Regulation of the Interferon-α Production Induced by RNA-Containing Immune Complexes in Plasmacytoid Dendritic Cells
Regulation of the Interferon-α Production Induced by RNA-Containing Immune Complexes in Plasmacytoid Dendritic Cells
复制标题
DOI：
10.1002/art.24686
复制
发表时间：
2009-08-01
影响因子：
--
通讯作者：
Ronnblom, Lars
中科院分区：
文献类型：
--
作者：
Eloranta, Maija-Leena;Lovgren, Tanja;Ronnblom, Lars
目标。干扰素-α在包括系统性红斑狼疮(SLE)在内的多种自身免疫性疾病中产生，可能在其发病机制中起重要作用。我们开展了这项研究，以探讨含RNA免疫复合体(ICs)诱导浆细胞样树突状细胞(PDCs)产生干扰素的机制。从正常人或SLE患者的外周血单个核细胞(PBMC)中提纯的正常PDCs与分离的其他细胞群共培养。由抗RNP自身抗体和U1核内RNP小颗粒组成的含RNA的ICs诱导产生干扰素-α，观察前列腺素E-2(PGE(2))、活性氧(ROS)或细胞因子干扰素-α2b、粒-巨噬细胞集落刺激因子(GM-CSF)、白介素10(IL-10)、肿瘤坏死因子(TNF-α)的影响。单核细胞可抑制PBMC培养的PDCs产生干扰素α，而自然杀伤细胞(NK细胞)具有刺激性。单核细胞对纯PDCs产生的干扰素影响不大，但对NK细胞的刺激有抑制作用。SLE患者的单核细胞抑制作用较弱。将PBMC或PDCs暴露于干扰素α2b/GM-CSF可增加其产生干扰素的能力。含有RNA的IC可导致ROS、PGE(2)和TNFα的产生，特别是在单核细胞中。这些介质和IL-10抑制PBMC培养产生干扰素α，ROS和PGE(2)也抑制纯化的PDCs产生干扰素α。除ROS外，所有这些药物的抑制作用均可被干扰素α2b/GM-CSF消除。ROS清除剂5-羟色胺和过氧化氢酶能明显拮抗单核细胞的抑制作用。由含有RNA的ICs诱导的PDCs产生的干扰素α受单核细胞、NK细胞和PDCs之间的相互作用网络的调节，涉及几个促炎和抗炎分子。在设计和应用新疗法时，应该考虑到这一点。
Objective. Interferon-alpha (IFN alpha) is produced in several autoimmune diseases, including systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We undertook this study to investigate how IFN alpha production induced by RNA-containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated.Methods. Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFN alpha production was induced by RNA-containing ICs, which consisted of anti-RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E-2 (PGE(2)), reactive oxygen species (ROS), or the cytokines IFN alpha 2b, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), or tumor necrosis factor alpha (TNF alpha) were explored.Results. Monocytes inhibited IFN alpha production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFN alpha production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFN alpha 2b/GM-CSF increased their IFN alpha production. RNA-containing ICs caused production of ROS, PGE(2), and TNF alpha, especially in monocytes. These mediators and IL-10 suppressed IFN alpha production in PBMC cultures, with ROS and PGE(2) also inhibiting IFN alpha production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFN alpha 2b/GM-CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase.Conclusion. IFN alpha production induced by RNA-containing ICs in PDCs is regulated by a network of interactions between monocytes, NK cells, and PDCs, involving several pro- and antiinflammatory molecules. This should be considered when designing and applying new therapies.