The Concept of the Immune-Pineal Axis Tested in Patients Undergoing an Abdominal Hysterectomy

Tatsch-Dias, Mirella de Oliveira; Levandovski, Rosa Maria; Souza, Izabel Cristina Custodio de; Rocha, Marcelo Gregianin; Fernandes, Pedro Augusto Carlos Magno; Torres, Iraci Lucena da Silva; Hidalgo, María Paz Loayza; Markus, Regina Pekelmann; Caumo, Wolnei

doi:10.1159/000347160

Cited by 21 publications

(11 citation statements)

References 43 publications

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“…While humans are diurnally active, mice are active both day and night having an opposite rhythm of glucocorticoid compared to humans. The interaction between immune system and pineal gland was investigated in a recent study, where patients undergoing hysterectomy showed an inverse relation between plasma levels of melatonin and TNF-α [37]. Higher postoperative levels of TNF-α and lower levels of cortisol were accompanied by lower levels of melatonin.…”

Section: Discussionmentioning

confidence: 99%

Pronounced Inflammatory Response to Endotoxaemia during Nighttime: A Randomised Cross-Over Trial

et al. 2014

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BackgroundCircadian variation in bodily functions has been shown to impact health in acute and chronic medical conditions. Little is known about the relationship between circadian rhythm and sepsis in humans. We aimed to investigate circadian variations in the host response in a human endotoxaemia model.Design and MethodsA cross-over study, where 12 healthy young men received E. coli endotoxin (lipopolysaccharide, LPS) 0.3 ng/kg at 12 noon and, on another day, at 12 midnight. Blood samples were analysed for pro- and anti-inflammatory cytokines: tumour-necrosis factor (TNF)-alpha, soluble TNF receptors (sTNF-R)-1 and -2, interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, and IL-10 as well as YKL-40 and the oxidative stress markers malondialdehyde (MDA), ascorbic acid (AA) and dehydroascorbic acid (DHA) before and at 2, 4, 6 and 8 hours after LPS administration.ResultsThe levels of MDA and IL-10 where significantly higher during the day time (P<0.05) whereas levels of TNF-alpha, sTNF-RI, sTNF-RII, IL-1Ra, IL-6, and YKL-40 were higher (P<0.01 for all comparisons) during the night time. No significant differences were seen in the levels of AA and DHA.ConclusionA day-night difference in the acute phase response to endotoxaemia exists in healthy volunteers with a more pronounced inflammatory response during the night time. This circadian difference in the response to endotoxaemia may play an important role in the clinical setting and should be investigated further.

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Section: Discussionmentioning

confidence: 99%

Pronounced Inflammatory Response to Endotoxaemia during Nighttime: A Randomised Cross-Over Trial

et al. 2014

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“…Patients with mastitis [19] or those undergoing a surgical procedure, such as caesarean section [79] or hysterectomy [80], exhibit a reduction or suppression in their normal nocturnal melatonin increase. The concentration of melatonin in the colostrum (third day milk) of healthy women presents a daily rhythm.…”

Section: Nf-κb and The Pineal Glandmentioning

confidence: 99%

Immune-Pineal Axis: Nuclear Factor κB (NF-kB) Mediates the Shift in the Melatonin Source from Pinealocytes to Immune Competent Cells

Markus

Cecon

Pires-Lapa

2013

IJMS

113

102

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Pineal gland melatonin is the darkness hormone, while extra-pineal melatonin produced by the gonads, gut, retina, and immune competent cells acts as a paracrine or autocrine mediator. The well-known immunomodulatory effect of melatonin is observed either as an endocrine, a paracrine or an autocrine response. In mammals, nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) blocks noradrenaline-induced melatonin synthesis in pinealocytes, which induces melatonin synthesis in macrophages. In addition, melatonin reduces NF-κB activation in pinealocytes and immune competent cells. Therefore, pathogen- or danger-associated molecular patterns transiently switch the synthesis of melatonin from pinealocytes to immune competent cells, and as the response progresses melatonin inhibition of NF-κB activity leads these cells to a more quiescent state. The opposite effect of NF-κB in pinealocytes and immune competent cells is due to different NF-κB dimers recruited in each phase of the defense response. This coordinated shift of the source of melatonin driven by NF-κB is called the immune-pineal axis. Finally, we discuss how this concept might be relevant to a better understanding of pathological conditions with impaired melatonin rhythms and hope it opens new horizons for the research of side effects of melatonin-based therapies.

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“…Extra-pineal synthesis of melatonin by cerebellar cells decreases LPS-induced neuronal death [45], melatonin synthesis by human glioma cell lines is inversely correlated with tumor aggressiveness [46], and the increase in daytime plasma melatonin concentration is associated with faster surgical (laparotomy) wound-healing [47], reinforcing the anti-inflammatory role of locally synthesized melatonin. Recently, it was shown that neuronal cells also produce melatonin and, intriguingly, this production is located in the mitochondria [48].…”

Section: Discussionmentioning

confidence: 99%

β-Adrenoceptors Trigger Melatonin Synthesis in Phagocytes

Pires-Lapa

Carvalho-Sousa

Cecon

et al. 2018

IJMS

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Melatonin (5-methoxy-N-acetylserotonin), the pineal hormone, is also synthesized by immune-competent cells. The pineal hormone signals darkness, while melatonin synthesized on demand by activated macrophages at any hour of the day acts locally, favoring regulatory/tolerant phenotypes. Activation of β-adrenoceptors in pinealocytes is the main route for triggering melatonin synthesis. However, despite the well-known role of β-adrenoceptors in the resolution macrophage phenotype (M2), and the relevance of macrophage synthesized melatonin in facilitating phagocytic activity, there is no information regarding whether activation of β-adrenoceptors would induce melatonin synthesis by monocytes. Here we show that catecholamines stimulate melatonin synthesis in bone marrow-derived dendritic cells and RAW 264.7 macrophages. Activation of β-adrenoceptors promotes the synthesis of melatonin by stimulating cyclic AMP/protein kinase A (PKA) pathway and by activating the nuclear translocation of NF-κB. Considering the great number of macrophages around sympathetic nerve terminals, and the relevance of this system for maintaining macrophages in stages compatible to low-grade inflammation, our data open the possibility that extra-pineal melatonin acts as an autocrine/paracrine signal in macrophages under resolution or tolerant phenotypes.

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The Concept of the Immune-Pineal Axis Tested in Patients Undergoing an Abdominal Hysterectomy

Cited by 21 publications

References 43 publications

Pronounced Inflammatory Response to Endotoxaemia during Nighttime: A Randomised Cross-Over Trial

Pronounced Inflammatory Response to Endotoxaemia during Nighttime: A Randomised Cross-Over Trial

Immune-Pineal Axis: Nuclear Factor κB (NF-kB) Mediates the Shift in the Melatonin Source from Pinealocytes to Immune Competent Cells

β-Adrenoceptors Trigger Melatonin Synthesis in Phagocytes

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