Immune-pineal axis: Nuclear factor κB (NF-κB) mediates the shift in the melatonin source from pinealocytes to immune competent cells

International Journal of Molecular Sciences

Volumn 14, Issue 6, 2013, Pages 10979-10997

  Markus, Regina P ^a   Cecon, Erika ^a   Pires Lapa, Marco Antonio ^a  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

Glucocorticoid; Immune pineal axis; Innate immune response; Macrophage; Melatonin; Nuclear factor B NF B; Pineal gland

Indexed keywords

GLUCOCORTICOID; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MELATONIN;

ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; CHRONOBIOLOGY; CIRCADIAN RHYTHM; DANGER ASSOCIATED MOLECULAR PATTERN; GENETIC TRANSCRIPTION; HORMONE SYNTHESIS; HUMAN; IMMUNE RESPONSE; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; INFLAMMATION; INNATE IMMUNITY; LIGHT DARK CYCLE; MACROPHAGE; NONHUMAN; PATHOGEN ASSOCIATED MOLECULAR PATTERN; PINEAL BODY; PINEALOCYTE; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; BIOSYNTHESIS; CYTOLOGY; IMMUNE SYSTEM; METABOLISM;

MAMMALIA;

ANIMALS; HUMANS; IMMUNE SYSTEM; MELATONIN; NF-KAPPA B; PINEAL GLAND; SIGNAL TRANSDUCTION;

EID: 84878461203     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms140610979     Document Type: Review

References (115)

1. Reiter, R.J. The melatonin rhythm: Both a clock and a calendar. Experientia 1993, 49, 654-664.
2. Tan, D.X.; Manchester, L.C.; Terron, M.P.; Flores, L.J.; Reiter, R.J. One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? J. Pineal Res. 2007, 42, 28-42.
3. Guerrero, J.M.; Reiter, R.J. Melatonin-immune system relationships. Curr. Top. Med. Chem. 2002, 2, 167-179.
4. Skwarlo-Sonta, K. Melatonin in immunity: Comparative aspects. Neuro Endocrinol. Lett. 2002, 23, 61-66.
5. Carrillo-Vico, A.; Guerrero, J.M.; Lardone, P.J.; Reiter, R.J. A review of the multiple actions of melatonin on the immune system. Endocrine 2005, 27, 189-200.
6. Carrillo-Vico, A.; Lardone, P.J.; Alvarez-Sanchez, N.; Rodriguez-Rodriguez, A.; Guerrero, J.M. Melatonin: Buffering the immune system. Int. J. Mol. Sci. 2013, 14, 8638-8683.
7. Radogna, F.; Diederich, M.; Ghibelli, L. Melatonin: A pleiotropic molecule regulating inflammation. Biochem. Pharmacol. 2010, 80, 1844-1852.
8. Haus, E.; Lakatua, D.J.; Swoyer, J.; Sackett-Lundeen, L. Chronobiology in hematology and immunology. Am. J. Anat. 1983, 168, 467-517.
9. Petrovsky, N.; Harrison, L.C. The chronobiology of human cytokine production. Int. Rev. Immunol. 1998, 16, 635-649.
10. Trufakin, V.A.; Shurlygina, A.V.; Michurina, S.V.; Verbitskaja, L.V.; Litvinenko, G.I.; Kovshik, I.G.; Panteleeva, N.G.; Melnikova, E.V.; Bitchaeva, M.V. The influence of experimental desynchronosis on the morphofunctional characteristics of mouse immune system. Alaska Med. 2007, 49, 169-176.
11. Mazzoccoli, G.; Carughi, S.; Greco, A.; Inglese, M.; Perfetto, F.; Tarquini, R. A possible mechanism for altered immune response in the elderly. In Vivo 2010, 24, 471-487.
12. Haldar, C.; Ahmad, R. Photoimmunomodulation and melatonin. J. Photochem. Photobiol. B 2010, 98, 107-117.
13. Lotufo, C.M.; Lopes, C.; Dubocovich, M.L.; Farsky, S.H.; Markus, R.P. Melatonin and N-acetylserotonin inhibit leukocyte rolling and adhesion to rat microcirculation. Eur. J. Pharmacol. 2001, 430, 351-357.
