title: Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma.
abstract: The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins Gαs, and Gαi, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of Gnas, the gene that encodes Gαs in mouse CD11c(+) cells (Gnas(ΔCD11c) mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by Gnas(ΔCD11c) DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gαs and Gαi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.
authors.affiliation: Departments of Medicine and.
authors.forename: Jihyung
authors.initials: J
authors.lastname: Lee
authors.affiliation: Departments of Medicine and Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul 136-705, Republic of Korea;
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Departments of Medicine and School of Medical Science, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland; and.
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.affiliation: Departments of Medicine and.
authors.forename: Xiangli
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments of Medicine and.
authors.forename: Sara S
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Departments of Medicine and.
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
authors.affiliation: Departments of Medicine and.
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.affiliation: Departments of Medicine and.
authors.forename: Jongdae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Departments of Medicine and Medical Research Service, Veteran Affairs San Diego Healthcare System, San Diego, CA 92161.
authors.forename: Nicholas J G
authors.initials: NJ
authors.lastname: Webster
authors.affiliation: Departments of Medicine and Pharmacology, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Paul A
authors.initials: PA
authors.lastname: Insel
authors.affiliation: Departments of Medicine and eraz@ucsd.edu.
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000276:immunology*; D002864:Chromogranins; D000242:Cyclic AMP / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D006967:Hypersensitivity / Q000276:immunology*; D051379:Mice; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D002864:Chromogranins; D000242:Cyclic AMP; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: PKA; Th2; asthma; cAMP; dendritic cells