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

Abstract

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.

Dual sources of melatonin and evidence for different primary functions

“…This switch in the primary site of melatonin synthesis relies on NF-ĸB activation. These highly mechanistic studies indicate that interleukin-10 (IL-10) levels modulate downstream immune responses which are operative in impacting both Source # 1 (pineal) and Source 2 (extrapineal) melatonin concentrations ( 89 ). The alterations in melatonin synthesis are predictably essential in modulating the immune response with the locally-synthesized melatonin by immune-competent cells exerting anti-inflammatory actions at the site of infection ( 129 ); the inhibitory actions of melatonin on inflammation have been documented in many studies ( 130 ).…”

“…Obviously, this is even more apparent in invertebrates, protists, and plants that have no pineal gland. This problem was solved when melatonin was identified in many peripheral organs ( 53 , 89 , 90 ) and even more so when it is located in the mitochondria of these cells as has been shown ( 91 ).…”