title: Dopamine inhibits the effector functions of activated NK cells via the upregulation of the D5 receptor.
abstract: Several lines of evidence indicate that dopamine (DA) plays a key role in the cross-talk between the nervous and immune systems. In this study, we disclose a novel immune-regulatory role for DA: inhibition of effector functions of activated NK lymphocytes via the selective upregulation of the D5 dopaminergic receptor in response to prolonged cell stimulation with rIL-2. Indeed, engagement of this D1-like inhibitory receptor following binding with DA suppresses NK cell proliferation and synthesis of IFN-γ. The inhibition of IFN-γ production occurs through blocking the repressor activity of the p50/c-REL dimer of the NF-κB complex. Indeed, the stimulation of the D5 receptor on rIL-2-activated NK cells inhibits the binding of p50 to the microRNA 29a promoter, thus inducing a de novo synthesis of this miRNA. In turn, the increased levels of microRNA 29a were inversely correlated with the ability of NK cells to produce IFN-γ. Taken together, our findings demonstrated that DA switches off activated NK cells, thus representing a checkpoint exerted by the nervous system to control the reactivity of these innate immune effectors in response to activation stimuli and to avoid the establishment of chronic and pathologic inflammatory processes.
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; and joanna.mikulak@humanitasresearch.it domenico.mavilio@humanitas.it.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mikulak
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; and.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bozzo
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; and.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Roberto
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Pontarini
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; and.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tentorio
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; and.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hudspeth
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; and.
authors.forename: Enrico
authors.initials: E
authors.lastname: Lugli
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; and Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20089 Milan, Italy joanna.mikulak@humanitasresearch.it domenico.mavilio@humanitas.it.
authors.forename: Domenico
authors.identifier: http://orcid.org/0000-0001-6147-0952
authors.initials: D
authors.lastname: Mavilio
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004298:Dopamine / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000276:immunology; D020569:Proto-Oncogene Proteins c-rel / Q000037:antagonists & inhibitors; D050641:Receptors, Dopamine D5 / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D007376:Interleukin-2; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel; D011994:Recombinant Proteins; D050641:Receptors, Dopamine D5; D007371:Interferon-gamma; D004298:Dopamine