title: NF-κB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene.
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.
authors.affiliation: Department of Physiology, Institute of Bioscience, University of São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Sandra Marcia
authors.initials: SM
authors.lastname: Muxel
authors.forename: Marco Antonio
authors.initials: MA
authors.lastname: Pires-Lapa
authors.forename: Alex Willian Arantes
authors.initials: AW
authors.lastname: Monteiro
authors.forename: Erika
authors.initials: E
authors.lastname: Cecon
authors.forename: Eduardo Koji
authors.initials: EK
authors.lastname: Tamura
authors.forename: Lucile Maria
authors.initials: LM
authors.lastname: Floeter-Winter
authors.forename: Regina P
authors.initials: RP
authors.lastname: Markus
mesh_terms: D000818:Animals; D047068:Arylalkylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008550:Melatonin / Q000096:biosynthesis*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D019899:Paracrine Communication; D010587:Phagocytosis / Q000276:immunology; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D020218:Response Elements; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D015054:Zymosan / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D015054:Zymosan; D047068:Arylalkylamine N-Acetyltransferase; D008550:Melatonin