Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
PLoS One. 2010 Feb 16;5(2):e9252. doi: 10.1371/journal.pone.0009252.
In recent years it has become clear that the therapeutic properties of bone marrow-derived mesenchymal stromal cells (MSC) are related not only to their ability to differentiate into different lineages but also to their capacity to suppress the immune response. We here studied the influence of MSC on macrophage function. Using mouse thioglycolate-elicited peritoneal macrophages (M) stimulated with LPS, we found that MSC markedly suppressed the production of the inflammatory cytokines TNF-alpha, IL-6, IL-12p70 and interferon-gamma while increased the production of IL-10 and IL-12p40. Similar results were observed using supernatants from MSC suggesting that factor(s) constitutively released by MSC are involved. Supporting a role for PGE(2) we observed that acetylsalicylic acid impaired the ability of MSC to inhibit the production of inflammatory cytokines and to stimulate the production of IL-10 by LPS-stimulated M. Moreover, we found that MSC constitutively produce PGE2 at levels able to inhibit the production of TNF-alpha and IL-6 by activated M. MSC also inhibited the up-regulation of CD86 and MHC class II in LPS-stimulated M impairing their ability to activate antigen-specific T CD4+ cells. On the other hand, they stimulated the uptake of apoptotic thymocytes by M. Of note, MSC turned M into cells highly susceptible to infection with the parasite Trypanosoma cruzi increasing more than 5-fold the rate of M infection. Using a model of inflammation triggered by s.c. implantation of glass cylinders, we found that MSC stimulated the recruitment of macrophages which showed a low expression of CD86 and the MHC class II molecule Ia(b) and a high ability to produce IL-10 and IL-12p40, but not IL-12 p70. In summary, our results suggest that MSC switch M into a regulatory profile characterized by a low ability to produce inflammatory cytokines, a high ability to phagocyte apoptotic cells, and a marked increase in their susceptibility to infection by intracellular pathogens.
近年来，人们已经清楚地认识到骨髓间充质基质细胞（MSC）的治疗特性不仅与其向不同谱系分化的能力有关，而且与其抑制免疫反应的能力有关。我们在这里研究了 MSC 对巨噬细胞功能的影响。我们使用脂多糖（LPS）刺激的鼠硫代乙醇酸诱导的腹腔巨噬细胞（M），发现 MSC 明显抑制了促炎细胞因子 TNF-α、IL-6、IL-12p70 和干扰素-γ的产生，同时增加了 IL-10 和 IL-12p40 的产生。使用 MSC 上清液也观察到了类似的结果，这表明 MSC 持续释放的某种因子参与了这一过程。我们观察到乙酰水杨酸（acetylsalicylic acid）损害了 MSC 抑制 LPS 刺激的 M 产生炎症细胞因子和刺激 IL-10 产生的能力，这支持了 PGE（2）的作用。此外，我们发现 MSC 持续产生 PGE2 的水平能够抑制激活的 M 产生 TNF-α和 IL-6。MSC 还抑制了 LPS 刺激的 M 中 CD86 和 MHC Ⅱ类分子的上调，从而损害了它们激活抗原特异性 T CD4+细胞的能力。另一方面，它们刺激 M 吞噬凋亡的胸腺细胞。值得注意的是，MSC 使 M 细胞极易受到寄生虫 Trypanosoma cruzi 的感染，使 M 细胞的感染率增加了 5 倍以上。使用皮下植入玻璃圆柱引发炎症的模型，我们发现 MSC 刺激了巨噬细胞的募集，这些巨噬细胞表现出低表达 CD86 和 MHC Ⅱ类分子 Ia(b)，并具有高产生 IL-10 和 IL-12p40 的能力，但不产生 IL-12p70。总之，我们的结果表明，MSC 将 M 细胞转化为具有以下特征的调节表型：产生促炎细胞因子的能力降低，吞噬凋亡细胞的能力增强，以及对细胞内病原体感染的易感性显著增加。
