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Immune Stimulation by Exogenous Melatonin During Experimental Endotoxemia

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Abstract

Melatonin has been shown to enhance the immune response under immune-compromised conditions. However, its immune-modulatory effects under inflammatory conditions are unclear at present. Both pro- and anti-inflammation has been reported. To study time-dependent effects of melatonin on the general immune response during endotoxemia in more detail, we used two models in male rats: per-acute endotoxemia was induced by lipopolysaccharide (LPS) bolus injection (2.5 mg/kg), sub-acute endotoxemia by LPS infusion (2.5 mg/kg × h). Melatonin was applied directly before and 2 h after LPS administration (3 mg/kg, each). The LPS-induced formation of the pro-inflammatory cytokines tumor necrosis factor alpha, interferon-gamma, interleukin (IL)-1α/β, IL-5, and IL-6 and of the anti-inflammatory cytokine IL-10 was further amplified by melatonin, although it was only significant during per-acute endotoxemia. In both models, melatonin had no effect on the LPS-induced nitric oxide release. These findings show that exogenous melatonin is capable of enhancing the general immune response under inflammatory conditions.

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References

  1. Bone, R. 1991. Gram-negative sepsis. Background, clinical features, and intervention. Chest 100: 802–808.

    Article  CAS  PubMed  Google Scholar 

  2. Trampuz, A., and W. Zimmerli. 2003. Pathogenesis und Therapie der Sepsis. Schweiz Medical Forum 35: 811–818.

    Google Scholar 

  3. Vincent, J.L., E.C. Serrano, and A. Dimoula. 2011. Current management of sepsis in critically ill adult patients. Expert Review of Anti-Infective Therapy 9: 847–856.

    Article  CAS  PubMed  Google Scholar 

  4. Poli-de-Figueiredo, L.F., A.G. Garrido, N. Nakagawa, and P. Sannomiya. 2008. Experimental models of sepsis and their clinical relevance. Shock 30(Suppl 1): 53–59.

    Article  CAS  PubMed  Google Scholar 

  5. Remick, D.G., and P.A. Ward. 2005. Evaluation of endotoxin models for the study of sepsis. Shock 24: 7–11.

    Article  CAS  PubMed  Google Scholar 

  6. Guardiola-Lemaitre, B. 1997. Toxicity of melatonin. Journal of Biological Rhythms 12: 697–706.

    Article  CAS  PubMed  Google Scholar 

  7. Challet, E. 2007. Minireview: entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals. Endocrinology 148: 5648–5655.

    Article  CAS  PubMed  Google Scholar 

  8. Luchetti, F., B. Canonico, M. Betti, et al. 2010. Melatonin signaling and cell protection function. FASEB Journal 24: 3603–3624.

    Article  CAS  PubMed  Google Scholar 

  9. Tan, D.X., L.C. Manchester, R. Hardeland, et al. 2003. Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. Journal of Pineal Research 34: 75–78.

    Article  CAS  PubMed  Google Scholar 

  10. Reiter, R.J., D.-X. Tan, L.C. Manchester, et al. 2007. Medical implication of melatonin: receptor-mediated and receptor-independent actions. Advanced Medical Science 52: 11–28.

    CAS  Google Scholar 

  11. Tan, D.X., L.D. Chen, B. Poeggeler, et al. 1993. Melatonin: a potent endogenous hydroxyl radical scavenger. Endocrine Journal 1: 57–60.

    Google Scholar 

  12. Genade, S., A. Genis, K. Ytrehus, et al. 2008. Melatonin receptor-mediated protection against myocardial ischaemia/reperfusion injury: role of its anti-adrenergic actions. Journal of Pineal Research 45: 449–458.

    Article  CAS  PubMed  Google Scholar 

  13. Jockers, R., P. Maurice, J.A. Boutin, and P. Delagrange. 2008. Melatonin receptors, heterodimerization, signal transduction and binding sites: what’s new? British Journal of Pharmacology 154: 1182–1195.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Krause, D.N. 1991. Melatonin receptors. Annual Review of Pharmacology and Toxicology 31: 549–568.

    Article  CAS  PubMed  Google Scholar 

  15. Carrillo-Vico, A., P.J. Lardone, N. Alvarez-Sanchez, et al. 2013. Melatonin: buffering the immune system. International Journal of Molecular Sciences 14: 8638–8683.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Tian, Y.M., G.Y. Zhang, and Y.R. Dai. 2003. Melatonin rejuvenates degenerated thymus and redresses peripheral immune functions in aged mice. Immunology Letters 88: 101–104.

