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Leonurine Exerts Anti-Inflammatory Effect by Regulating Inflammatory Signaling Pathways and Cytokines in LPS-Induced Mouse Mastitis

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Abstract

Bovine mastitis is defined as the inflammation of mammary gland and is the most multiple diseases in dairy cattle. There is still no effective treatment now. Leonurine, extracted from Leonurus cardiaca, has been proved to have anti-inflammatory effect. In the present study, we utilized a mouse mastitis model to study the effect of leonurine on LPS-induced mastitis. Leonurine was administered three times during the 24 h after inducing infection in the mammary gland. The results showed that leonurine significantly alleviated LPS-induced histopathological changes, downregulated the levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), upregulated the level of anti-inflammatory cytokine interleukin-10 (IL-10), and inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Further study revealed that leonurine inhibited the expression of Toll-like receptor 4 (TLR4) and the activation of nuclear factor-kappaB (NF-κB) and the phosphorylation of p38, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK). Therefore, the results demonstrated that leonurine could downregulate the expression of TNF-α, IL-6, iNOS, and COX-2 and upregulate the expression of IL-10 mainly by inhibiting the expression of TLR4 and the activation of NF-κB and the phosphorylation of p38, ERK, and JNK. Leonurine may be a potential agent for mastitis therapy.

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References

  1. Viguier, C., S. Arora, N. Gilmartin, K. Welbeck, and R. O’Kennedy. 2009. Mastitis detection: current trends and future perspectives. Trends in Biotechnology 27(8): 486–493.

    Article  CAS  PubMed  Google Scholar 

  2. Gilbert, F.B., P. Cunha, K. Jensen, E.J. Glass, G. Foucras, C. Robert-Granie, R. Rupp, and P. Rainard. 2013. Differential response of bovine mammary epithelial cells to Staphylococcus aureus or Escherichia coli agonists of the innate immune system. Veterinary Research 44: 40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Coliform mastitis—a review. Journal of dairy science 1979, 62 (1):1–22.

  4. Zhao, X., and P. Lacasse. 2008. Mammary tissue damage during bovine mastitis: causes and control. Journal of Animal Science 86(13 Suppl): 57–65.

    Article  CAS  Google Scholar 

  5. Schalm, O.W., E.J. Carroll, and N.C. Jain. 1971. Bovine mastitis. In Bovine mastitis A symposium. Philadelphia: Lea & Febiger.

    Google Scholar 

  6. Oliver, S., and L. Calvinho. 1995. Influence of inflammation on mammary gland metabolism and milk composition. Journal of Animal Science 73(suppl 2): 18–33.

    Google Scholar 

  7. Aderem, A., and R.J. Ulevitch. 2000. Toll-like receptors in the induction of the innate immune response. Nature 406(6797): 782–787.

    Article  CAS  PubMed  Google Scholar 

  8. Hirschfeld, M., Y. Ma, J.H. Weis, S.N. Vogel, and J.J. Weis. 2000. Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. Journal of Immunology 165(2): 618–622.

    Article  CAS  Google Scholar 

  9. Espinosa-Oliva AM, de Pablos RM, Herrera AJ. 2013. Intracranial injection of LPS in rat as animal model of neuroinflammation. In: Microglia. edn.: Springer : 295–305.

  10. González-Terán, B., J.R. Cortés, E. Manieri, N. Matesanz, Á. Verdugo, M.E. Rodríguez, Á. González-Rodríguez, Á. Valverde, P. Martín, and R.J. Davis. 2013. Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis. The Journal of Clinical Investigation 123(1): 164–178.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Han, J.G., Y.S. Kim, B.S. Kim, and Y.K. Yim. 2014. The effect of Alismatis Rhizoma herbal-acupuncture at KI10 on LPS-induced nephritis in rats. The Acupuncture 31(1): 51–60.

    Article  Google Scholar 

  12. Takeuchi, O., K. Hoshino, T. Kawai, H. Sanjo, H. Takada, T. Ogawa, K. Takeda, and S. Akira. 1999. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11(4): 443–451.

    Article  CAS  PubMed  Google Scholar 

  13. Chandler, R.L. 1970. Experimental bacterial mastitis in the mouse. Journal of Medical Microbiology 3(2): 273–282.

    Article  CAS  PubMed  Google Scholar 

  14. Chandler, R.L. 1969. Preliminary report on the production of experimental mastitis in the mouse. The Veterinary Record 84(26): 671–672.

    Article  CAS  PubMed  Google Scholar 

  15. Notebaert, S., and E. Meyer. 2006. Mouse models to study the pathogenesis and control of bovine mastitis. A review. Vet Quart 28(1): 2–13.

