English Karen, Barry Frank P, Field-Corbett Ciara P, Mahon Bernard P
Mucosal Immunology Laboratory, Institute of Immunology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
Immunol Lett. 2007 Jun 15;110(2):91-100. doi: 10.1016/j.imlet.2007.04.001. Epub 2007 Apr 26.
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-beta1 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.
小鼠间充质干细胞（MSC）具有抑制同种异体免疫反应的能力。目前已提出两种不同机制来解释这种免疫抑制作用，即细胞接触依赖性或非依赖性机制。本研究的重点是阐明在炎症环境中小鼠MSC分泌的可溶性抑制因子的作用及其在MSC免疫调节中的作用。在非炎症环境中，骨髓来源的小鼠MSC组成性表达低水平的COX-2、PGE-2、TGF-β1和HGF，但不表达IL-10、PD-1、PD-L1或PD-L2。这些MSC能够显著降低混合淋巴细胞反应中同种异体抗原驱动的增殖以及丝裂原驱动的增殖。促炎细胞因子IFN-γ和TNF-α并未消除MSC介导的免疫抑制作用。这些细胞因子对MSC中PGE-2、IDO和PD-L1的表达有不同的调节作用。IFN-γ和TNF-α均上调了MSC中COX-2和PGE-2的表达，使用生化抑制剂表明这在调节同种异体抗原驱动的增殖中具有重要的、非冗余的作用。然而，PD-L1的表面表达仅由IFN-γ诱导，而TNF-α不能诱导，同样，功能性IDO表达仅由IFN-γ刺激诱导。使用中和抗体和生化拮抗剂进行的阻断研究表明，虽然PD-L1的诱导不是必需的，但IDO表达是IFN-γ介导的MSC免疫调节的先决条件。这些数据表明，在促炎环境中，小鼠MSC免疫调节因子的表达发生了显著变化，尤其是IFN-γ在调节MSC免疫调节因子表达中具有重要作用。