14. Bertuglia, S.; Colantuoni, A.; Intaglietta, M. Effect of leukocyte adhesion and microvascular permeability on capillary perfusion during ischemia-reperfusion injury in hamster cheek pouch. Int. J. Microcirc. Clin. Exp. 1993, 13, 13-26.
15. Shi, Y.; Evans, J.E.; Rock, K.L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003, 425, 516-521.
16. Panayi, G.S.; Corrigall, V.M.; Henderson, B. Stress cytokines: Pivotal proteins in immune regulatory networks: Opinion. Curr. Opin. Immunol. 2004, 16, 531-534.
17. Fernandes, P.A.; Cecon, E.; Markus, R.P.; Ferreira, Z.S. Effect of TNF-alpha on the melatonin synthetic pathway in the rat pineal gland: Basis for a "feedback" of the immune response on circadian timing. J. Pineal Res. 2006, 41, 344-350.
18. da Silveira Cruz-Machado, S.; Carvalho-Sousa, C.E.; Tamura, E.K.; Pinato, L.; Cecon, E.; Fernandes, P.A.; de Avellar, M.C.; Ferreira, Z.S.; Markus, R.P. TLR4 and CD14 receptors expressed in rat pineal gland trigger NFKB pathway. J. Pineal Res. 2010, 49, 183-192.
19. Pontes, G.N.; Cardoso, E.C.; Carneiro-Sampaio, M.M.; Markus, R.P. Injury switches melatonin production source from endocrine (pineal) to paracrine (phagocytes)-melatonin in human colostrum and colostrum phagocytes. J. Pineal Res. 2006, 41, 136-141.
20. Muxel, S.M.; Pires-Lapa, M.A.; Monteiro, A.W.; Cecon, E.; Tamura, E.K.; Floeter-Winter, L.M.; Markus, R.P. NF-kappaB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene. PLoS One 2012, 7, e52010.
21. Markus, R.P.; Ferreira, Z.S.; Fernandes, P.A.; Cecon, E. The immune-pineal axis: A shuttle between endocrine and paracrine melatonin sources. Neuroimmunomodulation 2007, 14, 126-133.
22. Markus, R.P.; Ferreira, Z.S. The Immune-pineal axis: The role of pineal and extra-pineal melatonin in modulating inflammation. Adv. Neuroimmune Biol. 2011, 1, 95-104.
23. Gilmore, T.D.; Wolenski, F.S. NF-kappaB: Where did it come from and why? Immunol. Rev. 2012, 246, 14-35.
24. Nabel, G.J.; Verma, I.M. Proposed NF-kappa B/I kappa B family nomenclature. Genes Dev. 1993, 7, 2063.
25. Zhang, Y.L.; Dong, C. MAP kinases in immune responses. Cell Mol. Immunol. 2005, 2, 20-27.
26. Li, J.; Tang, Y.; Cai, D. IKKbeta/NF-kappaB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat. Cell Biol. 2012, 14, 999-1012.
27. Colombo, B.M.; Canevali, P.; Magnani, O.; Rossi, E.; Puppo, F.; Zocchi, M.R.; Poggi, A. Defective expression and function of the leukocyte associated Ig-like receptor 1 in B lymphocytes from systemic lupus erythematosus patients. PLoS One 2012, 7, e31903.
28. Gaudio, E.; Spizzo, R.; Paduano, F.; Luo, Z.; Efanov, A.; Palamarchuk, A.; Leber, A.S.; Kaou, M.; Zanesi, N.; Bottoni, A.; et al. Tcl1 interacts with Atm and enhances NF-kappaB activation in hematologic malignancies. Blood 2012, 119, 180-187.
29. Basak, S.; Kim, H.; Kearns, J.D.; Tergaonkar, V.; O'Dea, E.; Werner, S.L.; Benedict, C.A.; Ware, C.F.; Ghosh, G.; Verma, I.M.; et al. A fourth IkappaB protein within the NF-kappaB signaling module. Cell 2007, 128, 369-381.
