title: Neuronal nitric oxide synthase modulates maturation of human dendritic cells.
abstract: Dendritic cells (DCs) are the most potent APCs of the immune system. Understanding the intercellular and intracellular signaling processes that lead to DC maturation is critical for determining how these cells initiate T cell-mediated immune processes. NO synthesized by the inducible NO synthase (iNOS) is important for the function of murine DCs. In our study, we investigated the regulation of the arginine/NO-system in human monocyte-derived DCs. Maturation of DCs induced by inflammatory cytokines (IL-1beta, TNF, IL-6, and PGE(2)) resulted in a pronounced expression of neuronal NOS (nNOS) but only minimal levels of iNOS and endothelial NOS were detected in human mature DCs. In addition, reporter cell assays revealed the production of NO by mature DCs. Specific inhibitors of NOS (N-nitro-L-arginine methyl ester) or of the NO target guanylyl cyclase (H-(1,2,4)-oxadiazolo [4,3-a] quinoxalin-1-one) prevented DC maturation (shown by decreased expression of MHC class II, costimulatory and CD83 molecules and reduced IL-12 production) and preserved an immature phenotype, indicating an autocrine effect of nNOS-derived NO on human DC maturation. Notably, inhibitor-treated DCs were incapable of inducing efficient T cell responses after primary culture and generated an anergic T cell phenotype. In conclusion, our results suggest that, in the human system, nNOS-, but not iNOS-derived NO, plays an important regulatory role for the maturation of DCs and, thus, the induction of pronounced T cell responses.
authors.affiliation: Department of Dermatology, University of Würzburg, Würzburg, Germany.
authors.forename: Henric S
authors.initials: HS
authors.lastname: Adler
authors.forename: Alexandra
authors.initials: A
authors.lastname: Simon
authors.forename: Edith
authors.initials: E
authors.lastname: Graulich
authors.forename: Alice
authors.initials: A
authors.lastname: Habermeier
authors.forename: Nicole
authors.initials: N
authors.lastname: Bacher
authors.forename: Andreas
authors.initials: A
authors.lastname: Friebe
authors.forename: Ellen I
authors.initials: EI
authors.lastname: Closs
authors.forename: Kerstin
authors.initials: K
authors.lastname: Steinbrink
mesh_terms: D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I