Role of nitric oxide in the maturation process of human dendritic cells

Paolucci, Clara (2003). Role of nitric oxide in the maturation process of human dendritic cells. PhD thesis The Open University.



Nitric oxide (NO) generated by phagocytes at inflammation sites contributes to regulate immune responses through both 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. In this thesis I report about the role of NO in two specific aspects of human DC maturation: i.e. endocytosis and ability to induce T cell activation. At variance with rodents, human DCs express the inducible isoform of the NO synthase neither when immature, nor after various treatment which induce DC maturation, indicating that regulation of these cells may occur only through exogenous NO. Exposure of DCs to NO, released by either bystander phagocytes or NO donors, reversed the inhibition of endocytosis induced by TNF-a. The intracellular accumulation of ceramide induced by TNF-a was also inhibited by NO. In addition, NO was found to exert an inhibitory effect downstream of the TNF-a-triggered ceramide accumulation, since NO donors reversed the inhibition of endocytosis induced by the cell-permeant C2-ceramide. I then studied the role of NO on DC ability of triggering T cell activation. DCs were exposed to the NO donor DETA-NO during their maturation process induced by treatment with TNF-a or lipopolysaccharide, or by CD40 activation. 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 and is due to enhanced release by DCs of soluble factors, in particular IL-12. All the effects described above were mimicked by the membrane-permeant cyclic GMP analogue, 8-Br cyclic GMP, and prevented by inhibition of the soluble guanyly 1-cyclase. The cGMP dependent modulation of DC function reported here is due to a synergism between NO and the various maturation stimuli since neither the changes in endocytic function nor the enhanced T cell activation and IL-12 release were observed after DC exposure to DETA-NO only. These results provide the first evidence that NO acts as a co-signalling molecule regulating human DC response to maturation stimuli.

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