Skip to main content
SpringerLink
Log in

Bone Marrow Mesenchymal Stem Cells Alleviate Extracellular Kynurenine Levels, as Detected by High-Performance Liquid Chromatography

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Endothelial cell dysfunction plays an important role in the occurrence and development of sepsis, which is a consequence of the interaction between coagulation and inflammation. Kynurenine (KYN) is an endothelium-derived relaxing factor that makes a large contribution to sepsis pathophysiology. In this study, we investigated the influence of bone marrow mesenchymal stem cells (BMSCs) on KYN production by cultured endothelial cells. KYN and tryptophan (TRP) concentrations in cell supernatants were simultaneously measured with a high-performance liquid chromatography (HPLC) system equipped with a fluorescence detector (FLD) and an ultraviolet detector (UVD). Our results revealed that lipopolysaccharide-stimulated endothelial cells produced more KYN, which was accompanied by a parallel decrease in TRP. When co-cultured with BMSCs, KYN and TRP production were significantly decreased compared to lipopolysaccharide (LPS)-induction alone. Our results suggest that BMSCs can attenuate endothelial cell damage by decreasing KYN as detected with HPLC. This method is the first to be capable of capturing functional changes in the cells and is simple, fast, and suitable for cellular level research purposes.

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

Similar content being viewed by others

REFERENCES

  1. Wang, Y., H. Liu, G. McKenzie, P.K. Witting, J.P. Stasch, M. Hahn, D. Changsirivathanathamro-ng, B.J. Wu, H.J. Ball, S.R. Thomas, V. Kapoor, D.S. Celermajer, A.L. Mellor, J.F. Keaney Jr., N.H. Hunt, and R. Stocker. 2010. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nature Medicine 16: 279–285.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Riedemann, N.C., R.F. Guo, and P.A. Ward. 2003. Novel strategies for the treatment of sepsis. Nature Medicine 9: 517–524.

    Article  CAS  PubMed  Google Scholar 

  3. Nemeth, K., A. Leelahavanichkul, P.S. Yuen, B. Mayer, A. Parmelee, K. Doi, P.G. Robey, K. Leelahavanichkul, B.H. Koller, J.M. Brown, X. Hu, I. Jelinek, R.A. Star, and E. Mezey. 2009. Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature Medicine 15: 42–49.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Elman, J.S., M. Li, F. Wang, J.M. Gimble, and B. Parekkadan. 2014. A comparison of adipose and bone marrow-derived mesenchymal stromal cell secreted factors in the treatment of systemic inflammation. Journal of Inflammation 11: 1186/1476–9255.

    Article  Google Scholar 

  5. Kusadasi, N., and A.B... Groeneveld. 2013. A perspective on mesenchymal stromal cell transplantation in the treatment of sepsis. Shock 40: 352–357.

  6. Hall, S.R., K. Tsoyi, B. Ith, R.F. Jr, J.A. Padera, Z. Lederer, X. Liu Wang, and M.A. Perrella. 2013. Mesenchymal stromal cells improve survival during sepsis in the absence of heme oxygenase-1: the importance of neutrophils. Stem Cells 31: 397–407.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Shin, S., Y. Kim, S. Jeong, S. Hong, I. Kim, W. Lee, and S. Choi. 2013. The therapeutic effect of human adult stem cells derived from adipose tissue in endotoxemic rat model. International Journal of Medical Sciences 10: 8–18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Zhao, Y., C. Yang, H. Wang, H. Li, J. Du, W. Gu, and J. Jiang. 2013. Therapeutic effects of bone marrow-derived mesenchymal stem cells on pulmonary impact injury complicated with endotoxemia in rats. International Immunopharmacology 15: 246–253.

    Article  CAS  PubMed  Google Scholar 

  9. Yagi, H., A. Soto-Gutierrez, N. Navarro-Alvarez, Y. Nahmias, Y. Goldwasser, Y. Kitagawa, A.W. Tilles, R.G. Tompkins, B. Parekkadan, and M.L. Yarmush. 2010. Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1. Molecular Therapy 18: 1857–1864.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Gotts, J.E., and M.A. Matthay. 2011. Mesenchymal stem cells and acute lung injury. Critical Care Clinics 27: 719–733.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Tang, K., X. Xiao, D. Liu, Y. Shen, Y. Chen, Y. Wang, B. Li, F. Yu, D. Ma, J. Yan, H. Liang, D. Yang, and J. Weng. 2014. Autografting of bone marrow mesenchymal stem cells alleviates streptozotocin-induced diabetes in miniature pigs: real-time tracing with MRI in vivo. International Journal of Molecular Medicine 33: 1469–1476.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Zhu, W., A.P. Stevens, K. Dettmer, E. Gottfried, S. Hoves, M. Kreutz, E. Holler, A.B... Canelas, I. Kema, and P.J. Oefner. 2011. Quantitative profiling of tryptophan metabolites in serum, urine, and cell culture supernatants by liquid chromatography-tandem mass spectrometry. Analytical and Bioanalytical Chemistry 401: 3249–3261.

