Advertisement

Inflammation

pp 1–10 | Cite as

Ellipticine Conveys Protective Effects to Lipopolysaccharide-Activated Macrophages by Targeting the JNK/AP-1 Signaling Pathway

  • Li-Xing Tian
  • Xiao-Yu Li
  • Xin Tang
  • Xiao-Ying Zhou
  • Li Luo
  • Xiao-Yuan Ma
  • Wan-Qi Tang
  • Jing Yu
  • Wei Ma
  • Xue Yang
  • Jun Yan
  • Xiang Xu
  • Hua-Ping LiangEmail author
Original Article
  • 35 Downloads

Abstract

Ellipticine, a natural product from Ochrosia elliptica, has been broadly investigated for its anticancer effects. Although inflammation has been clearly identified as a key factor in the onset and progression of cancer, the relationship between ellipticine and inflammation remains unknown. Hence, the aims of the present study were to assess the effects of ellipticine on the inflammatory responses to lipopolysaccharide (LPS)-induced macrophages and to potentially identify the underlying mechanisms involved. Viability testing showed that ellipticine was not significantly toxic to Raw264.7 cells and actually conveyed protective effects to LPS-stimulated Raw264.7 cells and human peripheral blood monocytes by decreasing the secretion of inflammatory factors (TNF-α and IL-6). The results of western blot analysis and electrophoretic mobility shift assays showed that ellipticine markedly suppressed LPS-induced activation of the JNK/AP-1 (c-Fos and c-Jun) signaling pathway, but not ERK/p38/NF-κB pathway (p65 and p50) activation. Furthermore, ellipticine reduced the inflammatory response and mortality in a mouse model of LPS-induced endotoxic shock. Collectively, these data indicate that ellipticine may be a potential therapeutic agent for the treatment of inflammation-associated diseases.

