Involvement of guanylyl cyclase signals of dendritic cells in allergic state

我们通过树突状细胞(DC)表达的两种鸟苷酸环化酶(GC-A是ANP的受体，以及可溶性GC(NO的受体))来研究其免疫调节机制。首先，我们研究了NO对人DC的影响，发现NO使CD11c+髓系树突状细胞和浆细胞样浆细胞样树突状细胞向Th2诱导表型分化。也就是说，加入NO供体后，髓系树突状细胞在内毒素刺激下产生的IL-12和在CpG寡核苷酸刺激下产生的干扰素-α减少，这些细胞诱导脐带来源的幼稚T细胞分化为Th2细胞(J.175：806-812,2005)。接下来，我们用共聚焦显微镜分析了治疗切除的扁桃体中的GC-A+细胞，发现GC-A+细胞存在于滤泡间T细胞区域。此外，流式细胞仪分析显示，CD123+细胞似乎代表PDCs，表达高水平的GC-A。新鲜外周血树突状细胞不表达GC-A，但经IL-3或CpG寡核苷酸短期培养后可表达GC-A。加入ANP后，细胞内cGMP水平升高，CpG寡核苷酸刺激下细胞产生干扰素-α，提示pDCs上的GC-A具有功能。这些结果表明，淋巴器官中的PDCs表达GC-A，并受ANP介导的免疫调节。我们的研究结果表明，树突状细胞上的两种鸟苷酸环化酶在Th2显性过敏状态的发病机制中起重要作用。

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.