30. Karin, M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb. Perspect Biol. 2009, 1, a000141.
31. Razani, B.; Zarnegar, B.; Ytterberg, A.J.; Shiba, T.; Dempsey, P.W.; Ware, C.F.; Loo, J.A.; Cheng, G. Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation. Sci. Signal 2010, 3, ra41.
32. Le Negrate, G. Subversion of innate immune responses by bacterial hindrance of NF-kappaB pathway. Cell Microbiol. 2012, 14, 155-167.
33. Courtine, E.; Pene, F.; Cagnard, N.; Toubiana, J.; Fitting, C.; Brocheton, J.; Rousseau, C.; Gerondakis, S.; Chiche, J.D.; Ouaaz, F.; et al. Critical role of cRel subunit of NF-kappaB in sepsis survival. Infect. Immun. 2011, 79, 1848-1854.
34. Pizzi, M.; Sarnico, I.; Lanzillotta, A.; Battistin, L.; Spano, P. Post-ischemic brain damage: NF-kappaB dimer heterogeneity as a molecular determinant of neuron vulnerability. FEBS J. 2009, 276, 27-35.
35. Sarnico, I.; Lanzillotta, A.; Boroni, F.; Benarese, M.; Alghisi, M.; Schwaninger, M.; Inta, I.; Battistin, L.; Spano, P.; Pizzi, M. NF-kappaB p50/RelA and c-Rel-containing dimers: Opposite regulators of neuron vulnerability to ischaemia. J. Neurochem. 2009, 108, 475-485.
36. Bhakar, A.L.; Tannis, L.L.; Zeindler, C.; Russo, M.P.; Jobin, C.; Park, D.S.; MacPherson, S.; Barker, P.A. Constitutive nuclear factor-kappa B activity is required for central neuron survival. J. Neurosci. 2002, 22, 8466-8475.
37. Pereira, S.G.; Oakley, F. Nuclear factor-kappaB1: Regulation and function. Int. J. Biochem. Cell Biol. 2008, 40, 1425-1430.
38. Saccani, S.; Pantano, S.; Natoli, G. Two waves of nuclear factor kappa B recruitment to target promoters. J. Exp. Med. 2001, 193, 1351-1359.
39. Nelson, D.E.; Ihekwaba, A.E.; Elliott, M.; Johnson, J.R.; Gibney, C.A.; Foreman, B.E.; Nelson, G.; See, V.; Horton, C.A.; Spiller, D.G.; et al. Oscillations in NF-kappaB signaling control the dynamics of gene expression. Science 2004, 306, 704-708.
40. Sanjabi, S.; Williams, K.J.; Saccani, S.; Zhou, L.; Hoffmann, A.; Ghosh, G.; Gerondakis, S.; Natoli, G.; Smale, S.T. A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation. Genes Dev. 2005, 19, 2138-2151.
41. Mohan, N.; Sadeghi, K.; Reiter, R.J.; Meltz, M.L. The neurohormone melatonin inhibits cytokine, mitogen and ionizing radiation induced NF-kappa B. Biochem. Mol. Biol. Int. 1995, 37, 1063-1070.
42. Gilad, E.; Wong, H.R.; Zingarelli, B.; Virag, L.; O'Connor, M.; Salzman, A.L.; Szabo, C. Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: Role of inhibition of NFkappaB activation. FASEB J. 1998, 12, 685-693.
43. Maldonado, M.D.; Mora-Santos, M.; Naji, L.; Carrascosa-Salmoral, M.P.; Naranjo, M.C.; Calvo, J.R. Evidence of melatonin synthesis and release by mast cells. Possible modulatory role on inflammation. Pharmacol. Res. 2010, 62, 282-287.
44. Pedrosa, A.M.; Weinlich, R.; Mognol, G.P.; Robbs, B.K.; Viola, J.P.; Campa, A.; Amarante-Mendes, G.P. Melatonin protects CD4+ T cells from activation-induced cell death by blocking NFAT-mediated CD95 ligand upregulation. J. Immunol. 2010, 184, 3487-3494.
