Eloranta Maija-Leena, Lövgren Tanja, Finke Doreen, Mathsson Linda, Rönnelid Johan, Kastner Berthold, Alm Gunnar V, Rönnblom Lars
Department of Medical Sciences, Uppsala University Hospital, and Uppsala University, Uppsala, Sweden.
Arthritis Rheum. 2009 Aug;60(8):2418-27. doi: 10.1002/art.24686.
Interferon-alpha (IFNalpha) 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 IFNalpha production induced by RNA-containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated.
Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFNalpha production was induced by RNA-containing ICs, which consisted of anti-RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E2 (PGE2), reactive oxygen species (ROS), or the cytokines IFNalpha2b, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), or tumor necrosis factor alpha (TNFalpha) were explored.
Monocytes inhibited IFNalpha production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFNalpha production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFNalpha2b/GM-CSF increased their IFNalpha production. RNA-containing ICs caused production of ROS, PGE2, and TNFalpha, especially in monocytes. These mediators and IL-10 suppressed IFNalpha production in PBMC cultures, with ROS and PGE2 also inhibiting IFNalpha production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFNalpha2b/GM-CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase.
IFNalpha 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.
α干扰素（IFNα）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。我们进行这项研究以探讨浆细胞样树突状细胞（PDC）中含RNA的免疫复合物（IC）诱导的IFNα产生是如何被调节的。
从外周血单核细胞（PBMC）中纯化的正常PDC与从健康个体或SLE患者分离的其他细胞群体共培养。含RNA的IC由抗RNP自身抗体和U1小核RNP颗粒组成，可诱导IFNα产生，我们探讨了前列腺素E2（PGE2）、活性氧（ROS）或细胞因子IFNα2b、粒细胞-巨噬细胞集落刺激因子（GM-CSF）、白细胞介素-10（IL-10）或肿瘤坏死因子α（TNFα）的作用。
单核细胞在PBMC培养中抑制PDC产生IFNα，而自然杀伤（NK）细胞具有刺激作用。单核细胞对纯PDC产生IFNα的影响很小，但抑制NK细胞对其的刺激。SLE患者的单核细胞抑制作用较弱。PBMC或PDC暴露于IFNα2b/GM-CSF可增加其IFNα产生。含RNA的IC导致ROS、PGE2和TNFα产生，尤其是在单核细胞中。这些介质和IL-10在PBMC培养中抑制IFNα产生，ROS和PGE2也抑制纯化的PDC产生IFNα。除ROS外，所有这些因子的抑制作用均被IFNα2b/GM-CSF消除。ROS清除剂血清素和过氧化氢酶可显著抵消单核细胞的抑制作用。
PDC中含RNA的IC诱导的IFNα产生受单核细胞、NK细胞和PDC之间相互作用网络的调节，涉及多种促炎和抗炎分子。在设计和应用新疗法时应考虑这一点。