KEY WORDS

ellipticine inflammation macrophages JNK/AP-1 

Notes

Funding Information

This work was supported by grants from the National Natural Science Foundation of China (grant no. 81871612), the Fund of State Key Laboratory of Trauma, Burn, and Combined Injury (grant no. SKLJYJF03, SKLZZ201709), and the Fund of Basic Science and Frontier Q8 Technology Research of Chongqing (grant no. cstc2017jcyjAX0159).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Chabane, N., and H. Fahmi. 2008. Histone deacetylase inhibitors suppressed interleukin-1beta-induced nitric oxide and prostaglandin E2 production in human chondrocytes. Osteoarthritis and Cartilage 16 (10): 1267–1274.PubMedCrossRefGoogle Scholar
  2. 2.
    Yue, S., L.S. Zhong, and L. Tiao. 2015. SeMet mediates anti-inflammation in LPS-induced U937 cells targeting NF-κB signaling pathway inflammation. Inflammation. 38 (2): 736–744.CrossRefGoogle Scholar
  3. 3.
    Aardoom, M.A., G. Veereman, and L. de Ridder. 2019. A review on the use of anti-TNF in children and adolescents with inflammatory bowel disease. Int J Mol Sci 20 (10): 2529.PubMedCentralCrossRefGoogle Scholar
  4. 4.
    Stiborova, M., V. Cerna, M. Moserova, I. Mrizova, V.M. Arlt, and E. Frei. 2014. The anticancer drug ellipticine activated with cytochrome P450 mediates DNA damage determining its pharmacological efficiencies: studies with rats, Hepatic Cytochrome P450 Reductase Null (HRN) mice and pure enzymes. Int J Mol Sci 16 (1): 284–306.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Stiborova, M., M. Rupertova, and E. Frei. 2011. Cytochrome P450 and peroxidase-mediated oxidation of anticancer alkaloid ellipticine dictates its anti-tumor efficiency. Biochim Biophys Acta 1814 (1): 175–185.PubMedCrossRefGoogle Scholar
  6. 6.
    Kizek, R., T. Eckschlager, S. Smutny, J.V. Burda, E. Frei, and M. Stiborova. 2012. Anthracyclines and ellipticines as DNA-damaging anticancer drugs: recent advances. Pharmacol Ther. 133 (1): 26–39.PubMedCrossRefGoogle Scholar
  7. 7.
    Fritsche, M., C. Haessler, and G. Brandner. 1993. Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. Oncogene 8: 307–318.PubMedGoogle Scholar
  8. 8.
    Stiborova, M., J. Poljakova, H. Ryslava, M. Dracinsky, T. Eckschlager, and E. Frei. 2007. Mammalian peroxidases activate anticancer drug ellipticine to intermediates forming deoxyguanosine adducts in DNA identical to those found in vivo and generated from 12-hydroxyellipticine and 13-hydroxyellipticine. Int J Cancer 120 (2): 243–251.PubMedCrossRefGoogle Scholar
  9. 9.
    Kim, J.Y., S.G. Lee, J.Y. Chung, Y.J. Kim, J.E. Park, H. Koh, M.S. Han, Y.C. Park, Y.H. Yoo, and J.M. Kim. 2011. Ellipticine induces apoptosis in human endometrial cancer cells: the potential involvement of reactive oxygen species and mitogen-activated protein kinases. Toxicology 289 (2-3): 91–102.PubMedCrossRefGoogle Scholar
  10. 10.
    Poljakova, J., T. Eckschlager, J. Hrabeta, J. Hrebackova, S. Smutny, E. Frei, V. Martinek, R. Kizek, and M. Stiborova. 2009. The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells. Biochem Pharmacol 77 (9): 1466–1479.PubMedCrossRefGoogle Scholar
  11. 11.
    Wen, H.L., G. Yang, and Q.R. Dong. 2017. Ellipticine inhibits the proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via the STAT3 pathway. Immunopharmacol Immunotoxicol. 39 (4): 219–224.PubMedCrossRefGoogle Scholar
  12. 12.
    Ji, Z., and Li He. 2019. Inflammatory regulatory network mediated by the joint action of NF-kB, STAT3, and AP-1 factors is involved in many human cancers. Proc Natl Acad Sci U S A. 116 (19): 9453–9462.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Cheng, X., H. Yonglian, G. Qiyuan, F. Zijian, L. Qi, and L. Zhen. 2019. Expression of activator protein-1 in papillary thyroid carcinoma and its clinical significance. World J Surg Oncol. 17 (1): 25.CrossRefGoogle Scholar
  14. 14.
    Qian BZ. And Pollard JW. 2010. Macrophage diversity enhances tumor progression and metastasis.Cell. ;141(1):39-51.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Eissmann, M.F., C. Dijkstra, and T. Phesse. 2019. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nature commun. 10 (1): 2735.CrossRefGoogle Scholar
  16. 16.
