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SIMPL 的缺失会损害 TNF-α 依赖的造血祖细胞的存活。

Loss of SIMPL compromises TNF-alpha-dependent survival of hematopoietic progenitors.

机构信息

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, USA.

出版信息

Exp Hematol. 2010 Feb;38(2):71-81. doi: 10.1016/j.exphem.2009.11.006. Epub 2009 Nov 23.

DOI:10.1016/j.exphem.2009.11.006
PMID:19941935
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2815193/
Abstract

OBJECTIVE

Emerging work has revealed an integral role of the tumor necrosis factor-alpha (TNF-alpha) nuclear factor (NF)-kappaB pathway in the regulation of hematopoiesis. TNF-alpha inhibition of hematopoietic stem/progenitor cell growth involves type I TNF-alpha receptor (TNF-RI) and type II TNF-alpha receptor (TNF-RII). However, the role of TNF-RI vs TNF-RII in mediating this response is less clear. Full induction of NF-kappaB-dependent gene expression through TNF-RI requires the transcriptional coactivator SIMPL (substrate that interacts with mouse pelle-like kinase). To address the role of SIMPL in TNF-alpha-dependent signaling in hematopoiesis, endothelial cells and hematopoietic progenitors expressing SIMPL short hairpin RNA were characterized.

MATERIAL AND METHODS

In vitro gene expression and progenitor assays employing SIMPL short hairpin RNA were used to examine the requirement for SIMPL in TNF-alpha-dependent effects upon cytokine gene expression and hematopoietic progenitor cell growth. Competitive repopulation studies were used to extend these studies in vivo.

RESULTS

SIMPL is required for full TNF-RI-dependent expression of NF-kappaB-controlled cytokines in endothelial cells. Hematopoietic progenitor cell expansion is not affected if progenitors lacked SIMPL or if progenitors are treated with human TNF-alpha, which signals through TNF-RI. In the absence of SIMPL, human TNF-alpha leads to a dramatic decrease in progenitor cell expansion that is not due to apoptosis. Loss of SIMPL does not affect the activity of transforming growth factor-beta1 and interferon-gamma, other known suppressors of hematopoiesis.

CONCLUSIONS

Suppression of myeloid progenitor cell expansion requires signaling through TNF-RI and TNF-RII. Signals transduced through the TNF-alpha-TNF-RI-SIMPL pathway support hematopoietic progenitor cell survival, growth and differentiation.

摘要

目的

新兴的工作揭示了肿瘤坏死因子-α（TNF-α）核因子（NF）-κB 通路在造血调节中的重要作用。TNF-α抑制造血干细胞/祖细胞生长涉及 I 型 TNF-α受体（TNF-RI）和 II 型 TNF-α受体（TNF-RII）。然而，TNF-RI 与 TNF-RII 在介导这种反应中的作用尚不清楚。通过 TNF-RI 完全诱导 NF-κB 依赖性基因表达需要转录共激活因子 SIMPL（与鼠 Pelle 样激酶相互作用的底物）。为了研究 SIMPL 在 TNF-α依赖的造血信号转导中的作用，我们对表达 SIMPL 短发夹 RNA 的内皮细胞和造血祖细胞进行了特征分析。

材料和方法

采用 SIMPL 短发夹 RNA 的体外基因表达和祖细胞测定，用于研究 SIMPL 在 TNF-α依赖的细胞因子基因表达和造血祖细胞生长中的作用。竞争性重编程研究用于体内扩展这些研究。

结果

SIMPL 是内皮细胞中 TNF-RI 依赖性 NF-κB 调控细胞因子完全表达所必需的。如果祖细胞缺乏 SIMPL 或如果祖细胞用人类 TNF-α（通过 TNF-RI 信号）处理，则不会影响造血祖细胞的扩增。在缺乏 SIMPL 的情况下，人类 TNF-α导致祖细胞扩增的急剧减少，而不是由于细胞凋亡。SIMPL 的缺失不影响转化生长因子-β1 和干扰素-γ的活性，这是其他已知的造血抑制因子。

结论

抑制髓样祖细胞的扩增需要通过 TNF-RI 和 TNF-RII 进行信号转导。通过 TNF-α-TNF-RI-SIMPL 途径转导的信号支持造血祖细胞的存活、生长和分化。

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