    Article  CAS  Google Scholar 

  16. Li, F., D. Liang, Z. Yang, T. Wang, W. Wang, X. Song, M. Guo, E. Zhou, D. Li, Y. Cao, et al. 2013. Astragalin suppresses inflammatory responses via down-regulation of NF-kappaB signaling pathway in lipopolysaccharide-induced mastitis in a murine model. International Immunopharmacology 17(2): 478–482.

    Article  CAS  PubMed  Google Scholar 

  17. Guo, M.Y., N.S. Zhang, D.P. Li, D.J. Liang, Z.C. Liu, F.Y. Li, Y.H. Fu, Y.G. Cao, X.M. Deng, and Z.T. Yang. 2013. Baicalin plays an anti-inflammatory role through reducing nuclear factor-kappa B and p38 phosphorylation in S. aureus-induced mastitis. International Immunopharmacology 16(2): 125–130.

    Article  PubMed  Google Scholar 

  18. Wang T, Guo M, Song X, Zhang Z, Jiang H, Wang W, Fu Y, Cao Y, Zhu L, Zhang N. 2014. Stevioside plays an anti-inflammatory role by regulating the nf-kappaB and MAPK pathways in S. aureus-infected mouse mammary glands. Inflammation.

  19. Liu, X.H., L.L. Pan, H.Y. Deng, Q.H. Xiong, D. Wu, G.Y. Huang, Q.H. Gong, and Y.Z. Zhu. 2013. Leonurine (SCM-198) attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4. Free Radical Biology & Medicine 54: 93–104.

    Article  CAS  Google Scholar 

  20. Liu, X.H., H. Xin, A.J. Hou, and Y.Z. Zhu. 2009. Protective effects of leonurine in neonatal rat hypoxic cardiomyocytes and rat infarcted heart. Clin Exp Pharmacol P 36(7): 696–703.

    Article  CAS  Google Scholar 

  21. Liu, X.H., L.L. Pan, Q.H. Gong, and Y.Z. Zhu. 2010. Antiapoptotic effect of novel compound from Herba leonuri-leonurine (SCM-198): a mechanism through inhibition of mitochondria dysfunction in H9c2 cells. Curr Pharm Biotechno 11(8): 895–905.

    Article  CAS  Google Scholar 

  22. Liu, X.H., L.L. Pan, X.L. Wang, Q.H. Gong, and Y.Z. Zhu. 2012. Leonurine protects against tumor necrosis factor-alpha-mediated inflammation in human umbilical vein endothelial cells. Atherosclerosis 222(1): 34–42.

    Article  CAS  PubMed  Google Scholar 

  23. Song X, Zhang W, Wang T, Jiang H, Zhang Z, Fu Y, Yang Z, Cao Y, Zhang N. 2014. Geniposide plays an anti-inflammatory role via regulating TLR4 and downstream signaling pathways in lipopolysaccharide-induced mastitis in mice. Inflammation.

  24. Li, Q., and I.M. Verma. 2002. NF-kappaB regulation in the immune system. Nature Reviews Immunology 2(10): 725–734.

    Article  CAS  PubMed  Google Scholar 

  25. Strandberg, Y., C. Gray, T. Vuocolo, L. Donaldson, M. Broadway, and R. Tellam. 2005. Lipopolysaccharide and lipoteichoic acid induce different innate immune responses in bovine mammary epithelial cells. Cytokine 31(1): 72–86.

    Article  CAS  PubMed  Google Scholar 

  26. Brouillette, E., and F. Malouin. 2005. The pathogenesis and control of Staphylococcus aureus-induced mastitis: study models in the mouse. Microbes and Infection 7(3): 560–568.

    Article  PubMed  Google Scholar 

  27. Bannerman, D.D., M.J. Paape, J.W. Lee, X. Zhao, J.C. Hope, and P. Rainard. 2004. Escherichia coli and Staphylococcus aureus elicit differential innate immune responses following intramammary infection. Clinical and Diagnostic Laboratory Immunology 11(3): 463–472.

    PubMed Central  PubMed  Google Scholar 

  28. Wojtyniak, K., M. Szymanski, and I. Matlawska. 2013. Leonurus cardiaca L. (motherwort): a review of its phytochemistry and pharmacology. Phytotherapy research : PTR 27(8): 1115–1120.

    Article  PubMed  Google Scholar 

  29. Xu, D., M. Chen, X. Ren, X. Ren, and Y. Wu. 2014. Leonurine ameliorates LPS-induced acute kidney injury via suppressing ROS-mediated NF-kappaB signaling pathway. Fitoterapia 97C: 148–155.

