Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes
Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes
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DOI：
10.1158/1078-0432.ccr-06-2108
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发表时间：
2007-02-15
影响因子：
11.5
通讯作者：
Voulgarelis, Michael
中科院分区：
文献类型：
--
作者：
Maratheftis, Christos I.;Andreakos, Evangelos;Voulgarelis, Michael
目的：研究骨髓增生异常综合征(MDS)患者骨髓细胞Toll样受体(TLR)的功能和表达，探讨其在MDS造血细胞凋亡现象中的作用。实验设计：检测MDS患者和正常对照骨髓细胞TLR基因和蛋白的表达。检测TLR-4对脂多糖的识别能力和上调自身基因和蛋白表达的能力。此外，还评估了肿瘤坏死因子在内毒素(LPS)诱导的TLR表达中的作用。结果：TLR-2和TLR-4在包括巨核细胞、红系细胞、髓系前体细胞、单核细胞和B淋巴细胞在内的几乎所有骨髓细胞系中均有表达，且MDS患者骨髓细胞系中TLR-2和TLR-4表达上调。在造血CD34(+)细胞中，TLR-4也表达，并在mRNA和蛋白水平显著上调。使用抗肿瘤坏死因子抗体治疗可降低组成性和脂多糖诱导的TLR-4水平。由于TLR-4几乎只存在于凋亡的骨髓单个核细胞和CD34(+)细胞中，因此TLR-4的表达增加与细胞凋亡率的增加相关。结论：MDS患者TLR-4等TLR表达明显上调，TLR-4参与促进细胞凋亡，可能是MDS细胞减少的原因之一。
Purpose: To investigate the function and expression of Toll-like receptors (TLR) in bone marrow cells of myelodysplastic syndrome (MDS) patients and to examine their involvement in the apoptotic phenomenon characterizing MDS hematopoiesis.Experimental Design: TLR mRNA and protein expression was investigated in bone marrow cell populations of MDS patients and controls. TLR-4 ability to recognize lipopolysaccharide and upregulate self mRNA and protein expression was examined. Tumor necrosis factor involvement in the constitutive and lipopolysaccharide (LPS) -induced TLR expression was also evaluated. Possible correlation between TLR-4 overexpression and apoptosis was investigated by simultaneous staining with Annexin V and TLR-4.Results: TLR-2 and TLR-4 are expressed in almost all bone marrow cell lineages including megakaryocytes, erythroid cells, myeloid precursors, monocytes, and B lymphocytes and are upregulated in MDS patients compared with controls. In hematopoietic CD34(+) cells,TLR-4 is also expressed and significantly up-regulated at both the mRNA and protein levels. Treatment with an anti - tumor necrosis factor antibody reduces both constitutive and LPS-induced TLR-4 levels. Increased TLR-4 expression correlates with increased apoptosis as TLR-4 is almost exclusively found in apoptotic bone marrow mononuclear and CD34(+) cells. The addition of the TLR-4 ligand LPS further enhances the apoptosis of these cells.Conclusions: TLR-4 and other TLRs are significantly up-regulated in MDS patients whereas TLR-4 is involved in promoting apoptosis, possibly contributing to MDS cytopenia.