  13. Xiang, Z.Y., A.G. Tang, Y.P. Ren, Q.X. Zhou, and X.B. Luo. 2010. Simultaneous determination of serum tryptophan metabolites in patients with systemic lupus erythematosus by high performance liquid chromatography with fluorescence detection. Clinical Chemistry Laboratory Medicine 48: 513–517.

    Article  CAS  PubMed  Google Scholar 

  14. Brouns, R., R. Verkerk, T. Aerts, S.D. De, A. Wauters, S. Scharpé, and P.P. De Deyn. 2010. The role of tryptophan catabolism along the kynurenine pathway in acute ischemic stroke. Neurochemical Research 35: 1315–1322.

    Article  CAS  PubMed  Google Scholar 

  15. Quak, J., B. Doornbos, A.M. Roest, H.E. Duivis, N. Vogelzangs, W.A. Nolen, B.W. Penninx, I.P. Kema, and J.P. De. 2014. Does tryptophan degradation along the kynurenine pathway mediate the association between pro-inflammatory immune activity and depressive symptoms? Psychoneuroendocrinology 45: 202–210.

    Article  CAS  PubMed  Google Scholar 

  16. Hou, W., G. Huang, X. Cao, Y. Zhang, J. Zhang, and Y. Li. 2014. Suppression of experimental autoimmune glomerulonephritis by tryptophan. Journal of Nephrology 27: 19–28.

    Article  PubMed  Google Scholar 

  17. Bao, Y.S., Y. Ji, S.L. Zhao, L.L. Ma, R.J. Xie, and S.P. Na. 2013. Serum levels and activity of indoleamine2,3-dioxygenase and tryptophanyl-tRNA synthetase and their association with disease severity in patients with chronic kidney disease. Biomarkers 18: 379–385.

    Article  CAS  PubMed  Google Scholar 

  18. Taguchi, A., M. Niwa, M. Hoshi, K. Saito, T. Masutani, K. Hisamatsu, K. Kobayashi, Y. Hatano, H. Tomita, and A. Hara. 2014. Indoleamine 2,3-dioxygenase 1 is upregulated in activated microglia in mice cerebellum during acute viral encephalitis. Neuroscience Letters 564: 120–125.

    Article  CAS  PubMed  Google Scholar 

  19. Tanizaki, Y., A. Kobayashi, S. Toujima, M. Shiro, M. Mizoguchi, Y. Mabuchi, S. Yagi, S. Minami, O. Takikawa, and K. Ino. 2014. Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment. Cancer Science 105: 966–973.

    Article  CAS  PubMed  Google Scholar 

  20. Xiao, C., Y. Chen, X. Liang, Z. Xie, M. Zhang, R. Li, Z. Li, X. Fu, X. Yu, and W. Shi. 2014. A modified HPLC method improves the simultaneous determination of plasma kynurenine and tryptophan concentrations in patients following maintenance hemodialysis. Experimental and Therapeutic Medicine 7: 907–910.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Mitsuhashi, S., T. Fukushima, M. Tomiya, T. Santa, K. Imai, and T. Toyo’oka. 2007. Determination of kynurenine levels in rat plasma by high-performance liquid chromatography with pre-column fluorescence derivatization. Analytical Chimica Acta 584: 315–321.

    Article  CAS  Google Scholar 

  22. Russell, J.A. 2006. Management of sepsis. The New England Journal of Medicine 355: 1699–1713.

    Article  CAS  PubMed  Google Scholar 

  23. Kager, L.M., W.J. Wiersinga, J.J. Roelofs, B.O.J. De, H. Weiler, C. van’t Veer, and T. van der Poll. 2014. A thrombomodulin mutation that impairs active protein C generation is detrimental in severe pneumonia-derived gram-negative sepsis (melioidosis). PLos Neglected Tropical Diseases 8: e2819.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Levi, M., and T. van der Poll. 2013. Endothelial injury in sepsis. Intensive Care Medicine 39: 1839–1842.

    Article  PubMed  Google Scholar 

  25. Levi, M., T. van der Poll, and M. Schultz. 2012. New insights into pathways that determine the link between infection and thrombosis. The Netherlands Journal of Medicine 70: 114–120.

