Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, United States.
Immunol Lett. 2012 May 30;144(1-2):49-59. doi: 10.1016/j.imlet.2012.03.006. Epub 2012 Mar 28.
As essential components of the innate immune system, dendritic cells (DCs) can interact directly with pathogens as well as participate in the adaptive immune response. In cells closely related to DCs such as macrophages and monocytes, prior exposure to minute amounts of endotoxin can lead to a refractory period where subsequent exposure to higher doses fails to induce an inflammatory response; little research has investigated this effect on DCs. This study tested if murine bone marrow-derived dendritic cells (BM-DCs) respond to endotoxin- and bacterial sonicate-induced tolerance by decreased inflammatory and increased anti-inflammatory response, and the role of IRAK-M, an intracellular negative regulator of TLR signaling, in this tolerance.
Tolerized BM-DCs exhibited a significant drop in TNF-α and IL-12p70 production and increased IL-10 expression compared to untolerized cells. BM-DCs also showed the ability to develop heterotolerance, in which the LPS exposure alone was able to induce tolerance to Helicobacter pylori sonicate and TLR2 agonist Pam3Cys. Furthermore, the expression of IRAK-M was increased after restimulation of tolerized BM-DCs as determined qPCR and Western blot. IRAK-M exhibited a suppressive effect on surface expression of major histocompatibilty complex class II (MHC II) and CD80 in LPS-tolerized BM-DCs. IL-10 expression in bacterial sonicate-tolerized IRAK-M-/- BM-DCs was altered as compared to wild type BM-DCs, with tolerance-induced expression of IL-10 mitigated in tolerized IRAK-M-/- BM-DCs.
Along with endotoxin, bacterial sonicate is able to induce refractory tolerance in BM-DCs, and IRAK-M plays a role in modulating cell surface expression of MHC class II and CD80 and release of IL-10 during this tolerance.
树突状细胞（DCs）作为固有免疫系统的重要组成部分，既能直接与病原体相互作用，又能参与适应性免疫反应。在与 DCs 密切相关的细胞（如巨噬细胞和单核细胞）中，先前接触少量内毒素会导致对后续高剂量内毒素刺激无反应的不应期；然而，针对这种现象在 DCs 中是否存在，相关研究较少。本研究旨在检测内毒素和细菌超声破碎物诱导的树突状细胞耐受是否会导致炎症反应降低和抗炎反应增强，并探讨其内在机制。
与未耐受的细胞相比，耐受的 BM-DCs 表现出 TNF-α 和 IL-12p70 产生显著下降，IL-10 表达增加。BM-DCs 还表现出异源耐受的能力，即 LPS 暴露本身能够诱导对幽门螺杆菌超声破碎物和 TLR2 激动剂 Pam3Cys 的耐受。此外，通过 qPCR 和 Western blot 检测，发现再刺激耐受的 BM-DCs 后 IRAK-M 的表达增加。IRAK-M 对 LPS 耐受的 BM-DCs 表面 MHC II 和 CD80 的表达具有抑制作用。与野生型 BM-DCs 相比，细菌超声破碎物耐受的 IRAK-M-/- BM-DCs 中的 IL-10 表达发生改变，耐受诱导的 IL-10 表达在耐受的 IRAK-M-/- BM-DCs 中受到抑制。
与内毒素一样，细菌超声破碎物也能诱导 BM-DCs 产生难治性耐受，IRAK-M 在调节细胞表面 MHC II 和 CD80 的表达以及在该耐受过程中释放 IL-10 方面发挥作用。
