IL-10-induced STAT3/NF-κB crosstalk modulates pineal and extra-pineal melatonin synthesis.

Immune-pineal axis activation is part of the assembly of immune responses. Proinflammatory cytokines inhibit the pineal synthesis of melatonin while inducing it in macrophages by mechanisms dependent on nuclear factor-κB (NF-κB) activation. Cytokines activating the Janus kinase/signal transducer and activator of transcription (STAT) pathways, such as interferon-gamma (IFN-γ) and interleukin-10 (IL-10), modulate melatonin synthesis in the pineal, bone marrow (BM), and spleen. The stimulatory effect of IFN-γ upon the pineal gland depends on STAT1/NF-κB interaction, but the mechanisms controlling IL-10 effects on melatonin synthesis remain unclear. Here, we evaluated the role of STAT3 and NF-κB activation by IL-10 upon the melatonin synthesis of rats' pineal gland, BM, spleen, and peritoneal cells. The results show that IL-10-induced interaction of (p)STAT3 with specific NF-κB dimmers leads to different cell effects. IL-10 increases the pineal's acetylserotonin O-methyltransferase (ASMT), N-acetylserotonin, and melatonin content via nuclear translocation of NF-κB/STAT3. In BM, the nuclear translocation of STAT3/p65-NF-κB complexes increases ASMT expression and melatonin content. Increased pSTAT3/p65-NF-κB nuclear translocation in the spleen enhances phosphorylated serotonin N-acetyltransferase ((p)SNAT) expression and melatonin content. Conversely, in peritoneal cells, IL-10 leads to NF-κB p50/p50 inhibitory dimmer nuclear translocation, decreasing (p)SNAT expression and melatonin content. In conclusion, IL-10's effects on melatonin production depend on the NF-κB subunits interacting with (p)STAT3. Thus, variations of IL-10 levels and downstream pathways during immune responses might be critical regulatory factors adjusting pineal and extra-pineal synthesis of melatonin.

MEL-Index: Estimation of Tissue Melatonin Levels Using Gene Expression Data.

Melatonin synthesis by extrapineal sources adjusts physiological and pathophysiological processes in several types of cells and tissues. As measuring locally produced melatonin in fresh tissues might be a challenge due to limited material availability, we created a simple predictive model, the MEL-Index, which infers the content of tissue melatonin using gene expression data. The MEL-Index can be a powerful tool to study the role of melatonin in different contexts. Applying the MEL-Index method to RNA-seq datasets, we have shed light into the clinical relevance of melatonin as a modulator tumor progression and lung infection due to COVID-19. The MEL-Index combines the z-normalized expressions of ASMT (Acetylserotonin O-Methyltransferase), last enzyme of the biosynthetic pathway, and CYP1B1 (cytochrome P450 family enzyme), which encodes the enzyme that metabolizes melatonin in extrahepatic tissues. In this chapter, we describe the steps for calculating the MEL-Index.

Behavioral fever decreases metabolic response to lipopolysaccharide in yellow Cururu toads (Rhinella icterica).

Ectothermic vertebrates develop behavioral fever in response to bacterial products, with potential corresponding metabolic costs associated with immune stimulation. Although behavioral fever has been described in several taxa under laboratory conditions, some important questions regarding metabolic response to bacterial products at different temperatures and effectiveness of behavioral fever remain open. Many ectotherms, such as nocturnal anurans, may be active in the field at environmental conditions that restrict thermoregulation during the immune response. How does the metabolic response to bacterial products under ecologically relevant but unfavorable thermal field conditions compare to that measured in fever thermal preferendum? Additionally, are there differences in the partitioning of metabolic costs associated with immune stimulation and Arrhenius effect (biochemical reactions rate) at normal versus fever thermal preferendum? We compared the energy expenditure untreated and LPS-treated yellow Cururu toads (Rhinella icterica) at temperature corresponding to field activity during winter nights, and at normal and fever thermal preferendum. It was hypothesized that the metabolic response to LPS would be proportionally lower at higher body temperatures. To test these hypotheses, we measured temperature in the field during night using agar models, as well as normal and fever thermal preferendum of the toads within a thermal gradient. Subsequently, we measured the toad's metabolic rates at mean agar models temperature, as well as at normal and fever thermal preferendum. Lastly, we calculated the Metabolic response to LPS as the ratio between MRLPS/MRSaline in each of these mean temperatures. Our results show that metabolic rates do not increase in response to LPS at the agar models temperature typical of the winter nights under which theses toads maintain reproductive activity. Moreover, LPS treatment increased the metabolic costs relative to Arrhenius effects at normal thermal preferendum but not at fever thermal preferendum. In this way, metabolic response to LPS was comparative lower at fever than normal thermal preferendum in yellow Cururu toads.