Murthy Raghav G, Greco Steven J, Taborga Marcelo, Patel Nitixa, Rameshwar Pranela
UMDNJ-New Jersey Medical School, MSB, Room E-579, 185 South Orange Ave, Newark, NJ 07103, USA.
Brain Behav Immun. 2008 May;22(4):442-50. doi: 10.1016/j.bbi.2007.10.009. Epub 2007 Dec 3.
Hematopoiesis is the process by which immune and blood cells are produced from a finite number of relatively few hematopoietic stem cells (HSCs). In adults, hematopoiesis occurs in the adult bone marrow (BM), with the support of stromal cells. This support partly occurs through the production of hematopoietic regulators belonging to the families of cytokines and neuropeptides/neurotransmitters, which mediate their actions through specific receptors. Thus, stromal cells could be central to the neural-hematopoietic-immune axis. This study focuses on Tac1, which encodes hematopoietic regulators belonging to the tachykinin family of neuropeptides. We examined post-transcriptional regulation of Tac1 in BM stroma. Since this gene is inducible in stroma, we selected cytokines with varying hematopoietic effects: stimulator Stem Cell Factor (SCF), broad-acting IL-11 and suppressive TGF-beta1. RNA shift with Tac1 mRNA and cytoplasmic extracts from IL-11 and SCF-stimulated stroma showed RNA shift after 15min at 37 degrees C, whereas a shift was detected with extracts from TGF-beta1-stimulated stroma after 5min at room temperature. Another level of post-transcriptional regulation was observed by the detection of miRNAs that interact with the 3' untranslated region of Tac1 mRNA. In summary, this study showed that cytokine induced miRNA downregulation and RNA-binding protein(s) are involved in post-transcriptional regulation of Tac1 in BM stroma. The broad categories of cytokines as hematopoietic stimulators or inhibitors might depend on the avidity of RNA-binding protein(s) for Tac1 mRNA, as well as the ability to degrade or stabilize the specific miRNAs.
造血作用是一个过程，通过这个过程，免疫细胞和血细胞由数量有限且相对较少的造血干细胞（HSCs）产生。在成年人中，造血作用发生在成年骨髓（BM）中，并得到基质细胞的支持。这种支持部分是通过产生属于细胞因子和神经肽/神经递质家族的造血调节因子来实现的，这些调节因子通过特定受体介导其作用。因此，基质细胞可能是神经 - 造血 - 免疫轴的核心。本研究聚焦于Tac1，它编码属于神经肽速激肽家族的造血调节因子。我们研究了Tac1在骨髓基质中的转录后调控。由于该基因在基质中是可诱导的，我们选择了具有不同造血作用的细胞因子：刺激因子干细胞因子（SCF）、广泛作用的白细胞介素 - 11（IL - 11）和抑制性转化生长因子 - β1（TGF - β1）。用Tac1 mRNA与来自IL - 11和SCF刺激的基质的细胞质提取物进行RNA迁移实验，结果显示在37℃下15分钟后出现RNA迁移，而在室温下5分钟后用来自TGF - β1刺激的基质的提取物检测到迁移。通过检测与Tac1 mRNA的3'非翻译区相互作用的微小RNA（miRNAs），观察到了转录后调控的另一个层面。总之，本研究表明细胞因子诱导的miRNA下调和RNA结合蛋白参与了骨髓基质中Tac1的转录后调控。作为造血刺激因子或抑制剂的细胞因子的广泛类别可能取决于RNA结合蛋白对Tac1 mRNA的亲和力，以及降解或稳定特定miRNAs的能力。