    Article  CAS  PubMed  Google Scholar 

  17. Akbulut, K.G., B. Gönül, and H. Akbulut. 2001. The effects of melatonin on humoral immune responses of young and aged rats. Immunological Investigations 30: 17–20.

    Article  CAS  PubMed  Google Scholar 

  18. Maestroni, G.J., A. Conti, and W. Pierpaoli. 1986. Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone. Journal of Neuroimmunology 13: 19–30.

    Article  CAS  PubMed  Google Scholar 

  19. Haldar, C., S. Rai, and R. Singh. 2004. Melatonin blocks dexamethasone-induced immunosuppression in a seasonally breeding rodent Indian palm squirrel, Funambulus pennan. Steroids 69: 367–377.

    Article  CAS  PubMed  Google Scholar 

  20. Miller, S.C., P.S.R. Pandi, A.I. Esquifino, et al. 2006. The role of melatonin in immuno-enhancement: potential application in cancer. International Journal of Experimental Pathology 87: 81–87.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Srinivasan, V., S.R. Pandi-Perumal, A. Brzezinski, et al. 2011. Melatonin, immune function and cancer. Recent Patent Endocrine Metabolic Immune Drug Discoveries 5: 109–123.

    Article  CAS  Google Scholar 

  22. Regodon, S., P. Martin-Palomino, R. Fernandez-Montesinos, et al. 2005. The use of melatonin as a vaccine agent. Vaccine 23: 5321–5327.

    Article  CAS  PubMed  Google Scholar 

  23. Regodon, S., M. Del Prado Miguez, I. Jardin, et al. 2009. Melatonin, as an adjuvant-like agent, enhances platelet responsiveness. Journal of Pineal Research 46: 275–285.

    Article  CAS  PubMed  Google Scholar 

  24. Shang, Y., S.-P. Xu, Y. Wu, et al. 2009. Melatonin reduces acute lung injury in endotoxemic rats. Chinese Medical Journal 122: 1388–1393.

    CAS  PubMed  Google Scholar 

  25. Wu, C.-C., C.-W. Chiao, G. Hsiao, et al. 2001. Melatonin prevents endotoxin-induced circulatory failure in rats. Journal of Pineal Research 30: 147–156.

    Article  CAS  PubMed  Google Scholar 

  26. Lowes, D.A., N.R. Webster, M.P. Murphy, and H.F. Galley. 2013. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. British Journal of Anaesthesia 110: 472–480.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Naidu, K.S., L.W. Morgan, and M.J. Bailey. 2010. Inflammation in the avian spleen: timing is everything. BMC Molecular Biology 11: 104.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Bitzer-Quintero, O.K., G.G. Ortiz, L. Ruiz-Rizo, et al. 2005. Effects of melatonin on plasma levels of TNFa, IL-1 and IL-6 in mice after lipopolysaccharide administration. Biological Rhythm Research 36: 159–168.

    Article  CAS  Google Scholar 

  29. Del Angel-Meza, A.R., A.J. Davalos-Marin, L.L. Ontiveros-Martinez, et al. 2011. Protective effects of tryptophan on neuro-inflammation in rats after administering lipopolysaccharide. Biomedicine and Pharmacotherapy 65: 215–219.

    Article  PubMed  Google Scholar 

  30. Carrillo-Vico, A., P.J. Lardone, L. Naji, et al. 2005. Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro-/anti-inflammatory cytokine network, protection against oxidative damage and anti-apoptotic effects. Journal of Pineal Research 39: 400–408.

    Article  CAS  PubMed  Google Scholar 

  31. Zhong, L.-Y., Z.-H. Yang, X.-R. Li, et al. 2009. Protective effects of melatonin against the damages of neuroendocrine-immune induced by lipopolysaccharide in diabetic rats. Experimental and Clinical Endocrinology and Diabetes 117: 463–469.

    Article  CAS  PubMed  Google Scholar 

  32. Sacco, S., L. Aquilini, P. Ghezzi, et al. 1998. Mechanism of the inhibitory effect of melatonin on tumor necrosis factor production in vivo and in vitro. E J Pharmacology 343: 249–255.

    Article  CAS  Google Scholar 

  33. Maestroni, G.J. 1996. Melatonin as a therapeutic agent in experimental endotoxic shock. Journal of Pineal Research 20: 84–89.