    CAS  PubMed  Google Scholar 

  26. de Stoppelaar, S.F., C. van 't Veer, and T. van der Poll. 2014. The role of platelets in sepsis. Thrombosis and Haemostasis 112: 666–677.

    Article  PubMed  Google Scholar 

  27. Bijli, K.M., B.G. Kanter, M. Minhajuddin, A. Leonard, L. Xu, F. Fazal, and A. Rahman. 2014. Regulation of endothelial cell inflammation and lung PMN Infiltration by transglutaminase 2. Shock 42: 562–569.

    Article  CAS  PubMed  Google Scholar 

  28. Levi, M., and T. van der Poll. 2005. Two-way interactions between inflammation and coagulation. Trends in Cardiovascular Medicine 15: 254–259.

    Article  CAS  PubMed  Google Scholar 

  29. Zhao, T., Y. Li, B. Liu, E. Wu, M. Sillesen, G.C. Velmahos, I. Halaweish, and H.B. Alam. 2014. Histone deacetylase inhibitor treatment attenuates coagulation imbalance in a lethal murine model of sepsis. Surgery 156: 214–220.

    Article  PubMed  Google Scholar 

  30. Krampera, M., L. Cosmi, R. Angeli, A. Pasini, F. Liotta, A. Andreini, V. Santarlasci, B. Mazzinghi, G. Pizzolo, F. Vinante, P. Romagnani, E. Maggi, S. Romagnani, and F. Annunziato. 2006. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24: 386–398.

    Article  CAS  PubMed  Google Scholar 

  31. Jones, S.P., G.J. Guillemin, and B.J. Brew. 2013. The kynurenine pathway in stem cell biology. International Journal of Tryptophan Research 15: 57–66.

    Article  Google Scholar 

  32. Lanz, T.V., C.A. Opitz, P.P. Ho, A. Agrawal, C. Lutz, M. Weller, A.L. Mellor, L. Steinman, W. Wick, and M. Platten. 2010. Mouse mesenchymal stem cells suppress antigen-specific TH cell immunity independent of indoleamine 2,3-dioxygenase 1 (IDO1). Stem Cells and Development 19: 657–668.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. O'Connor, J.C., M.A. Lawson, C. André, M. Moreau, J. Lestage, N. Castanon, K.W. Kelley, and R. Dantzer. 2009. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Molecular Psychiatry 14: 511–522.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Furchgott, R.F., and J.V. Zawadzki. 1980. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373–376.

    Article  CAS  PubMed  Google Scholar 

  35. Stamler, J.S., O. Jaraki, J. Osborne, D.I. Simon, J. Keaney, J. Vita, D. Singel, C.R. Valeri, and J. Loscalzo. 1992. Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin. Proceedings of the National Academy Sciences of the United States of America 89: 7674–7677.

    Article  CAS  Google Scholar 

  36. Thomas, S.R., A.C. Terentis, H. Cai, O. Takikawa, A. Levina, P.A. Lay, M. Freewan, and R. Stocker. 2007. Post-translational regulation of human indoleamine 2,3-dioxygenase activity by nitric oxide. The Joural of Biological Chemistry 282: 23778–23787.

    Article  CAS  Google Scholar 

  37. Thomas, S.R., D. Mohr, and R. Stocker. 1994. Nitric oxide inhibits indoleamine 2,3-dioxygenase activity in interferon-gamma primed mononuclear phagocytes. The Joural of Biological Chemistry 269: 14457–14464.

    CAS  Google Scholar 

Download references

ACKNOWLEDGEMENTS

This work was supported by the National Natural Science Foundation of China (81171787) and Zhejiang Province Natural Science Foundation of China (LY12H15001). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Department of the First Clinical Medical, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China

    Yuanyuan Wang, Jing Zhao, Lifei Tan & Min Li

  2. Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China

    Yueyue Huang & Jingye Pan

  3. Department of Traumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China

    Dequan Li

  4. Department of General Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China

    Shichao Quan

Authors
  1. Yuanyuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lifei Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yueyue Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dequan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shichao Quan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Min Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jingye Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jingye Pan.

Additional information

Submitted to Inflammation

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Zhao, J., Tan, L. et al. Bone Marrow Mesenchymal Stem Cells Alleviate Extracellular Kynurenine Levels, as Detected by High-Performance Liquid Chromatography. Inflammation 38, 1450–1457 (2015). https://doi.org/10.1007/s10753-015-0119-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-015-0119-z

KEY WORDS

Search

Navigation