STAT1‐NFκB crosstalk triggered by interferon gamma regulates noradrenaline‐induced pineal hormonal production

Abstract

Melatonin production by pineal glands is modulated by several immune signals. The nuclear translocation of nuclear factor kappa‐B (NFκB) homodimers, lacking transactivation domains, once induced by lipopolysaccharide (LPS) or tumor necrosis factor (TNF), inhibits the expression of Aanat gene and the synthesis of noradrenaline (NA)‐induced melatonin. Interferon gamma (IFN‐γ), on the other hand, increases melatonin synthesis. Furthermore, this cytokine activates the signal transducer as well as the activator of transcription 1 (STAT1) pathway, which was never evaluated as a melatonin synthesis modulator before. Reports demonstrated that IFN‐γ might also activate NFκB. The present study evaluated the role of STAT1‐NFκB crosstalk triggered by IFN‐γ regarding the regulation of NA‐induced pineal glands’ hormonal production. Moreover, IFN‐γ treatment increased NA‐induced Aanat transcription, in addition to the synthesis of N‐acetylserotonin (NAS) and melatonin. These effects were associated with STAT1 nuclear translocation, confirmed by the co‐immunoprecipitation of STAT1 and Aanat promoter. Pharmacological STAT1 enhancement augmented NA‐induced Aanat transcription as well as NAS and melatonin production. Additionally, IFN‐γ induced the nuclear translocation of RelA‐NFκB subunits. The blockade of this pathway prevented IFN‐γ effects on the pineal function. The present data show that STAT1 and NFκB crosstalk controls melatonin production through a synergistic mechanism, disclosing a new integrative mechanism regarding pineal hormonal activity control.

Exenatide inhibits NF-κB and attenuates ER stress in diabetic cardiomyocyte models

“…In contrast, hyperglycemia-activated NF-κB was inhibited by Exenatide. These results demonstrate that Exenatide exerts protective effects on cardiomyocytes through the NF-κB signaling pathway, in agreement with previous studies [42,43]. Indeed, such studies have shown that inhibition of NF-κB prevents heart inflammation [44,45] while improving oxidative stress and countering the downregulation of anti-oxidative factors [46,47].…”

The Circadian Rhythms of STAT3 in the Rat Pineal Gland and Its Involvement in Arylalkylamine-N-Acetyltransferase Regulation

“…Although our experimental setup is in time-course with this study, it is possible that methodical differences, such as culturing conditions or dosing, could differ from our study. In support, a recent study shows that IFN-γ enhances the aa-nat mRNA in the dose 100 ng/mL, but the dose 30 ng/mL has no effect [ 60 ]. Furthermore, in ewes, the direction of the response of pineal AANAT to intracerebroventricular injection of IL-1𝛽 depends on the photoperiod [ 61 ], suggesting more complex interactions between the immune system and the melatonin synthetic pathway.…”

Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

“…GSK3β inhibition has reciprocal positive interactions with melatonin, with melatonin increasing the PI3K/Akt and ser9 phosphorylation and inhibition of GSK3β and GSK3β inhibition suppressing IDO [174]. However, a STAT1 binding site is present in the AANAT promotor [177], allowing STAT1 activation of IDO by IFNγ to induce the melatonergic pathway and melatonin release. It is likely that the concurrent release of melatonin would negatively feedback on the IFNγ/GSK3β/JAK1/PKCδ/STAT1/IDO, although AhR/CYP1B1 via the backward conversion of melatonin to NAS would have contrasting effects via TrkB activation.…”