Reduction of c-Fos via Overexpression of miR-34a Results in Enhancement of TNF- Production by LPS in Neutrophils from Myelodysplastic Syndrome Patients.
Reduction of c-Fos via Overexpression of miR-34a Results in Enhancement of TNF- Production by LPS in Neutrophils from Myelodysplastic Syndrome Patients.
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DOI：
10.1371/journal.pone.0158527
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kimura J
中科院分区：
文献类型：
--
作者：
Shikama Y;Cao M;Ono T;Feng X;Noji H;Kimura H;Ogawa K;Suzuki Y;Ikeda K;Takeishi Y;Kimura J
尽管TNF-α升高被认为是骨髓增生异常综合征（MDS）中无效造血的原因，但TNF-α升高的机制尚不清楚。我们最近发现，c-Fos mRNA的稳定抑制刺激下，MDS衍生的嗜中性粒细胞受损。在目前的研究中，我们确定c-Fos靶向miR-34 a和miR-155的过表达是损伤的原因。流式细胞术检测MDS来源的CD 16+中性粒细胞中miR-34 a的表达水平与c-Fos阳性细胞比例呈负相关（r =-0.618，P <0.05），miR-155的表达水平与c-Fos阳性细胞比例无相关性。在17名患者中，8名患者（A组）的CD 16+细胞中的c-Fos表达低于60%，而5名患者（B组）的CD 16+细胞中的c-Fos表达高于80%，与对照组（88.6 ± 7.8%）一致。1 μM LPS刺激3 h，A组粒细胞分泌TNF-α（735.4 ± 237.5pg/mL）明显高于B组（143.5 ± 65.7pg/mL，P<0.05）和健康对照组（150.8 ± 91.5pg/mL，P<0.05）。在HL 60细胞中敲低c-Fos可增加NF-κB p65与TNF-α DNA启动子区的结合。因此，c-Fos通过miR-34 a的过表达而减少有助于MDS中炎症刺激下TNF-α的过度产生。
Although increased TNF-α has been considered to cause ineffective hematopoiesis in myelodysplastic syndromes (MDS), the mechanisms of TNF-α elevation are not known. We recently found that c-Fos mRNA stabilization under translation-inhibiting stimuli was impaired in MDS-derived neutrophilic granulocytes. In the current study, we identified overexpression of c-Fos-targeting miR-34a and miR-155 as the cause of impairment. Expression levels of miR-34a but not miR-155 inversely correlated with ratios of c-Fos-positive cells in MDS-derived CD16+ neutrophils (r = -0.618, P<0.05), which were analyzed by flow cytometry. Among the seventeen patients, c-Fos was detectable in less than 60% of CD16+ cells in eight patients (Group A), while five (Group B) expressed c-Fos in more than 80% of CD16+ cells, which was consistent with the controls (88.6 ± 7.8%). Group A-derived granulocytes secreted more TNF-α in response to 1 μM LPS for 3 hours (735.4 ± 237.5 pg/mL) than Group B (143.5 ± 65.7 pg/mL, P<0.05) and healthy controls (150.8 ± 91.5 pg/mL, P<0.05). Knockdown of c-Fos in neutrophil-like differentiated HL60 increased the binding of NF-κB p65 to the promoter region of TNF-α DNA. Thus, c-Fos reduction via overexpression of miR-34a contributes to TNF-α overproduction under inflammatory stimuli in MDS.