45. Choi, E.Y.; Jin, J.Y.; Lee, J.Y.; Choi, J.I.; Choi, I.S.; Kim, S.J. Melatonin inhibits Prevotella intermedia lipopolysaccharide-induced production of nitric oxide and interleukin-6 in murine macrophages by suppressing NF-kappaB and STAT1 activity. J. Pineal Res. 2011, 50, 197-206.
46. Murakami, Y.; Yuhara, K.; Takada, N.; Arai, T.; Tsuda, S.; Takamatsu, S.; Machino, M.; Fujisawa, S. Effect of melatonin on cyclooxygenase-2 expression and nuclear factor-kappa B activation in RAW264.7 macrophage-like cells stimulated with fimbriae of Porphyromonas gingivalis. In Vivo 2011, 25, 641-647.
47. Chang, C.C.; Tien, C.H.; Lee, E.J.; Juan, W.S.; Chen, Y.H.; Hung, Y.C.; Chen, T.Y.; Chen, H.Y.; Wu, T.S. Melatonin inhibits matrix metalloproteinase-9 (MMP-9) activation in the lipopolysaccharide (LPS)-stimulated RAW 264.7 and BV2 cells and a mouse model of meningitis. J. Pineal Res. 2012, 53, 188-197.
48. Post, A.; Holsboer, F.; Behl, C. Induction of NF-kappaB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: Suppression of NF-kappaB and neuroprotection by antioxidants. J. Neurosci. 1998, 18, 8236-8246.
49. Fang, Q.; Chen, G.; Zhu, W.; Dong, W.; Wang, Z. Influence of melatonin on cerebrovascular proinflammatory mediators expression and oxidative stress following subarachnoid hemorrhage in rabbits. Mediators Inflamm. 2009, 2009, 426346.
50. Bruck, R.; Aeed, H.; Avni, Y.; Shirin, H.; Matas, Z.; Shahmurov, M.; Avinoach, I.; Zozulya, G.; Weizman, N.; Hochman, A. Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats. J. Hepatol. 2004, 40, 86-93.
51. Quiroz, Y.; Ferrebuz, A.; Romero, F.; Vaziri, N.D.; Rodriguez-Iturbe, B. Melatonin ameliorates oxidative stress, inflammation, proteinuria, and progression of renal damage in rats with renal mass reduction. Am. J. Physiol. Renal Physiol. 2008, 294, F336-F344.
52. Ozbek, E.; Ilbey, Y.O.; Ozbek, M.; Simsek, A.; Cekmen, M.; Somay, A. Melatonin attenuates unilateral ureteral obstruction-induced renal injury by reducing oxidative stress, iNOS, MAPK, and NF-kB expression. J. Endourol. 2009, 23, 1165-1173.
53. Shang, Y.; Xu, S.P.; Wu, Y.; Jiang, Y.X.; Wu, Z.Y.; Yuan, S.Y.; Yao, S.L. Melatonin reduces acute lung injury in endotoxemic rats. Chin. Med. J. (Engl.) 2009, 122, 1388-1393.
54. Veneroso, C.; Tunon, M.J.; Gonzalez-Gallego, J.; Collado, P.S. Melatonin reduces cardiac inflammatory injury induced by acute exercise. J. Pineal Res. 2009, 47, 184-191.
55. Sasaki, M.; Jordan, P.; Joh, T.; Itoh, M.; Jenkins, M.; Pavlick, K.; Minagar, A.; Alexander, S.J. Melatonin reduces TNF-a induced expression of MAdCAM-1 via inhibition of NF-kappaB. BMC Gastroenterol. 2002, 2, 9.
56. Li, J.H.; Yu, J.P.; Yu, H.G.; Xu, X.M.; Yu, L.L.; Liu, J.; Luo, H.S. Melatonin reduces inflammatory injury through inhibiting NF-kappaB activation in rats with colitis. Mediators Inflamm. 2005, 2005, 185-193.
