CpG-ODN 2006 and human parvovirus B19 genome consensus sequences selectively inhibit growth and development of erythroid progenitor cells
CpG-ODN 2006 and human parvovirus B19 genome consensus sequences selectively inhibit growth and development of erythroid progenitor cells
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DOI：
10.1182/blood-2009-08-239202
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发表时间：
2010-06-03
期刊：
影响因子：
20.3
通讯作者：
Sawada, Kenichi
中科院分区：
文献类型：
--
作者：
Guo, Yong-Mei;Ishii, Keiko;Sawada, Kenichi
最近的研究表明，贫血通常在暴露于病原体或病原体衍生产物后观察到，这些病原体或病原体衍生产物通过Toll样受体9（TLR 9）识别。在目前的研究中，我们证明了CpG oligodeoxynucleotide-2006，一种具有磷酸二酯（PO; 2006-PO）但不具有硫代磷酸酯骨架的TLR 9配体，选择性地抑制人CD 34（+）细胞衍生的红系细胞生长。2006-PO在30分钟内被红系祖细胞内化;然而，在这些细胞中未检测到TLR 9 mRNA的表达。2006-PO直接抑制红系细胞的生长，使S期和G（2）/M期细胞增多，细胞体积增大，凋亡细胞增多。这些特征类似于在感染人细小病毒B19的红系祖细胞中观察到的那些特征，该病毒导致纯红细胞再生障碍性贫血。2006-PO的共有序列被定义为5 '-GTTTTGT-3'，位于B19的P6启动子区域，以序列特异性方式抑制红细胞生长，并下调促红细胞生成素受体（EPOR）mRNA和EPOR的表达。血清B19基因组也能抑制红系细胞的生长，下调血型糖蛋白A（+）细胞EPOR的表达。这些结果为我们理解人细小病毒B19介导的抑制红细胞生成的机制提供了可能的见解。（血。2010; 115（22）：4569-4579）
Recent studies have shown that anemia is commonly observed after exposure to pathogens or pathogen-derived products, which are recognized via Toll-like receptor 9 (TLR9). In the current study, we demonstrate that CpG oligodeoxynucleotide-2006, a TLR9 ligand with phosphodiester (PO; 2006-PO) but not with the phosphorothioate backbone, selectively inhibits the erythroid growth derived from human CD34(+) cells. The 2006-PO was internalized by the erythroid progenitors within 30 minutes; however, expression of TLR9 mRNA was not detected in these cells. The 2006-PO directly inhibited burst-forming unit-erythroid growth, resulted in the accumulation of cells in S and G(2)/M phases, and increased cell size and frequency of apoptotic cells. These features were similar to those observed in erythroid progenitors infected with human parvovirus B19 that causes pure red cell aplasia. The consensus sequence of 2006-PO was defined as 5'-GTTTTGT-3', which was located in the P6-promoter region of B19 and inhibited erythroid growth in a sequence-specific manner and down-regulated expression of erythropoietin receptor (EPOR) mRNA and EPOR. B19 genome extracted from serum also inhibited erythroid growth and down-regulated expression of EPOR on glycophorin A(+) cells. These results provide a possible insight into our understanding of the mechanisms of human parvovirus B19-mediated inhibition of erythropoiesis. (Blood. 2010; 115(22): 4569-4579)