Maratheftis Christos I, Andreakos Evangelos, Moutsopoulos Haralampos M, Voulgarelis Michael
Department of Pathophysiology, Medical School, National University of Athens, Greece.
Clin Cancer Res. 2007 Feb 15;13(4):1154-60. doi: 10.1158/1078-0432.CCR-06-2108.
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.
TLR mRNA and protein expression was investigated in bone marrow cell populations of MDS patients and controls. TLR-4 ability to recognize lipopolysaccharide and up-regulate 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.
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 up-regulated 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.
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.
研究髓系发育异常综合征（MDS）患者骨髓细胞中Toll样受体（TLR）的功能和表达，并探讨其在MDS造血特征性凋亡现象中的作用。
研究MDS患者和对照组骨髓细胞群体中TLR mRNA和蛋白的表达。检测TLR-4识别脂多糖并上调自身mRNA和蛋白表达的能力。还评估了肿瘤坏死因子在组成性和脂多糖（LPS）诱导的TLR表达中的作用。通过Annexin V和TLR-4同时染色研究TLR-4过表达与凋亡之间的可能相关性。
TLR-2和TLR-4在几乎所有骨髓细胞谱系中均有表达，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，与对照组相比，MDS患者中TLR-2和TLR-4表达上调。在造血CD34(+)细胞中，TLR-4也有表达，且在mRNA和蛋白水平均显著上调。用抗肿瘤坏死因子抗体处理可降低组成性和LPS诱导的TLR-4水平。TLR-4表达增加与凋亡增加相关，因为TLR-4几乎仅在凋亡的骨髓单核细胞和CD34(+)细胞中发现。添加TLR-4配体LPS可进一步增强这些细胞的凋亡。
MDS患者中TLR-4和其他TLR显著上调，而TLR-4参与促进凋亡，可能导致MDS血细胞减少。
