The Immune-Pineal Axis
The immune-pineal axis: changing melatonin role from chronobiotic to regulator of inflammatory response. In normal conditions, noradrenaline (NA) induces nocturnal melatonin synthesis in the pineal gland, which plays a role in surveillance by controlling the amount of leukocytes that migrate to tissues. Molecules from pathogens (PAMPs) or pro-inflammatory cytokines impair nocturnal production of melatonin, favoring the entry of leukocytes. In sequence, activated macrophages produces melatonin, which acts locally as a regulator of the inflammatory response.
Markus RP et al., Immune-Pineal Axis: Nuclear Factor κB (NF-kB) Mediates the Shift in the Melatonin Source from Pinealocytes to Immune Competent Cells., 2013.
Cecon E and Markus RP. Relevance of the chronobiological and non-chronobiological actions of melatonin for enhancing therapeutic efficacy in neurodegenerative disorders., 2011.
Markus RP et al., Is modulation of nicotinic acetylcholine receptors by melatonin relevant for therapy with cholinergic drugs?, 2010.
Markus RP et al., The immune-pineal axis: a shuttle between endocrine and paracrine melatonin sources., 2007.
Regulation of Pineal Gland’s melatonin Synthesis
Toll-Like Receptor 4 and Tumor Necrosis Factor Receptor 1 are expressed in the pinealocytes. The blockade of melatonin synthesis by the pro-inflammatory ligands is translated through phosphorylation and degradation of the nuclear factor kappa B inhibitor (NFKBI) allowing the nuclear translocation of both gene transcription repressor (p50/p50) and activator (p50/RelA) NF-kB forms. Therefore, melatonin (MEL) and N-acetylserotonin (NAS) production is suppressed due to the repressive activity of the p50/p50 NF-kB dimer. In microglia, TLR4 activation induces TNF production that may activate TNFR1 expressed in pinealocytes. In addition, LPS up-regulates TNFR1 expression, most probably to allow maximal TNF signaling. This mechanisms were proposed due to observations both in rodents and humans.
Related Publications (Selected):
Pinato L et al., Selective protection of the cerebellum against intracerebroventricular LPS is mediated by local melatonin synthesis., 2013.
De Oliveira Tatsch-Dias M et al., The concept of the immune-pineal axis tested in patients undergoing an abdominal hysterectomy., 2013.
Da Silveira Cruz-Machado S et al., Glia-pinealocyte network: the paracrine modulation of melatonin synthesis by tumor necrosis factor (TNF)., 2012.
Carvalho-Sousa CE et al., Molecular basis for defining the pineal gland and pinealocytes as targets for tumor necrosis factor., 2011.
Tamura EK et al., Long-lasting priming of endothelial cells by plasma melatonin levels., 2010.
Reinhardt EL et al., Daily rhythm of salivary IL-1ß, cortisol and melatonin in day and night workers., 2012.
Ferreira ZS et al., Plasma corticosterone elevation inhibits the activation of nuclear factor kappa B (NFKB) in the Syrian hamster pineal gland., 2012.
Da Silveira Cruz-Machado S et al., TLR4 and CD14 receptors expressed in rat pineal gland trigger NFKB pathway. 2010.
Cecon E et al., Daily variation of constitutively activated nuclear factor kappa B (NFKB) in rat pineal gland., 2010.
Fernandes PA et al., Local corticosterone infusion enhances nocturnal pineal melatonin production in vivo., 2009.
Pontes GN et al., Pineal melatonin and the innate immune response: the TNF-alpha increase after cesarean section suppresses nocturnal melatonin production., 2007.
Fernandes PA et al., 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., 2006.
Pontes GN et al., Injury switches melatonin production source from endocrine (pineal) to paracrine (phagocytes) - melatonin in human colostrum and colostrum phagocytes., 2006.
Extra-Pineal Melatonin Synthesis
Interaction of PAMPs or DAMPs with its receptors triggers the nuclear translocation of NF-κB both in the macrophages or glia cells in the Brain. NF-κB dimers bind to κB elements located in the gene that codes for AA-NAT and control its transcription in a tissue-specific manner. In the macrophages the heterodimer RelA/c-Rel induces AA-NAT transcription and local melatonin production.
Related Publications (Selected):
Pinato L et al., Selective protection of the cerebellum against intracerebroventricular LPS is mediated by local melatonin synthesis., 2013.
Pires-Lapa MA et al., Melatonin synthesis in human colostrum mononuclear cells enhances dectin-1-mediated phagocytosis by mononuclear cells., 2013.
Muxel et al., NF-κB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene., 2012.
Pontes GN et al., Injury switches melatonin production source from endocrine (pineal) to paracrine (phagocytes) - melatonin in human colostrum and colostrum phagocytes., 2006.