title: Calcium signaling inhibits interleukin-12 production and activates CD83(+) dendritic cells that induce Th2 cell development.
abstract: Mature dendritic cells (DCs), in addition to providing costimulation, can define the Th1, in contrast to the Th2, nature of a T-cell response through the production of cytokines and chemokines. Because calcium signaling alone causes rapid DC maturation of both normal and transformed myeloid cells, it was evaluated whether calcium-mobilized DCs polarize T cells toward a Th1 or a Th2 phenotype. After human monocytes were cultured for 24 hours in serum-free medium and granulocyte-macrophage colony-stimulating factor to produce immature DCs, additional overnight culture with either calcium ionophore (CI) or interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and soluble CD40L resulted in phenotypically mature DCs that produced interleukin-8 (IL-8) and displayed marked expression of CD80, CD86, CD40, CD54, CD83, DC-LAMP, and RelB. DCs matured by IFN-gamma, TNF-alpha, and soluble CD40L were additionally distinguished by undetectable CD4 expression, marked secretion of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th1/Tc1 characteristics during T-cell sensitization. In contrast, DCs matured by CI treatment were distinguished by CD4 expression, modest or absent levels of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th2/Tc2 characteristics. Calcium signaling selectively antagonized IL-12 production by mature DCs activated with IFN-gamma, TNF-alpha, and soluble CD40L. Although the activation of DCs by calcium signals is largely mediated through calcineurin phosphatase, the inhibition of IL-12 production by calcium signaling was independent of this enzyme. Naturally occurring calcium fluxes in immature DCs, therefore, negatively regulate Dc1 differentiation while promoting Dc2 characteristics and Th2/Tc2 polarization. Calcium-mobilized DCs may have clinical usefulness in treating disease states with excessive Th1/Tc1 activity, such as graft-versus-host disease or autoimmunity.
authors.affiliation: Department of Surgery and the Harrison Surgical Research Center, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Faries
authors.forename: I
authors.initials: I
authors.lastname: Bedrosian
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.forename: G
authors.initials: G
authors.lastname: Koski
authors.forename: J G
authors.initials: JG
authors.lastname: Roros
authors.forename: M A
authors.initials: MA
authors.lastname: Moise
authors.forename: H Q
authors.initials: HQ
authors.lastname: Nguyen
authors.forename: F H
authors.initials: FH
authors.lastname: Engels
authors.forename: P A
authors.initials: PA
authors.lastname: Cohen
authors.forename: B J
authors.initials: BJ
authors.lastname: Czerniecki
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors*; D007937:Leukapheresis; D008562:Membrane Glycoproteins / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D007136:Immunoglobulins; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D051841:Transcription Factor RelB; D014157:Transcription Factors; D000097802:CD83 Antigen; C497593:RELB protein, human