57. Ganguly, K.; Swarnakar, S. Chronic gastric ulceration causes matrix metalloproteinases-9 and-3 augmentation: Alleviation by melatonin. Biochimie 2012, 94, 2687-2698.
58. Negi, G.; Kumar, A.; Sharma, S.S. Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: Effects on NF-kappaB and Nrf2 cascades. J. Pineal Res. 2011, 50, 124-131.
59. Esposito, E.; Paterniti, I.; Mazzon, E.; Bramanti, P.; Cuzzocrea, S. Melatonin reduces hyperalgesia associated with inflammation. J. Pineal Res. 2010, 49, 321-331.
60. Genovese, T.; Mazzon, E.; Muia, C.; Bramanti, P.; de Sarro, A.; Cuzzocrea, S. Attenuation in the evolution of experimental spinal cord trauma by treatment with melatonin. J. Pineal Res. 2005, 38, 198-208.
61. Jung, K.H.; Hong, S.W.; Zheng, H.M.; Lee, D.H.; Hong, S.S. Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model. J. Pineal Res. 2009, 47, 173-183.
62. Cai, C.; Zhang, H.Y.; Le, J.J.; Dong, J.C.; Cui, Y.; Xu, C.Q.; Liu, B.J.; Wu, J.F.; Duan, X.H.; Cao, Y.X. Inflammatory airway features and hypothalamic-pituitary-adrenal axis function in asthmatic rats combined with chronic obstructive pulmonary disease. Chin. Med. J. (Engl.) 2010, 123, 1720-1726.
63. Huang, S.H.; Cao, X.J.; Wei, W. Melatonin decreases TLR3-mediated inflammatory factor expression via inhibition of NF-kappa B activation in respiratory syncytial virus-infected RAW264.7 macrophages. J. Pineal Res. 2008, 45, 93-100.
64. Cristofanon, S.; Uguccioni, F.; Cerella, C.; Radogna, F.; Dicato, M.; Ghibelli, L.; Diederich, M. Intracellular prooxidant activity of melatonin induces a survival pathway involving NF-kappaB activation. Ann. N. Y. Acad. Sci. 2009, 1171, 472-478.
65. Radogna, F.; Nuccitelli, S.; Mengoni, F.; Ghibelli, L. Neuroprotection by melatonin on astrocytoma cell death. Ann. N. Y. Acad. Sci. 2009, 1171, 509-513.
66. Soybir, G.; Topuzlu, C.; Odabas, O.; Dolay, K.; Bilir, A.; Koksoy, F. The effects of melatonin on angiogenesis and wound healing. Surg. Today 2003, 33, 896-901.
67. Pugazhenthi, K.; Kapoor, M.; Clarkson, A.N.; Hall, I.; Appleton, I. Melatonin accelerates the process of wound repair in full-thickness incisional wounds. J. Pineal Res. 2008, 44, 387-396.
68. Klein, D.C. Arylalkylamine N-acetyltransferase: "the Timezyme". J. Biol. Chem. 2007, 282, 4233-4237.
69. Ekstrom, P.; Meissl, H. Evolution of photosensory pineal organs in new light: The fate of neuroendocrine photoreceptors. Philos. Trans. R. Soc. Lond. B 2003, 358, 1679-1700.
70. Ferreira, Z.S.; Fernandes, P.A.; Duma, D.; Assreuy, J.; Avellar, M.C.; Markus, R.P. Corticosterone modulates noradrenaline-induced melatonin synthesis through inhibition of nuclear factor kappa B. J. Pineal Res. 2005, 38, 182-188.
71. Cecon, E.; Fernandes, P.A.; Pinato, L.; Ferreira, Z.S.; Markus, R.P. Daily variation of constitutively activated nuclear factor kappa B (NFKB) in rat pineal gland. Chronobiol. Int. 2010, 27, 52-67.
72. de Freitas, M.S.; Spohr, T.C.; Benedito, A.B.; Caetano, M.S.; Margulis, B.; Lopes, U.G.; Moura-Neto, V. Neurite outgrowth is impaired on HSP70-positive astrocytes through a mechanism that requires NF-kappaB activation. Brain Res. 2002, 958, 359-370.
