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(Journal of Leukocyte Biology. 2003;73:253-262.)
© 2003 by Society for Leukocyte Biology

Synergism of nitric oxide and maturation signals on human dendritic cells occurs through a cyclic GMP-dependent pathway

Clara Paolucci^*, Samuele E. Burastero^*, Patrizia Rovere-Querini^*, Clara De Palma^*, Sestina Falcone^*,, Cristiana Perrotta^*,, Annalisa Capobianco^*, Angelo A. Manfredi^* and Emilio Clementi^*,

^* Department Neuroscience and Department Immunology, DIBIT-H San Raffaele Institute, Milano, Italy;
Department Pharmacology, University of Milano, Italy; and
Department Pharmaco-Biology, University of Calabria, Rende, Italy

Correspondence: Dr. Emilio Clementi, DIBIT-H San Raffaele Institute, via Olgettina 58, 20132 Milano, Italy; E-mail: clementi.emilio{at}hsr.it

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 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.

Key Words: guanylate cyclase • IL-12 • T cell activation • TNF- • CD40 • lipopolysaccharide

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