    Article  CAS  PubMed  Google Scholar 

  34. Tyagi, E., R. Agrawal, C. Nath, and R. Shukla. 2010. Effect of melatonin on neuroinflammation and acetylcholinesterase activity induced by LPS in rat brain. European Journal of Pharmacology 640: 206–210.

    Article  CAS  PubMed  Google Scholar 

  35. Wang, H., W. Wei, Y.-X. Shen, et al. 2004. Protective effect of melatonin against liver injury in mice induced by Bacillus Calmette-Guerin plus lipopolysaccharide. World Journal of Gastroenterology 10: 2690–2696.

    CAS  PubMed  Google Scholar 

  36. Yavuz, T., D. Kaya, M. Behcet, et al. 2007. Effects of melatonin on Candida sepsis in an experimental rat model. Advances in Therapy 24: 91–100.

    Article  CAS  PubMed  Google Scholar 

  37. Wu, J.-Y., M.-Y. Tsou, T.-H. Chen, et al. 2008. Therapeutic effects of melatonin on peritonitis-induced septic shock with multiple organ dysfunction syndrome in rats. Journal of Pineal Research 45: 106–116.

    Article  CAS  PubMed  Google Scholar 

  38. Petrat, F., J. Drowatzky, K. Boengler, et al. 2011. Protection from glycine at low doses in ischemia-reperfusion injury of the rat small intestine. European Surgical Research 46: 180–187.

    Article  CAS  PubMed  Google Scholar 

  39. Effenberger-Neidnicht, K., M. Al Nator, L. Brencher, et al. 2013. Prevention of endotoxin-induced hypotension in rats by the circadian hormone melatonin. Infection 41: S11–S12.

    Google Scholar 

  40. Hamburger, T., M. Broecker-Preuss, M. Hartmann, et al. 2013. Effects of glycine, pyruvate, resveratrol, and nitrite on tissue injury and cytokine response in endotoxemic rats. Journal of Surgical Research 183: e7–e21.

    Article  CAS  PubMed  Google Scholar 

  41. Di, W.-L., A. Kadva, O. Djahanbakhch, and R. Silman. 1998. Radioimmunoassay of bound and free melatonin in plasma. Clinical Chemistry 44: 304–310.

    CAS  PubMed  Google Scholar 

  42. Rittirsch, D., M.A. Flierl, and P.A. Ward. 2008. Harmful molecular mechanisms in sepsis. Nature Reviews Immunology 8: 776–787.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Jean-Baptiste, E. 2007. Cellular mechanisms in sepsis. Journal of Intensive Care Medicine 22: 63–72.

    Article  PubMed  Google Scholar 

  44. Dinarello, C.A. 1997. Pro-inflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest 112: 321S–329S.

    Article  CAS  PubMed  Google Scholar 

  45. Green, L.C., D.A. Wagner, and J. Glogowski. 1982. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Analytical Biochemistry 126: 131–138.

    Article  CAS  PubMed  Google Scholar 

  46. Habbal, O.A., and A.A. Al-Jabri. 2009. Circadian rhythm and the immune response: a review. International Reviews of Immunology 28: 93–108.

    Article  CAS  PubMed  Google Scholar 

  47. Vgontzas, A.N., D.A. Papanicolaou, E.O. Bixler, et al. 1999. Circadian interleukin-6 secretion and quantity and depth of sleep. Endocrinology and Metabolism 84: 2603–2607.

    Article  CAS  Google Scholar 

  48. Dominguez-Rodriguez, A., P. Abreu-Gonzalez, M. Garcia, et al. 2004. Light/dark patterns of interleukin-6 in relation to the pineal hormone melatonin in patients with acute myocardial infarction. Cytokine 26: 89–93.

    Article  CAS  PubMed  Google Scholar 

  49. Oliveira, L.G., C.C. Kuehn, C.D. Santos, et al. 2010. Enhanced protection by melatonin and meloxicam combination in experimental infection by Trypanosoma cruzi. Parasite Immunology 32: 245–251.

    Article  CAS  PubMed  Google Scholar 

  50. Valero, N., E. Bonilla, H. Pons, et al. 2002. Melatonin induces changes to serum cytokines in mice infected with the Venezuelan equine encephalomyelitis virus. Transactions of the Royal Society of Tropical Medicine and Hygiene 96: 348–351.

    Article  CAS  PubMed  Google Scholar 

  51. Arias, J., E. Melean, N. Valero, et al. 2003. Effect of melatonin on lymphocyte proliferation and production of interleukin-2 (il-2) and interleukin-1 beta (il-1 beta) in mice splenocytes. Investigación Clínica 44: 41–50.

