Imune-pineal Axis: injury shifts melatonin production from endocrine to paracrine

• Grant number: 07/07871-6
• Support Opportunities: Research Projects - Thematic Grants
• Duration: August 01, 2008 - July 31, 2012
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Regina Pekelmann Markus
• Grantee: Regina Pekelmann Markus
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Cláudia Lúcia Martins da Silva ; Wolnei Caumo ; Zulma Felisbina da Silva Ferreira
• Associated scholarship(s): 12/04508-6 - Effect of urban air pollution in São Paulo on pineal gland production of melatonin and on the rat endothelial cell reactivity., BP.DR; 11/12649-6 - Effect of purinergic stimulation on TNF production by rat pineal gland, BP.IC; 09/17800-4 - Immune-pineal axis: modulatory effect of melatonin on the NFKB pathway in cerebellar cells cultures, BP.DR; 09/17923-9 - Pineal gland as a target for B-amyloid peptide, BP.DR; 09/04000-0 - Effect of the Hour of the Day on the Reactivity of Primary Cultures of Endothelial Cells, BP.MS

Abstract

The time-course of the innate immunological response involves a pro-inflammatory phase followed by an anti-inflammatory phase. Pro-inflammatory responses are defense reaction against several stressor conditions. They are followed by an anti-inflammatory phase which avoid exacerbation or chronification of the inflammation. Recently we have shown that the pineal gland is a player in the bidirectional control of the inflammatory response. Healthy organisms stay in stand-by mode, ready to react. The nocturnal melatonin surge impairs the rolling and adherance of leukocytes to endothelial layers, limiting cell migration, and stimulates nocturnal production of IL-2 by T helper lymphocytes, exerting an immunostimulatory effect. Otherwise, the release of TNF-alpha; from activated macrophages suppresses the nocturnal melatonin surge, allowing a full cell migration and inhibiting IL-2 production. In sequence, activated mononuclear and polymorphonuclear cells produce melatonin in a paracrine manner at the site of injury, which scavenges free radicals and collaborates to resolve the inflammatory response. The sequential diminution of TNFá production is followed by the recovery of the nocturnal melatonin surge and IL-2 production. In summary, the immune-pineal axis, implicated in the sequential involvement of the melatonin produced by the pineal gland and immune-competent cells, is an integral participant of the innate immune response. The present project was designed to determine the cellular and molecular mechanisms involved in the control of pineal and extra-pineal melatonin by pro- and anti-inflammatory mediator, as to extend if other forms of injury, such as psychological stress may also impairs pineal melatonin production, interfering therefore in the transduction of the light/dark cycle to the whole body. We also will increase our clinical observations providing new paradigm for testing the immune-pineal axis. Therefore, this project intend to establish the molecular, cellular and organismic conditions for a shuttle between endocrine and paracrine production of melatonin. (AU)

Scientific publications

(15)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MARCOLA, MARINA; CRUZ-MACHADO, SANSERAY DA SILVEIRA; CARLOS MAGNO FERNANDES, PEDRO AUGUSTO; ARANTES MONTEIRO, ALEX WILLIAN; MARKUS, REGINA P.; TAMURA, EDUARDO KOJI. Endothelial cell adhesiveness is a function of environmental lighting and melatonin level. Journal of Pineal Research, v. 54, n. 2, p. 162-169, MAR 2013. (07/07871-6)

SOUZA-TEODORO, LUIS HENRIQUE; DARGENIO-GARCIA, LETICIA; PETRILLI-LAPA, CAMILA LOPES; SOUZA, EWERTON DA SILVA; FERNANDES, PEDRO A. C. M.; MARKUS, REGINA P.; FERREIRA, ZULMA S.. Adenosine triphosphate inhibits melatonin synthesis in the rat pineal gland. Journal of Pineal Research, v. 60, n. 2, p. 242-249, MAR 2016. (12/06110-0, 07/07871-6, 13/13691-1, 09/12307-8)

CAMARINI, ROSANA; PAUTASSI, RICARDO MARCOS. Behavioral sensitization to ethanol: Neural basis and factors that influence its acquisition and expression. Brain Research Bulletin, v. 125, p. 53-78, JUL 2016. (10/12968-1, 07/07871-6, 12/10260-7)

TAMURA, EDUARDO KOJI; CECON, ERIKA; ARANTES MONTEIRO, ALEX WILLIAN; MARTINS SILVA, CLAUDIA LUCIA; MARKUS, REGINA PEKELMANN. Melatonin inhibits LPS-induced NO production in rat endothelial cells. Journal of Pineal Research, v. 46, n. 3, p. 268-274, APR 2009. (07/07871-6)

TAMURA, EDUARDO KOJI; FERNANDES, PEDRO AUGUSTO; MARCOLA, MARINA; CRUZ-MACHADO, SANSERAY DA SILVEIRA; MARKUS, REGINA PEKELMANN. Long-Lasting Priming of Endothelial Cells by Plasma Melatonin Levels. PLoS One, v. 5, n. 11, p. e13958, 2010. (07/07871-6)