73. Luningschror, P.; Stocker, B.; Kaltschmidt, B.; Kaltschmidt, C. miR-290 cluster modulates pluripotency by repressing canonical NF-kappaB signaling. Stem Cells 2012, 30, 655-664.
74. Imielski, Y.; Schwamborn, J.C.; Luningschror, P.; Heimann, P.; Holzberg, M.; Werner, H.; Leske, O.; Puschel, A.W.; Memet, S.; Heumann, R.; et al. Regrowing the adult brain: NF-kappaB controls functional circuit formation and tissue homeostasis in the dentate gyrus. PLoS One 2012, 7, e30838.
75. Lee, I.C.; Kim, S.H.; Lee, S.M.; Baek, H.S.; Moon, C.; Kim, S.H.; Park, S.C.; Kim, H.C.; Kim, J.C. Melatonin attenuates gentamicin-induced nephrotoxicity and oxidative stress in rats. Arch. Toxicol. 2012, 86, 1527-1536.
76. Tamura, E.K.; Cecon, E.; Monteiro, A.W.; Silva, C.L.; Markus, R.P. Melatonin inhibits LPS-induced NO production in rat endothelial cells. J. Pineal Res. 2009, 46, 268-274.
77. Lopes, C.; Mariano, M.; Markus, R.P. Interaction between the adrenal and the pineal gland in chronic experimental inflammation induced by BCG in mice. Inflamm. Res. 2001, 50, 6-11.
78. Carvalho-Sousa, C.E.; da Silveira Cruz-Machado, S.; Tamura, E.K.; Fernandes, P.A.; Pinato, L.; Muxel, S.M.; Cecon, E.; Markus, R.P. Molecular basis for defining the pineal gland and pinealocytes as targets for tumor necrosis factor. Front. Endocrinol. (Lausanne) 2011, 2, 10.
79. Pontes, G.N.; Cardoso, E.C.; Carneiro-Sampaio, M.M.; Markus, R.P. Pineal melatonin and the innate immune response: The TNF-alpha increase after cesarean section suppresses nocturnal melatonin production. J. Pineal Res. 2007, 43, 365-371.
80. Tatsch-Dias, M.O.; Levandovski, R.M.; Rocha, M.G.; Fernandes, P.A.; Torres, I.S.L.; Hidalgo, M.P.L.; Markus, R.P.; Caumo, W. Evaluating the immune-pineal axis in patients undergoing abdominal hysterectomy. Neuroimmunomodulation 2013, 20, 205-212.
81. Brugger, P.; Marktl, W.; Herold, M. Impaired nocturnal secretion of melatonin in coronary heart disease. Lancet 1995, 345, 1408.
82. Fiorina, P.; Lattuada, G.; Silvestrini, C.; Ponari, O.; Dall'Aglio, P. Disruption of nocturnal melatonin rhythm and immunological involvement in ischaemic stroke patients. Scand. J. Immunol. 1999, 50, 228-231.
83. Carvalho, L.A.; Gorenstein, C.; Moreno, R.A.; Markus, R.P. Melatonin levels in drug-free patients with major depression from the southern hemisphere. Psychoneuroendocrinology 2006, 31, 761-768.
84. Anderson, G.; Maes, M.; Berk, M. Inflammation-related disorders in the tryptophan catabolite pathway in depression and somatization. Adv. Protein Chem. Struct. Biol. 2012, 88, 27-48.
85. Antonioli, M.; Rybka, J.; Carvalho, L.A. Neuroimmune endocrine effects of antidepressants. Neuropsychiatr. Dis. Treat. 2012, 8, 65-83.
86. Liu, R.Y.; Zhou, J.N.; van Heerikhuize, J.; Hofman, M.A.; Swaab, D.F. Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype. J. Clin. Endocrinol. Metab. 1999, 84, 323-327.
87. Lahiri, D.K.; Chen, D.M.; Lahiri, P.; Bondy, S.; Greig, N.H. Amyloid, cholinesterase, melatonin, and metals and their roles in aging and neurodegenerative diseases. Ann. N. Y. Acad. Sci. 2005, 1056, 430-449.
