Fringe controls naïve CD4(+)T cells differentiation through modulating notch signaling in asthmatic rat models.
Fringe controls naïve CD4(+)T cells differentiation through modulating notch signaling in asthmatic rat models.
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DOI：
10.1371/journal.pone.0047288
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Guo X
中科院分区：
文献类型：
--
作者：
Gu W;Xu W;Ding T;Guo X
Notch信号转导调节T辅助细胞发育和分化的能力已被广泛接受。Fringe，O-岩藻糖-β 1，3-N-乙酰葡糖胺转移酶通过受体-配体结合调节Notch受体表达并促进Notch信号通路。在这项研究中，我们检测了三个边缘同源物在哮喘大鼠的幼稚CD 4 +T细胞的表达水平。我们发现，激进的边缘（Rfng）是高表达，而无论是精神病边缘（Lfng）和躁狂边缘（Mfng）的表达水平较低。使用siRNA下调Rfng以及过表达Lfng或Mfng增强了Th 1亚群谱系并减少了Th 2亚群谱系。Notch信号在哮喘初始CD 4 +T细胞中比在对照细胞中更活化，并且Lfng部分抑制哮喘初始CD 4 +T细胞中的Notch信号，而不是Mfng或Rfng。Lfng过表达导致哮喘中Th 2细胞因子的产生显著减少，这与单独GSI（γ-分泌酶抑制剂）治疗的效果相同，但对Th 1细胞因子的影响比GSI治疗增加。总的来说，这些数据确定了Fringe通过Notch信号传导调节幼稚CD 4 +T细胞分化的重要作用。Lfng通过Notch依赖的方式调节Th 2细胞分化，通过Notch非依赖的方式调节Th 1细胞分化。Fringe可能是治疗和预防过敏性哮喘的一种治疗策略。
The ability of Notch signaling to regulate T helper cell development and differentiation has been widely accepted. Fringe, O-fucose-β1,3-N-acetylglucosaminyltransferases modulate Notch receptor expression and promote the Notch signaling pathway through receptor-ligand binding. In this study, we assayed the expression levels of three Fringe homologs in naive CD4+T cells in asthmatic rats. We found that Radical Fringe (Rfng) was highly expressed, whereas both Lunatic Fringe (Lfng) and Manic Fringe (Mfng) were expressed at low levels. Down-regulation of Rfng using siRNA, and overexpression of Lfng or Mfng enhanced Th1 subset lineages and diminished Th2 subset lineages. Notch signaling was more activated in asthmatic naïve CD4+T cells than in control cells, and Lfng, but not Mfng or Rfng, partly inhibited Notch signaling in asthmatic naïve CD4+T lymphocytes. Lfng overexpression resulted in significantly decreased Th2 cytokine production in asthma, which was the same effect as the GSI (γ-secretase inhibitor) treatment alone, but had an increased effect on Th1 cytokines than GSI treatment. Collectively, these data identify the essential role of Fringe modulating naïve CD4+T cells differentiation through Notch signaling. Lfng regulated Th2 cells differentiation via a Notch-dependent manner and Th1 cells differentiation via a Notch-independent manner. Fringe could be a therapeutic strategy for the management and prevention of allergic asthma.
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