title: Dopamine induces IL-6-dependent IL-17 production via D1-like receptor on CD4 naive T cells and D1-like receptor antagonist SCH-23390 inhibits cartilage destruction in a human rheumatoid arthritis/SCID mouse chimera model.
abstract: A major neurotransmitter dopamine transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1-D5. Several studies have shown that dopamine not only mediates interactions into the nervous system, but can contribute to the modulation of immunity via receptors expressed on immune cells. We have previously shown an autocrine/paracrine release of dopamine by dendritic cells (DCs) during Ag presentation to naive CD4(+) T cells and found efficacious results of a D1-like receptor antagonist SCH-23390 in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis and in the NOD mouse model of type I diabetes, with inhibition of Th17 response. This study aimed to assess the role of dopaminergic signaling in Th17-mediated immune responses and in the pathogenesis of rheumatoid arthritis (RA). In human naive CD4(+) T cells, dopamine increased IL-6-dependent IL-17 production via D1-like receptors, in response to anti-CD3 plus anti-CD28 mAb. Furthermore, dopamine was localized with DCs in the synovial tissue of RA patients and significantly increased in RA synovial fluid. In the RA synovial/SCID mouse chimera model, although a selective D2-like receptor antagonist haloperidol significantly induced accumulation of IL-6(+) and IL-17(+) T cells with exacerbated cartilage destruction, SCH-23390 strongly suppressed these responses. Taken together, these findings indicate that dopamine released by DCs induces IL-6-Th17 axis and causes aggravation of synovial inflammation of RA, which is the first time, to our knowledge, that actual evidence has shown the pathological relevance of dopaminergic signaling with RA.
authors.affiliation: The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakano
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yamaoka
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hanami
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Saito
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katsuki
authors.forename: Sho
authors.initials: S
authors.lastname: Matsushita
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000494:pharmacology*; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000378:metabolism; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011897:Random Allocation; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D013585:Synovitis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018183:Transplantation Chimera
chemical_list: D001552:Benzazepines; D020381:Interleukin-17; D015850:Interleukin-6; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D004298:Dopamine