    PubMed  Google Scholar 

  52. Currier, N.L., L.Z. Sun, and S.C. Miller. 2000. Exogenous melatonin: quantitative enhancement in vivo of cells mediating non-specific immunity. Journal of Neuroimmunology 104: 101–108.

    Article  CAS  PubMed  Google Scholar 

  53. Maestroni, G.J. 2001. The immunotherapeutic potential of melatonin. Experimental Opinion Investigative Drugs 10: 467–476.

    Article  CAS  Google Scholar 

  54. Maestroni, G.J. 1995. T-helper-2 lymphocytes as a peripheral target of melatonin. Journal of Pineal Research 18: 84–89.

    Article  CAS  PubMed  Google Scholar 

  55. Carrillo-Vico, A., A. Garcia-Perganeda, L. Naji, et al. 2003. Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cellular and Molecular Life Sciences 60: 2272–2278.

    Article  CAS  PubMed  Google Scholar 

  56. Drazen, D.L., and R.J. Nelson. 2001. Melatonin receptor subtype MT2 (Mel 1b) and not mt1 (Mel 1a) is associated with melatonin-induced enhancement of cell-mediated and humoral immunity. Neuroendocrinology 74: 178–184.

    Article  CAS  PubMed  Google Scholar 

  57. Kidd, P. 2003. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Alternative Medicine Review 8: 223–246.

    PubMed  Google Scholar 

  58. Standage, S.W., and H.R. Wong. 2011. Biomarkers for pediatric sepsis and septic shock. Expert Review of Anti-Infective Therapy 9: 71–79.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Xing, Z., J. Gauldie, G. Cox, et al. 1998. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. Journal of Clinical Investigation 101: 311–320.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Loddick, S.A., A.V. Turnbull, and N.J. TRothwell. 1998. Cerebral interleukin-6 is protective during permanent focal cerebral ischemia in the rat. Journal of Cerebral Blood Flow and Metabolism 18: 176–179.

    Article  CAS  PubMed  Google Scholar 

  61. Toulmond, S., X. Vige, D. Fage, and J. Benavides. 1992. Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons. Neuroscience Letters 144: 49–52.

    Article  CAS  PubMed  Google Scholar 

  62. Xu, L.L., A. Kitani, I. Fuss, and W. Strober. 2007. Cutting edge: regulatory T cells induce CD4+CD25-Foxp3- T cells or are self-induced to become TH17 cells in the absence of exogenous TGF-b. Journal of Immunology 178: 6725–6729.

    Article  CAS  Google Scholar 

  63. Bettelli, E., Y. Carrier, W. Gao, et al. 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441: 235–238.

    Article  CAS  PubMed  Google Scholar 

  64. Wang, T.S., and J.C. Deng. 2008. Molecular and cellular aspects of sepsis-induced immunosuppression. Journal of Molecular Medicine (Berl) 86: 495–506.

    Article  CAS  Google Scholar 

  65. Benjamim, C.F., C.M. Hogaboam, and S.L. Kunkel. 2004. The chronic consequences of severe sepsis. Journal of Leukocyte Biology 75: 408–412.

    Article  CAS  PubMed  Google Scholar 

  66. Li, C.X., D.D. Liang, G.H. Xie, et al. 2013. Altered melatonin secretion and circadian gene expression with increased proinflammatory cytokine expression in early-stage sepsis patients. Molecular Medicine Reports 7: 1117–1122.

    CAS  PubMed  Google Scholar 

  67. Pinheiro da Silva F, Cesar Machado MC, Sallet PC et al. Neuropeptide downregulation in sepsis. Inflammation 2013 (in press).

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We would like to thank Mrs. Katrin Rehmann for carrying out the Bio-Plex-Assay.

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Authors and Affiliations

  1. Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany

    Katharina Effenberger-Neidnicht, Lisa Brencher, Tim Hamburger, Frank Petrat & Herbert de Groot

  2. Department of Endocrinology and Metabolic Diseases, Central Laboratory Research and Academics, University Hospital Essen, Essen, Germany

    Martina Broecker-Preuss

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  1. Katharina Effenberger-Neidnicht
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Correspondence to Katharina Effenberger-Neidnicht.

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Effenberger-Neidnicht, K., Brencher, L., Broecker-Preuss, M. et al. Immune Stimulation by Exogenous Melatonin During Experimental Endotoxemia. Inflammation 37, 738–744 (2014). https://doi.org/10.1007/s10753-013-9792-y

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