title: Norepinephrine Controls Effector T Cell Differentiation through β2-Adrenergic Receptor-Mediated Inhibition of NF-κB and AP-1 in Dendritic Cells.
abstract: Despite accumulating evidence indicating that neurotransmitters released by the sympathetic nervous system can modulate the activity of innate immune cells, we still know very little about how norepinephrine impacts signaling pathways in dendritic cells (DC) and the consequence of that in DC-driven T cell differentiation. In this article, we demonstrate that β2-adrenergic receptor (β2AR) activation in LPS-stimulated DC does not impair their ability to promote T cell proliferation; however, it diminishes IL-12p70 secretion, leading to a shift in the IL-12p70/IL-23 ratio. Although β2AR stimulation in DC induces protein kinase A-dependent cAMP-responsive element-binding protein phosphorylation, the effect of changing the profile of cytokines produced upon LPS challenge occurs in a protein kinase A-independent manner and, rather, is associated with inhibition of the NF-κB and AP-1 signaling pathways. Moreover, as a consequence of the inverted IL-12p70/IL-23 ratio following β2AR stimulation, LPS-stimulated DC promoted the generation of CD4(+) T cells that, upon TCR engagement, produced lower amounts of IFN-γ and higher levels of IL-17. These findings provide new insights into molecular and cellular mechanisms by which β2AR stimulation in murine DC can influence the generation of adaptive immune responses and may explain some aspects of how sympathetic nervous system activity can modulate immune function.
authors.affiliation: Departamento de Microbiologia, Imunologia, e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil; and.
authors.forename: Maisa Carla
authors.initials: MC
authors.lastname: Takenaka
authors.affiliation: Departamento de Microbiologia, Imunologia, e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil; and.
authors.forename: Leandro Pires
authors.initials: LP
authors.lastname: Araujo
authors.affiliation: Departamento de Microbiologia, Imunologia, e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil; and.
authors.forename: Juliana Terzi
authors.initials: JT
authors.lastname: Maricato
authors.affiliation: Departamento de Microbiologia, Imunologia, e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil; and.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Nascimento
authors.affiliation: Departamento de Microbiologia, Imunologia, e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil; and.
authors.forename: Marcia Grando
authors.initials: MG
authors.lastname: Guereschi
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Rafael Machado
authors.identifier: http://orcid.org/0000-0003-3998-8012
authors.initials: RM
authors.lastname: Rezende
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Francisco J
authors.identifier: http://orcid.org/0000-0001-8156-0736
authors.initials: FJ
authors.lastname: Quintana
authors.affiliation: Departamento de Microbiologia, Imunologia, e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil; and asbasso@unifesp.br.
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Basso
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D009638:Norepinephrine / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D018343:Receptors, Adrenergic, beta-2 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000276:immunology
chemical_list: D016328:NF-kappa B; D018343:Receptors, Adrenergic, beta-2; D018808:Transcription Factor AP-1; D009638:Norepinephrine