title: Neuropeptide signaling activates dendritic cell-mediated type 1 immune responses through neurokinin-2 receptor.
abstract: Neurokinin A (NKA), a neurotransmitter distributed in the central and peripheral nervous system, strictly controls vital responses, such as airway contraction, by intracellular signaling through neurokinin-2 receptor (NK2R). However, the function of NKA-NK2R signaling on involvement in immune responses is less-well defined. We demonstrate that NK2R-mediated neuropeptide signaling activates dendritic cell (DC)-mediated type 1 immune responses. IFN-γ stimulation significantly induced NK2R mRNA and remarkably enhanced surface protein expression levels of bone marrow-derived DCs. In addition, the DC-mediated NKA production level was significantly elevated after IFN-γ stimulation in vivo and in vitro. We found that NKA treatment induced type 1 IFN mRNA expressions in DCs. Transduction of NK2R into DCs augmented the expression level of surface MHC class II and promoted Ag-specific IL-2 production by CD4(+) T cells after NKA stimulation. Furthermore, blockade of NK2R by an antagonist significantly suppressed IFN-γ production by both CD4(+) T and CD8(+) T cells stimulated with the Ag-loaded DCs. Finally, we confirmed that stimulation with IFN-γ or TLR3 ligand (polyinosinic-polycytidylic acid) significantly induced both NK2R mRNA and surface protein expression of human PBMC-derived DCs, as well as enhanced human TAC1 mRNA, which encodes NKA and Substance P. Thus, these findings indicate that NK2R-dependent neuropeptide signaling regulates Ag-specific T cell responses via activation of DC function, suggesting that the NKA-NK2R cascade would be a promising target in chronic inflammation caused by excessive type 1-dominant immunity.
authors.affiliation: Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Kitamura
authors.forename: Minoru
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Daiko
authors.initials: D
authors.lastname: Wakita
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000502:physiology; D007369:Interferon Inducers / Q000494:pharmacology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015288:Neurokinin A / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018041:Receptors, Neurokinin-2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; D007369:Interferon Inducers; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D018041:Receptors, Neurokinin-2; C495344:TLR3 protein, human; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D007371:Interferon-gamma; D015288:Neurokinin A; D011070:Poly I-C