88. Cecon, E.; Markus, R.P. Relevance of the chronobiological and non-chronobiological actions of melatonin for enhancing therapeutic efficacy in neurodegenerative disorders. Recent Pat. Endocr. Metab. Immune Drug Discov. 2011, 5, 91-99.
89. Cardinali, D.P.; Vigo, D.E.; Olivar, N.; Vidal, M.F.; Furio, A.M.; Brusco, L.I. Therapeutic application of melatonin in mild cognitive impairment. Am. J. Neurodegener. Dis. 2012, 1, 280-291.
90. Tosini, G.; Baba, K.; Hwang, C.K.; Iuvone, P.M. Melatonin: An underappreciated player in retinal physiology and pathophysiology. Exp. Eye Res. 2012, 103, 82-89.
91. Jimenez-Jorge, S.; Guerrero, J.M.; Jimenez-Caliani, A.J.; Naranjo, M.C.; Lardone, P.J.; Carrillo-Vico, A.; Osuna, C.; Molinero, P. Evidence for melatonin synthesis in the rat brain during development. J. Pineal Res. 2007, 42, 240-246.
92. Bubenik, G.A. Thirty four years since the discovery of gastrointestinal melatonin. J. Physiol. Pharmacol. 2008, 59, 33-51.
93. Konturek, S.J.; Konturek, P.C.; Brzozowski, T.; Bubenik, G.A. Role of melatonin in upper gastrointestinal tract. J. Physiol. Pharmacol. 2007, 58, 23-52.
94. Conti, A.; Conconi, S.; Hertens, E.; Skwarlo-Sonta, K.; Markowska, M.; Maestroni, J.M. Evidence for melatonin synthesis in mouse and human bone marrow cells. J. Pineal Res. 2000, 28, 193-202.
95. Carrillo-Vico, A.; Calvo, J.R.; Abreu, P.; Lardone, P.J.; Garcia-Maurino, S.; Reiter, R.J.; Guerrero, J.M. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: Possible role as intracrine, autocrine, and/or paracrine substance. FASEB J. 2004, 18, 537-539.
96. Martins, E., Jr.; Ferreira, A.C.; Skorupa, A.L.; Afeche, S.C.; Cipolla-Neto, J.; Costa Rosa, L.F. Tryptophan consumption and indoleamines production by peritoneal cavity macrophages. J. Leukoc. Biol. 2004, 75, 1116-1121.
97. Liu, Y.J.; Zhuang, J.; Zhu, H.Y.; Shen, Y.X.; Tan, Z.L.; Zhou, J.N. Cultured rat cortical astrocytes synthesize melatonin: Absence of a diurnal rhythm. J. Pineal Res. 2007, 43, 232-238.
98. Markus, R.P.; Tamura, E.K. G protein-Coupled Receptors and Other Mechanisms that Translate Melatonin Effects. In G Protein-Coupled Receptors in Vertebrates: Comparative Perspectives; Research Signpost: Kerala, Índia, 2009; Volume 2, pp. 93-111.
99. Luchetti, F.; Canonico, B.; Betti, M.; Arcangeletti, M.; Pilolli, F.; Piroddi, M.; Canesi, L.; Papa, S.; Galli, F. Melatonin signaling and cell protection function. FASEB J. 2010, 24, 3603-3624.
100. Tan, D.X.; Manchester, L.C.; Sanchez-Barcelo, E.; Mediavilla, M.D.; Reiter, R.J. Significance of high levels of endogenous melatonin in Mammalian cerebrospinal fluid and in the central nervous system. Curr. Neuropharmacol. 2010, 8, 162-167.
101. Silva, S.O.; Rodrigues, M.R.; Ximenes, V.F.; Bueno-da-Silva, A.E.; Amarante-Mendes, G.P.; Campa, A. Neutrophils as a specific target for melatonin and kynuramines: Effects on cytokine release. J. Neuroimmunol. 2004, 156, 146-152.
