title: Synergism of nitric oxide and maturation signals on human dendritic cells occurs through a cyclic GMP-dependent pathway.
abstract: Nitric oxide (NO), generated by phagocytes at inflammation sites, contributes to regulate immune responses through autocrine and paracrine actions on bystander cells. Among the latter are dendritic cells (DCs). Little is known about regulation of DC function by NO, especially in the human system. We exposed human monocyte-derived DCs to the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate (DETA-NO) during their maturation process induced by treatment with tumor necrosis factor alpha or lipopolysaccharide or by CD40 activation. We report here that after exposure to DETA-NO, DCs exhibit a significantly increased ability to activate T lymphocytes stimulated by mycobacterial antigens, Staphylococcus aureus Cowen strain B, allo-antigens, or cross-linking of the CD3-T cell receptor complex. This effect persists after removal of DETA-NO, depends on the generation of cyclic guanosine 5'-monophosphate, and is a result of enhanced release by DCs of soluble factors, in particular interleukin (IL)-12. This modulation of DC function is a result of a synergism between NO and the various maturation stimuli, as neither enhanced T cell activation nor IL-12 release was observed after DC exposure to DETA-NO only. These results provide the first evidence that NO acts as a cosignaling molecule regulating human DC response to maturation stimuli.
authors.affiliation: Department Neuroscience, DIBIT-H San Raffaele Institute, via Olgettina 58, 20132 Milan, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Paolucci
authors.forename: Samuele E
authors.initials: SE
authors.lastname: Burastero
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rovere-Querini
authors.forename: Clara
authors.initials: C
authors.lastname: De Palma
authors.forename: Sestina
authors.initials: S
authors.lastname: Falcone
authors.forename: Cristiana
authors.initials: C
authors.lastname: Perrotta
authors.forename: Annalisa
authors.initials: A
authors.lastname: Capobianco
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Manfredi
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
mesh_terms: D019013:CD40 Antigens / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D009569:Nitric Oxide / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D019013:CD40 Antigens; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D009569:Nitric Oxide; D006152:Cyclic GMP