206–209.

    PubMed  Article  CAS  Google Scholar 

  18. Aggarwal, B.B., and K. Natarajan. 1996. Tumor necrosis factors: developments during the last decade. European Cytokine Network 7(2): 93–124.

    PubMed  CAS  Google Scholar 

  19. Fiorentino, D.F., A. Zlotnik, T.R. Mosmann, and M. Howard. 1991. Garra AO'. IL-10 inhibits cytokine production by activated macrophages. The Journal of Immunology 146: 3444–3451.

    PubMed  CAS  Google Scholar 

  20. Kramer, H.F., and L.J. Goodyear. 2007. Exercise, MAPK, and NF-κB signaling in skeletal muscle. Journal of Applied Physiology 103: 388–395.

    PubMed  Article  CAS  Google Scholar 

  21. Han, J.M., Y.Y. Jin, H.Y. Kim, K.H. Park, W.S. Lee, and T.S. Jeong. 2010. Lavandulyl flavonoids from Sophora flavescens suppress lipopolysaccharide-induced activation of nuclear factor-κB and mitogen-activated protein kinases in RAW264.7 cells. Biological & Pharmaceutical Bulletin 33(6): 1019–1023.

    Article  CAS  Google Scholar 

  22. Li, Q., and I.M. Verma. 2002. NF-κB regulation in the immune system. Immunol 2: 25–34.

    Google Scholar 

  23. Gilmore, T.D. 2006. Introduction to NF-κB: players, pathways, perspectives. Oncogene 25: 6680–6684.

    PubMed  Article  CAS  Google Scholar 

  24. Delhalle, S., R. Blasius, and M. Dicato. 2004. A beginner's guide to NF-kappaB signaling pathways. Annals of the New York Academy of Sciences 1030: 1–13.

    PubMed  Article  CAS  Google Scholar 

  25. Yoon, W.J., J.Y. Moon, G. Song, Y.K. Lee, M.S. Han, J.S. Lee, et al. 2010. Artemisia fukudo essential oil attenuates LPS-induced inflammation by suppressing NF-κB and MAPK activation in RAW 264.7 macrophages. Food and Chemical Toxicology 48: 1222–1229.

    PubMed  Article  CAS  Google Scholar 

  26. Wang, Y.P., Y. Wu, L.Y. Li, J. Zheng, R.G. Liu, and J.P. Zhou. 2011. Aspirin-triggered lipoxin A4 attenuates LPS-induced pro-inflammatory responses by inhibiting activation of NF-κB and MAPKs in BV-2 microglial cells. Journal of Neuroinflammation 8: 95.

    PubMed  Article  CAS  Google Scholar 

  27. Ajizian, S.J., B.K. English, and E.A. Meals. 1999. Specific inhibitors of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways block inducible nitric oxide synthase and tumor necrosis factor accumulation in murine macrophages stimulated with lipopolysaccharide and interferon-gamma. The Journal of Infectious Diseases 179: 939–944.

    PubMed  Article  CAS  Google Scholar 

  28. Pearson, G., F. Robinson, T.B. Gibson, B. Xu, M. Karandikar, K. Berman, et al. 2001. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocrine Reviews 22(2): 153–83.

    PubMed  Article  CAS  Google Scholar 

  29. Lu, Y.C., W.C. Yeh, and P.S. Ohashi. 2008. LPS/TLR4 signal transduction pathway. Cytokine 42: 145–151.

    PubMed  Article  CAS  Google Scholar 

  30. Paul, A., A. Cuenda, C.E. Bryant, J. Murray, E.R. Chilvers, P. Cohen, et al. 1999. Involvement of mitogen-activated protein kinase homologues in the regulation of lipopolysaccharide-mediated induction of cyclo-oxygenase-2 but not nitric oxide synthase in RAW264.7 macrophages. Cellular Signalling 11: 491–497.

    PubMed  Article  CAS  Google Scholar 

  31. Guan, Z., L.D. Baier, and A.R. Morrison. 1997. p38 mitogen-activated protein kinase downregulates nitric oxide and upregulates prostaglandin E2 biosynthesis stimulated by interleukin-1beta. The Journal of Biological Chemistry 272(12): 8083–8089.

    PubMed  Article  CAS  Google Scholar 

  32. Guan, Z., S.Y. Buckman, B.W. Miller, L.D. Springer, and A.R. Morrison. 1998. Interleukin-1beta-induced cyclooxygenase-2 expression requires activation of both c-Jun NH2-terminal kinase and p38 MAPK signal pathways in rat renal mesangial cells. The Journal of Biological Chemistry 273(44): 28670–28676.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from National Nature Science Foundation of China (No. 30972212) and China Postdoctoral Science Foundation (No. 20090461034).

Author information

Affiliations

  1. Department of Veterinary Pharmacology, College of Animal Science and Veterinary Medicine, Jilin University, Xi’an Road 5333, Changchun, Jilin, 130062, People’s Republic of China

    Weixiao Guo, Jingjing Sun, Meixia Huo, Na Chen, Weiting Zhong, Lanan Wassy, Zhenguo Yang & Haihua Feng

  2. Department of Dermatology, Second Hospital of Jilin University, ChangChun, 130041, People’s Republic of China

    Lanxiang Jiang

  3. Hebei Normal University of Science and Technology, Qinhuangdao, 066600, People’s Republic of China

    Lingxin Duan

Authors
  1. Weixiao Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingjing Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lanxiang Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lingxin Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meixia Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Na Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weiting Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lanan Wassy
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhenguo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Haihua Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhenguo Yang or Haihua Feng.

Additional information

Weixiao Guo and Jingjing Sun contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Guo, W., Sun, J., Jiang, L. et al. Imperatorin Attenuates LPS-Induced Inflammation by Suppressing NF-κB and MAPKs Activation in RAW 264.7 Macrophages. Inflammation 35, 1764–1772 (2012). https://doi.org/10.1007/s10753-012-9495-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-012-9495-9

KEY WORDS

  • imperatorin
  • cytokines
  • NF-κB
  • MAPK