NF-κB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene

PLoS One. 2012;7(12):e52010. doi: 10.1371/journal.pone.0052010. Epub 2012 Dec 21.

Abstract

We demonstrate that during inflammatory responses the nuclear factor kappa B (NF-κB) induces the synthesis of melatonin by macrophages and that macrophage-synthesized melatonin modulates the function of these professional phagocytes in an autocrine manner. Expression of a DsRed2 fluorescent reporter driven by regions of the aa-nat promoter, that encodes the key enzyme involved in melatonin synthesis (arylalkylamine-N-acetyltransferase), containing one or two upstream κB binding sites in RAW 264.7 macrophage cell lines was repressed when NF-κB activity was inhibited by blocking its nuclear translocation or its DNA binding activity or by silencing the transcription of the RelA or c-Rel NF-κB subunits. Therefore, transcription of aa-nat driven by NF-κB dimers containing RelA or c-Rel subunits mediates pathogen-associated molecular patterns (PAMPs) or pro-inflammatory cytokine-induced melatonin synthesis in macrophages. Furthermore, melatonin acts in an autocrine manner to potentiate macrophage phagocytic activity, whereas luzindole, a competitive antagonist of melatonin receptors, decreases macrophage phagocytic activity. The opposing functions of NF-κB in the modulation of AA-NAT expression in pinealocytes and macrophages may represent the key mechanism for the switch in the source of melatonin from the pineal gland to immune-competent cells during the development of an inflammatory response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arylalkylamine N-Acetyltransferase / genetics*
  • Arylalkylamine N-Acetyltransferase / metabolism
  • Cell Line
  • Cell Nucleolus / metabolism
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Melatonin / biosynthesis*
  • Mice
  • NF-kappa B / metabolism*
  • Paracrine Communication
  • Phagocytosis / immunology
  • Promoter Regions, Genetic
  • Protein Transport
  • Response Elements
  • Transcription, Genetic* / drug effects
  • Transcriptional Activation / drug effects
  • Zymosan / metabolism

Substances

  • Lipopolysaccharides
  • NF-kappa B
  • Zymosan
  • Arylalkylamine N-Acetyltransferase
  • Melatonin

Grant support

This work was supported by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, 07/7871-6) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.