102. Pires-Lapa, M.A.; Tamura, E.K.; E.M. A, Salustiano.; Markus, R.P. Local melatonin synthesis enhances dectin-1-mediated phagocytosis by human colostrum mononuclear cells. J. Pineal Res. 2013, in press.
103. Carrillo-Vico, A.; Garcia-Maurino, S.; Calvo, J.R.; Guerrero, J.M. Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human lymphocytes via its mt1 membrane receptor. FASEB J. 2003, 17, 755-757.
104. Brunner, T.; Mogil, R.J.; LaFace, D.; Yoo, N.J.; Mahboubi, A.; Echeverri, F.; Martin, S.J.; Force, W.R.; Lynch, D.H.; Ware, C.F.; et al. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 1995, 373, 441-444.
105. Lissoni, P.; Brivio, F.; Barni, S.; Tancini, G.; Cattaneo, G.; Archili, C.; Conti, A.; Maestroni, G.J. Neuroimmunotherapy of human cancer with interleukin-2 and the neurohormone melatonin: Its efficacy in preventing hypotension. Anticancer Res. 1990, 10, 1759-1761.
106. Srinivasan, V.; Spence, D.W.; Trakht, I.; Pandi-Perumal, S.R.; Cardinali, D.P.; Maestroni, G.J. Immunomodulation by melatonin: Its significance for seasonally occurring diseases. Neuroimmunomodulation 2008, 15, 93-101.
107. Ban, J.Y.; Kim, B.S.; Kim, S.C.; Kim, D.H.; Chung, J.H. Microarray analysis of gene expression profiles in response to treatment with melatonin in lipopolysaccharide activated raw 264.7 cells. Korean J. Physiol. Pharmacol. 2011, 15, 23-29.
108. Xia, M.Z.; Liang, Y.L.; Wang, H.; Chen, X.; Huang, Y.Y.; Zhang, Z.H.; Chen, Y.H.; Zhang, C.; Zhao, M.; Xu, D.X.; et al. Melatonin modulates TLR4-mediated inflammatory genes through MyD88-and TRIF-dependent signaling pathways in lipopolysaccharide-stimulated RAW264.7 cells. J. Pineal Res. 2012, 53, 325-334.
109. Newton, K.; Dixit, V.M. Signaling in innate immunity and inflammation. Cold Spring Harb. Perspect. Biol. 2012, doi:10.1101/cshperspect.a006049.
110. Tamura, E.K.; Fernandes, P.A.; Marcola, M.; da Silveira Cruz-Machado, S.; Markus, R.P. Long-lasting priming of endothelial cells by plasma melatonin levels. PLoS One 2010, 5, e13958.
111. Marcola, M.; da Silveira Cruz-Machado, S.; Fernandes, P.A.; Monteiro, A.W.; Markus, R.P.; Tamura, E.K. Endothelial cell adhesiveness is a function of environmental lighting and melatonin level. J. Pineal Res. 2013, 54, 162-169.
112. Skwarlo-Sonta, K.; Majewski, P.; Markowska, M.; Oblap, R.; Olszanska, B. Bidirectional communication between the pineal gland and the immune system. Can. J. Physiol. Pharmacol. 2003, 81, 342-349.
113. Fernandes, P.A.; Markus, R.P. Melatonin and Inflammation-The Role of the Immune-Pineal Axis and the Sympathetic Tonus. In Melatonin in the Promotion of Health, 2nd ed.; Watson, R.R., Ed.; CRC Press: Tucson, AZ, USA, 2011; pp. 435-450.
114. Mauriz, J.L.; Collado, P.S.; Veneroso, C.; Reiter, R.J.; Gonzalez-Gallego, J. A review of the molecular aspects of melatonin's anti-inflammatory actions: Recent insights and new perspectives. J. Pineal Res. 2012, doi:10.1111/j.1600-079X.2012.01014.x.
115. Fernandes, P.A.; Bothorel, B.; Clesse, D.; Monteiro, A.W.; Calgari, C.; Raison, S.; Simonneaux, V.; Markus, R.P. Local corticosterone infusion enhances nocturnal pineal melatonin production in vivo. J. Neuroendocrinol. 2009, 21, 90-97.