MARKUS, REGINA P.; CECON, ERIKA; PIRES-LAPA, MARCO ANTONIO. Immune-Pineal Axis: Nuclear Factor kappa B (NF-kappa B) Mediates the Shift in the Melatonin Source from Pinealocytes to Immune Competent Cells. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 14, n. 6, p. 10979-10997, JUN 2013. (07/07871-6)

FERREIRA, Z. S.; BOTHOREL, B.; MARKUS, R. P.; SIMONNEAUX, V.. Plasma corticosterone elevation inhibits the activation of nuclear factor kappa B (NFKB) in the Syrian hamster pineal gland. STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS, v. 15, n. 3, p. 339-347, MAY 2012. (07/07871-6)

MARKUS, REGINA P.; SILVA, CLAUDIA L. M.; FRANCO, DAIANE GIL; BARBOSA, JR., EDUARDO MORTANI; FERREIRA, ZULMA S.. Is modulation of nicotinic acetylcholine receptors by melatonin relevant for therapy with cholinergic drugs?. PHARMACOLOGY & THERAPEUTICS, v. 126, n. 3, p. 251-262, JUN 2010. (02/02957-6, 07/07871-6)

PINATO, LUCIANA; CRUZ-MACHADO, SANSERAY DA SILVEIRA; FRANCO, DAIANE G.; CAMPOS, LEILA M. G.; CECON, ERIKA; FERNANDES, PEDRO A. C. M.; BITTENCOURT, JACKSON C.; MARKUS, REGINA P.. Selective protection of the cerebellum against intracerebroventricular LPS is mediated by local melatonin synthesis. Brain Structure & Function, v. 220, n. 2, p. 827-840, MAR 2015. (04/13849-5, 11/51495-4, 07/07871-6)

CRUZ-MACHADO, SANSERAY DA SILVEIRA; TAMURA, EDUARDO K.; CARVALHO-SOUSA, CLAUDIA E.; ROCHA, VANDERLEI AMADEU; PINATO, LUCIANA; FERNANDES, PEDRO A. C.; MARKUS, REGINA P.. Daily corticosterone rhythm modulates pineal function through NF kappa B-related gene transcriptional program. SCIENTIFIC REPORTS, v. 7, MAY 18 2017. (07/07871-6, 13/13691-1)

CECON, ERIKA; CHEN, MIN; MARCOLA, MARINA; FERNANDES, PEDRO A. C.; JOCKERS, RALF; MARKUS, REGINA P.. Amyloid beta peptide directly impairs pineal gland melatonin synthesis and melatonin receptor signaling through the ERK pathway. FASEB JOURNAL, v. 29, n. 6, p. 2566-2582, JUN 2015. (09/17923-9, 11/01304-8, 07/07871-6, 13/13691-1)

CRUZ-MACHADO, SANSERAY DA SILVEIRA; CARVALHO-SOUSA, CLAUDIA EMANUELE; TAMURA, EDUARDO KOJI; PINATO, LUCIANA; CECON, ERIKA; MAGNO FERNANDES, PEDRO AUGUSTO CARLOS; WERNECK DE AVELLAR, MARIA CHRISTINA; FERREIRA, ZULMA SILVA; MARKUS, REGINA PEKELMANN. TLR4 and CD14 receptors expressed in rat pineal gland trigger NFKB pathway. Journal of Pineal Research, v. 49, n. 2, p. 183-192, SEP 2010. (07/07871-6)

CRUZ-MACHADO, SANSERAY DA SILVEIRA; PINATO, LUCIANA; TAMURA, EDUARDO KOJI; CARVALHO-SOUSA, CLAUDIA EMANUELE; MARKUS, REGINA P.. Glia-Pinealocyte Network: The Paracrine Modulation of Melatonin Synthesis by Tumor Necrosis Factor (TNF). PLoS One, v. 7, n. 7, p. e40142, 2012. (07/07871-6)

SOARES-SIMI, SABRINA L.; PASTRELLO, DANIEL M.; FERREIRA, ZULMA S.; YONAMINE, MAURICIO; MARCOURAKIS, TANIA; SCAVONE, CRISTOFORO; CAMARINI, ROSANA. Changes in CREB activation in the prefrontal cortex and hippocampus blunt ethanol-induced behavioral sensitization in adolescent mice. FRONTIERS IN INTEGRATIVE NEUROSCIENCE, v. 7, p. 12-pg., 2013-01-01. (07/07871-6)

CECON, ERIKA; MARKUS, REGINA P.. Relevance of the Chronobiological and Non-chronobiological Actions of Melatonin for Enhancing Therapeutic Efficacy in Neurodegenerative Disorders. RECENT PATENTS ON ENDOCRINE METABOLIC & IMMUNE DRUG DISCOVERY, v. 5, n. 2, p. 9-pg., 2011-01-01. (07/07871-6)