    Corbacioglu, S., E.J. Jabbour, and M. Mohty. 2019. Risk factors for development of and progression of hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Biol Blood Marrow Transplant. 22.  https://doi.org/10.1016/j.bbmt.2019.02.018.PubMedCrossRefGoogle Scholar
  17. 17.
    Furst, D.E., J. Belasco, and J.S. Louie. 2019. Genetic and inflammatory factors associated with psoriatic arthritis: Relevance to diagnosis and management. Clin Immunol 202: 59–75.PubMedCrossRefGoogle Scholar
  18. 18.
    Gombert, M., J. Carrasco-Luna, G. Pin-Arboledas, and P. Codoner-Franch. 2019. The connection of circadian rhythm to inflammatory bowel disease. Transl Res 206: 107–118.PubMedCrossRefGoogle Scholar
  19. 19.
    Bhatia, M., and S. Moochhala. 2004. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol 202 (2): 145–156.PubMedCrossRefGoogle Scholar
  20. 20.
    Kizek, R., V. Adam, J. Hrabeta, T. Eckschlager, S. Smutny, J.V. Burda, E. Frei, and M. Stiborova. 2012. Anthracyclines and ellipticines as DNA-damaging anticancer drugs: Recent advances. Pharmacol. Ther. 133 (1): 26–39.PubMedCrossRefGoogle Scholar
  21. 21.
    Auclair, C. 1987. Multimodal action of antitumor agents on DNA: The ellipticine series. Arch. Biochem. Biophys. 259 (1): 1–14.PubMedCrossRefGoogle Scholar
  22. 22.
    Garbett, N.C., and D.E. Graves. 2004. Extending nature’s leads: The anticancer agent ellipticine. Curr. Med. Chem. Anti-Cancer Agents 4 (2): 149–172.PubMedCrossRefGoogle Scholar
  23. 23.
    Prosperi, D., M. Colombo, I. Zanoni, and F. Granucci. 2017. Drug nanocarriers to treat autoimmunity and chronic inflammatory diseases. Semin Immunol 34: 61–67.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Jeong, S.O., Y. Son, J.H. Lee, Y.K. Cheong, S.H. Park, H.T. Chung, and H.O. Pae. 2015. Resveratrol analog piceatannol restores the palmitic acid-induced impairment of insulin signaling and production of endothelial nitric oxide via activation of anti-inflammatory and antioxidative heme oxygenase-1 in human endothelial cells. Mol Med Rep 12 (1): 937–944.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Kim, K.N., Y.J. Ko, M.C. Kang, H.M. Yang, S.W. Roh, T. Oda, Y.J. Jeon, W.K. Jung, S.J. Heo, W.J. Yoon, and D. Kim. 2013. Anti-inflammatory effects of trans-1,3-diphenyl-2,3-epoxypropane-1-one mediated by suppression of inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. Food Chem Toxicol 53: 371–375.PubMedCrossRefGoogle Scholar
  26. 26.
    Medzhitov, R., and T. Horng. 2009. Transcriptional control of the inflammatory response. Nat. Rev. Immunol. 9 (10): 692–703.PubMedCrossRefGoogle Scholar
  27. 27.
    Liu, Y., D. Li, Q. Jiang, Q. Zhang, P. Liu, L. Wang, and M. Zong. 2019. (3R, 7R)-7-Acetoxyl-9-Oxo-de-O-Methyllasiodiplodin, a Secondary Metabolite of Penicillium Sp., Inhibits LPS-Mediated Inflammation in RAW 264.7 Macrophages through Blocking ERK/MAPKs and NF-kappaB Signaling Pathways. Inflammation.  https://doi.org/10.1007/s10753-019-01009-x.PubMedCrossRefGoogle Scholar
  28. 28.
    Stiborova, M., and M. Rupertova. 2006. Molecular mechanisms of antineoplastic action of an anticancer drug ellipticine. Biomed Pap Med 150 (1): 13–23.CrossRefGoogle Scholar
  29. 29.
    Contreras, I., M.A. Gomez, O. Nguyen, M.T. Shio, R.W. McMaster, and M. Olivier. 2010. Leishmania-induced inactivation of the macrophage transcription factor AP-1 is mediated by the parasite metalloprotease GP63. PLoS Pathog 6 (10): e1001148.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Hu, X., J. Chen, L. Wang, and L.B. Ivashkiv. 2007. Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. J Leukoc Biol 82 (2): 237–243.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Li-Xing Tian
    • 1
  • Xiao-Yu Li
    • 2
  • Xin Tang
    • 1
  • Xiao-Ying Zhou
    • 1
  • Li Luo
    • 1
  • Xiao-Yuan Ma
    • 1
  • Wan-Qi Tang
    • 1
  • Jing Yu
    • 1
  • Wei Ma
    • 1
  • Xue Yang
    • 1
  • Jun Yan
    • 1
  • Xiang Xu
    • 1
  • Hua-Ping Liang
    • 1
    Email author
  1. 1.State Key Laboratory of Trauma, Burns and Combined InjuryDepartment of Wound Infection and Drug, Daping Hospital, Army Medical UniversityChongqingChina
  2. 2.Department Of emergencyThe Third Affiliated Hospital of Chongqing Medical UniversityChongqingChina

Personalised recommendations