Department of Transplantation Immunology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Videnska 1083, 14220, Prague 4, Czech Republic.
Department of Cell Biology, Faculty of Natural Science, Charles University, Vinicna 7, 12843, Prague 4, Czech Republic.
Stem Cell Rev Rep. 2016 Dec;12(6):654-663. doi: 10.1007/s12015-016-9688-y.
Mesenchymal stem cells (MSCs) represent a population of cells which have the ability to regulate reactivity of T and B lymphocytes by multiple mechanisms. The immunoregulatory activities of MSCs are strictly influenced by the cytokine environment. Here we show that two functionally distinct cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), significantly potentiate the ability of MSCs to inhibit IL-10 production by activated regulatory B cells (Bregs). However, MSCs in the presence of IL-4 or IFN-γ inhibit the IL-10 production by different mechanisms. Preincubation of MSCs with IFN-γ led to the suppression, but pretreatment with IL-4 of neither MSCs nor B cells resulted in the suppression of IL-10 production. The search for candidate regulatory molecules expressed in cytokine-treated MSCs revealed different patterns of the gene expression. Pretreatment of MSCs with IFN-γ, but not with IL-4, induced expression of indoleamine-2,3-dioxygenase, cyclooxygenase-2 and programmed cell death-ligand 1. To identify the molecule(s) responsible for the suppression of IL-10 production, we used specific inhibitors of the putative regulatory molecules. We found that indomethacine, an inhibitor of cyclooxygenase-2 (Cox-2) activity, completely abrogated the inhibition of IL-10 production in cultures containing MSCs and IFN-γ, but had no effect on the suppression in cell cultures containing MSCs and IL-4. The results show that MSCs can inhibit the response of B cells to one stimulus by different mechanisms in dependence on the cytokine environment and thus support the idea of the complexity of immunoregulatory action of MSCs.
间充质干细胞（MSCs）是一群能够通过多种机制调节 T 和 B 淋巴细胞反应性的细胞。MSCs 的免疫调节活性严格受细胞因子环境的影响。我们在此表明，两种功能不同的细胞因子，白细胞介素 4（IL-4）和干扰素-γ（IFN-γ），显著增强了 MSCs 抑制活化调节性 B 细胞（Bregs）产生 IL-10 的能力。然而，在存在 IL-4 或 IFN-γ的情况下，MSCs 通过不同的机制抑制 IL-10 的产生。IFN-γ预处理的 MSCs 导致抑制，但 IL-4 预处理的 MSCs 和 B 细胞均未导致 IL-10 产生抑制。对在细胞因子处理的 MSCs 中表达的候选调节分子的搜索揭示了不同的基因表达模式。IFN-γ预处理而不是 IL-4 预处理诱导了吲哚胺 2,3-双加氧酶、环氧化酶-2 和程序性细胞死亡配体 1 的表达。为了确定负责抑制 IL-10 产生的分子，我们使用了推测的调节分子的特异性抑制剂。我们发现，非甾体抗炎药吲哚美辛，环氧化酶-2（Cox-2）活性的抑制剂，完全阻断了含有 MSCs 和 IFN-γ的培养物中 IL-10 产生的抑制，但对含有 MSCs 和 IL-4 的培养物中的抑制没有影响。结果表明，MSCs 可以通过不同的机制抑制 B 细胞对一种刺激的反应，这取决于细胞因子环境，从而支持 MSCs 免疫调节作用复杂性的观点。
