Immune-pineal axis: nuclear factor κB (NF-kB) mediates the shift in the melatonin source from pinealocytes to immune competent cells

Abstract

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.

Figure 1

Schematic representation of NF-κB-mediated shift in melatonin sources upon activation of the immune-pineal axis. Left side—Physiological conditions: Melatonin synthesized at nighttime by the pineal gland impairs leukocyte migration. Right side—Interaction of PAMPs or DAMPs with their receptors triggers the nuclear translocation of NF-κB both in the pinealocytes and macrophages. 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 pinealocytes, the homodimer p50/p50 blocks AA-NAT transcription, while in macrophages the heterodimer RelA/c-Rel induces AA-NAT transcription and local melatonin production. Bottom—Melatonin also participates in the resolution phase, as it reduces the nuclear concentration of NF-κB, thereby reducing the transcription of genes involved in the pro-inflammatory phase of the innate immune response. During this phase, the effect of melatonin and corticosterone are synergic, as both reduce the nuclear content of NF-κB. In the pineal gland, corticosterone increases the noradrenaline-induced melatonin production in vitro, and nocturnal melatonin levels subsequently rise in rats [70,115] (see text for further details).