IFN-γ and TNF-α differentially regulate immunomodulation by murine mesenchymal stem cells
IFN-γ and TNF-α differentially regulate immunomodulation by murine mesenchymal stem cells
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DOI：
10.1016/j.imlet.2007.04.001
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发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Mahon, Bernard P.
中科院分区：
文献类型：
--
作者：
English, Karen;Barry, Frank P.;Mahon, Bernard P.
小鼠间充质干细胞(MSC)具有抑制同种异体免疫反应的能力。已经提出了两种不同的机制来解释这种免疫抑制，要么是细胞接触依赖的，要么是独立的。本研究的重点是阐明小鼠MSC分泌的可溶性抑制因子在炎症环境中的作用，以及它们在MSC免疫调节中的作用。在非炎性环境中，小鼠骨髓间充质干细胞呈低水平表达COX-2、PGE-2、TGF-β1和HGF，但不表达IL-10、PD-1、PD-L1或PD-L2。这些MSC能够显着降低混合淋巴细胞反应中的同种异体抗原诱导的增殖反应以及丝裂原诱导的增殖反应。促炎细胞因子干扰素-γ和肿瘤坏死因子-α不能阻断MSC介导的免疫抑制。PGE-2、IDO和PD-L1的MSC表达受这些细胞因子的不同调控。MSC的COX-2和PGE-2的表达在干扰素-γ和肿瘤坏死因子-α的共同作用下被上调，并且使用一种生化抑制剂，这被证明在调节同种异体抗原驱动的增殖中具有基本的、非多余的作用。然而，干扰素-γ可诱导PD-L1的表面表达，但不能诱导肿瘤坏死因子-α的表达，同样功能的IDO的表达也仅由干扰素-γ刺激才能诱导。使用中和抗体和生化拮抗剂的阻断研究表明，虽然PD-L1的诱导不是必需的，但IDO的表达是干扰素-γ介导的MSC免疫调节的先决条件。这些数据表明，小鼠MSC的免疫调节因子的表达在促炎环境中发生了显着的变化，尤其是干扰素-γ在调节MSC的免疫调节因子的表达中具有重要的作用。(C)2007 Elsevier B.V.保留所有权利。
Murine mesenchymal stem cells (MSC) have the ability to inhibit allogeneic immune responses. Two different mechanisms, either cell contact-dependent or independent, have been proposed to account for this immunosuppression. The focus of this study was to elucidate the involvement of soluble suppressive factors secreted by murine MSC in an inflammatory setting, and their role in MSC immunomodulation. In a non-inflammatory environment, bone marrow derived murine MSC constitutively expressed low levels of COX-2, PGE-2, TGF-beta 1 and HGF, but not IL-10, PD-1, PD-L1 or PD-L2. These MSC were able to significantly reduce alloantigen driven proliferation in mixed lymphocyte reactions as well as mitogen driven proliferation. The pro-inflammatory cytokines IFN-gamma and TNF-alpha did not ablate MSC mediated immunosuppression. MSC expression of PGE-2, IDO and PD-L1 was differentially regulated by these cytokines. COX-2 and PGE-2 expression by MSC were upregulated by both IFN-gamma and TNF-alpha, and using a biochemical inhibitor this was shown to have an essential, non-redundant role in modulating alloantigen-driven proliferation. However, the surface expression of PD-L1 was induced by IFN-gamma but not TNF-alpha and similarly functional IDO expression was only induced by IFN-gamma stimulation. Blocking studies using neutralising antibodies and biochemical antagonists revealed that while PD-L1 induction was not essential, IDO expression was a prerequisite for IFN-gamma mediated MSC immunomodulation. These data demonstrate that murine MSC expression of immunomodulatory factors dramatically changes in a pro-inflammatory environment and that IFN-gamma in particular has an important role in regulating MSC immunomodulatory factor expression. (c) 2007 Elsevier B.V. All rights reserved.