Multiple Mechanisms Downstream of TLR-4 Stimulation Allow Expression of NKG2D Ligands To Facilitate Macrophage/NK Cell Crosstalk
Multiple Mechanisms Downstream of TLR-4 Stimulation Allow Expression of NKG2D Ligands To Facilitate Macrophage/NK Cell Crosstalk
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DOI：
10.4049/jimmunol.0903985
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发表时间：
2010-06-15
影响因子：
4.4
通讯作者：
Davis, Daniel M.
中科院分区：
文献类型：
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作者：
Eissmann, Philipp;Evans, J. Henry;Davis, Daniel M.
激活受体NKG2D识别通常不在大多数细胞表面表达但在细胞“应激”反应中表达的蛋白质（例如，在诱导DNA损伤途径时）。这建立了“诱导自我”的识别作为监测感染或肿瘤转化的重要策略。然而，NKG2D配体也可以通过TLR刺激诱导到人巨噬细胞上，这方面的研究还远远不够。在本文中，我们澄清了连接TLR-4的LPS优先上调MICA而不是MICB；连接TLR-7/8的CL097上调MICA和MICB；而连接TLR-3的多肌苷-多胞酸则没有上调。为了探究LPS刺激如何触发MICA表达，我们确定MICA mRNA的稳定性比MICB mRNA的稳定性长得多，但两者都没有被LPS刺激改变。这一发现表明，LPS刺激后MICA mRNA水平升高是由于转录增加所致。然而，表面蛋白的表达是不够的，表面蛋白的表达是通过一个单独的途径转录后控制的，该途径涉及共济失调毛细血管扩张突变/共济失调毛细血管扩张和Rad3相关激酶。此外，LPS刺激降低了靶向MICA的microrna (miRNA)-miR-17-5、miR-20a和mir -93的表达，暗示miRNA在NKG2D配体表达中的新作用。因此，TLR刺激允许NKG2D配体通过多种途径表达，包括特异性mirna的下调。免疫学杂志，2010,18(4):691 - 691。
The activating receptor NKG2D recognizes proteins that are not normally expressed at the surface of most cells but are expressed during a cellular "stress" response (e.g., upon induction of the DNA damage pathway). This establishes recognition of "induced self" as an important strategy for surveillance of infections or tumor transformation. However, NKG2D ligands can also be induced on human macrophages by TLR stimulation, which has been far less studied. In this paper, we clarify that LPS, which ligates TLR-4, preferentially upregulated MICA and not MICB; CL097, which ligates TLR-7/8, upregulated both MICA and MICB; and polyinosinic-polycytidylic acid, which ligates TLR-3, upregulated neither. To probe how LPS stimulation triggers MICA expression, we determined that the stability of MICA mRNA was much longer than that of MICB mRNA, but neither was changed by LPS stimulation. This finding suggests that increased levels of MICA mRNA following LPS stimulation resulted from increased transcription. However, it was not sufficient for surface protein expression, which was controlled posttranscriptionally via a separate pathway involving the ataxia telangiectasia mutated/ataxia telangiectasia and Rad3 related kinases. Moreover, LPS stimulation decreased expression of microRNAs (miRNA)-miR-17-5, miR-20a, and miR-93-which target MICA, implicating a novel role for miRNAs in NKG2D ligand expression. Thus, TLR stimulation allows expression of NKG2D ligands through multiple pathways, including downmodulation of specific miRNAs. The Journal of Immunology, 2010, 184: 6901-6909.