Involvement of guanylyl cyclase signals of dendritic cells in allergic state

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We investigated the immune regulatory mechanism via two kinds of guanylyl cyclases expressed in dendritic cells (DCs), GC-A that is the receptor for ANP and soluble GC that is the receptor for NO. First we examined the effects of NO on human DCs and found that NO polarizes both CD11c+ myeloid DCs and Plasmacytoid-plasmacytoid DCs (pDCs) toward a Th2-inducing phenotypes. Namely, IL-12 production of myeloid DCs on LPS stimulation as well as IFN-a production of pDCs on CpG oligo DNA stimulation was decreased by the addition of NO donor and these cells induced differentiation of umbilical cord-derived naive T cells into Th2 cells (J. Immunol. 175:806-812, 2005). Next, we analyzed GC-A+ cells in therapeutically resected tonsils by confocal microscopy and found that GC-A+ cells were present in the interfollicular T cell areas. Furthermore, flow cytometric analysis revealed that CD123+ cells that seemed to represent pDCs expressed high levels of GC-A. Fresh peripheral blood pDCs did not express GC-A but they were induced to express it after a short term culture with IL-3 or CpG oligo DNA. Addition of ANP induced an increase in intracellular cGMP levels and down-regulated production of IFN-a upon CpG oligo DNA stimulation, indicating that GC-A on pDCs was functional. These results suggest that pDCs in lymphoid organs express GC-A and are subjected to ANP-mediated immune regulation. Our results demonstrated that two kinds of guanylyl cyclases of DCs are deeply involved in the pathogenesis of Th2-dominant allergic state.