    Article  Google Scholar 

  30. Oviedo-Boyso, J., J.J. Valdez-Alarcon, M. Cajero-Juarez, A. Ochoa-Zarzosa, J.E. Lopez-Meza, A. Bravo-Patino, and V.M. Baizabal-Aguirre. 2007. Innate immune response of bovine mammary gland to pathogenic bacteria responsible for mastitis. The Journal of Infection 54(4): 399–409.

    Article  PubMed  Google Scholar 

  31. Persson Waller, K., I.G. Colditz, S. Lun, and K. Ostensson. 2003. Cytokines in mammary lymph and milk during endotoxin-induced bovine mastitis. Research in Veterinary Science 74(1): 31–36.

    Article  CAS  PubMed  Google Scholar 

  32. Platzer, C. 2003. Interleukin-10: an anti-inflammatory and immunosuppressive cytokine in the normal and pathological immune response. Current Medicinal Chemistry-Anti-Inflammatory & Anti-Allergy Agents 2(4): 309–323.

    Article  CAS  Google Scholar 

  33. Redpath, S., P. Ghazal, and N.R. Gascoigne. 2001. Hijacking and exploitation of IL-10 by intracellular pathogens. Trends in Microbiology 9(2): 86–92.

    Article  CAS  PubMed  Google Scholar 

  34. Liang, D., F. Li, Y. Fu, Y. Cao, X. Song, T. Wang, W. Wang, M. Guo, E. Zhou, D. Li, et al. 2014. Thymol inhibits LPS-stimulated inflammatory response via down-regulation of NF-kappaB and MAPK signaling pathways in mouse mammary epithelial cells. Inflammation 37(1): 214–222.

    Article  CAS  PubMed  Google Scholar 

  35. Muller-Decker, K., and G. Furstenberger. 2007. The cyclooxygenase-2-mediated prostaglandin signaling is causally related to epithelial carcinogenesis. Molecular Carcinogenesis 46(8): 705–710.

    Article  PubMed  Google Scholar 

  36. Sakthivel, K.M., and C. Guruvayoorappan. 2013. Amentoflavone inhibits iNOS, COX-2 expression and modulates cytokine profile, NF-kappaB signal transduction pathways in rats with ulcerative colitis. International Immunopharmacology 17(3): 907–916.

    Article  CAS  PubMed  Google Scholar 

  37. Xiong H, Cheng Y, Zhang X, Zhang X. 2014. Effects of taraxasterol on iNOS and COX-2 expression in LPS-induced RAW 264.7 macrophages. Journal of ethnopharmacology.

  38. Zhu, Y., M. Zhu, and P. Lance. 2012. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts. Experimental Cell Research 318(16): 2116–2127.

    Article  CAS  PubMed  Google Scholar 

  39. Kundu, J.K., and Y.-J. Surh. 2004. Molecular basis of chemoprevention by resveratrol: NF-κB and AP-1 as potential targets. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 555(1): 65–80.

    Article  CAS  Google Scholar 

  40. Thalhamer, T., M.A. McGrath, and M.M. Harnett. 2008. MAPKs and their relevance to arthritis and inflammation. Rheumatology 47(4): 409–414.

    Article  CAS  PubMed  Google Scholar 

  41. Lu, Y.C., W.C. Yeh, and P. Ohashi. 2008. LPS/TLR4 signal transduction pathway. Cytokine 42(2): 145–151.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China (Nos. 31272622, 31201925), the Research Fund for the Doctoral Program of Higher Education of China (Nos. 20110061130010, 20120061120098), and Jilin Province Science Foundation for Youths (No. 20130522087JH).

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The authors declare that there is no conflict of interests regarding the publication of this paper.

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Authors and Affiliations

  1. Department of Clinical Veterinary Medicine College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, People’s Republic of China

    Xiaojing Song, Tiancheng Wang, Zecai Zhang, Haichao Jiang, Wei Wang, Yongguo Cao & Naisheng Zhang

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  1. Xiaojing Song
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Correspondence to Yongguo Cao or Naisheng Zhang.

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Xiaojing Song and Tiancheng Wang contributed equally to this work and are to be considered the first authors.

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Song, X., Wang, T., Zhang, Z. et al. Leonurine Exerts Anti-Inflammatory Effect by Regulating Inflammatory Signaling Pathways and Cytokines in LPS-Induced Mouse Mastitis. Inflammation 38, 79–88 (2015). https://doi.org/10.1007/s10753-014-0009-9

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