Gutzmer Ralf, Lisewski Margarete, Zwirner Jörg, Mommert Susanne, Diesel Carola, Wittmann Miriam, Kapp Alexander, Werfel Thomas
Department of Dermatology and Allergology, Hannover Medical University, Hannover, Germany.
Immunology. 2004 Apr;111(4):435-43. doi: 10.1111/j.1365-2567.2004.01829.x.
The anaphylatoxin C3a is an important inflammatory mediator in the innate and adaptive immune systems. Recent reports in various animal models have fostered the role of C3a in mediating allergic reactions such as pulmonary allergies. However, data in humans are limited and the cellular targets for C3a are not fully understood. We sought to explore human dendritic cells as a new target for C3a, because C3a receptor (C3aR) expression has been described on myeloid cells, and dendritic cells are likely make contact with C3a at sites of inflammatory reactions. In this study, we demonstrated the expression of the C3aR on human monocyte-derived dendritic cells (MoDC) and its up-regulation by interferon (IFN)-alpha, IFN-gamma and prostaglandin E2 (PGE2). The strongest up-regulation was yielded by the combination of IFN-alpha+ IFN-gamma. Tumour necrosis factor-alpha (TNF-alpha) down-regulated the C3aR. After up-regulation of the C3aR by IFN-alpha+ IFN-gamma, C3a significantly up-regulated the surface expression of CD54, CD83 and CD86, but not of CD40, CD80 or human leucocyte antigen (HLA)-DR. C3a had no effect on the production of interleukin (IL)-10 or IL-12p70, or on the capacity of MoDC to stimulate autologous T-cell proliferation. However, C3a had a direct migratory effect on MoDC, as indicated by the induction of F-actin polymerization and migration in Boyden chamber experiments, which was pronounced after up-regulation of the C3aR with IFN-alpha+ IFN-gamma. Therefore, dendritic cells represent another group of target cells that might be recruited by C3a to areas of inflammation, in particular under conditions where IFNs are increased in the surrounding environment.
过敏毒素C3a是先天性和适应性免疫系统中的一种重要炎症介质。最近在各种动物模型中的报告证实了C3a在介导过敏反应（如肺部过敏）中的作用。然而，人类相关数据有限，且C3a的细胞靶点尚未完全明确。我们试图探索人类树突状细胞作为C3a的新靶点，因为已有研究表明髓系细胞上表达C3a受体（C3aR），并且树突状细胞可能在炎症反应部位与C3a接触。在本研究中，我们证实了人类单核细胞来源的树突状细胞（MoDC）上C3aR的表达，以及干扰素（IFN）-α、IFN-γ和前列腺素E2（PGE2）对其表达的上调作用。IFN-α + IFN-γ联合使用时上调作用最强。肿瘤坏死因子-α（TNF-α）下调C3aR。经IFN-α + IFN-γ上调C3aR后，C3a显著上调CD54、CD83和CD86的表面表达，但对CD40、CD80或人类白细胞抗原（HLA）-DR无影响。C3a对白细胞介素（IL）-10或IL-12p70的产生以及MoDC刺激自体T细胞增殖的能力没有影响。然而，C3a对MoDC有直接的迁移作用，如在Boyden小室实验中诱导F-肌动蛋白聚合和迁移所示，在用IFN-α + IFN-γ上调C3aR后这种作用更为明显。因此，树突状细胞代表了另一组可能被C3a招募到炎症区域的靶细胞，特别是在周围环境中IFN增加的情况下。
