NF-kappaB activation limits airway branching through inhibition of Sp1-mediated fibroblast growth factor-10 expression.
NF-kappaB activation limits airway branching through inhibition of Sp1-mediated fibroblast growth factor-10 expression.
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DOI：
10.4049/jimmunol.1001857
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发表时间：
2010-10-15
期刊：
影响因子：
--
通讯作者：
Prince LS
中科院分区：
文献类型：
--
作者：
Benjamin JT;Carver BJ;Plosa EJ;Yamamoto Y;Miller JD;Liu JH;van der Meer R;Blackwell TS;Prince LS
支气管肺发育不良（BPD）是早产的常见并发症。这种慢性肺病是由于囊状气道发育受阻所致，最常见于暴露于炎症刺激的婴儿。在实验模型中，炎症抑制成纤维细胞生长因子-10（FGF-10）的表达，并在肺发育过程中损害上皮-间充质相互作用;然而，连接炎症信号与生长因子表达减少的机制尚未了解。在这项研究中，我们发现早产儿气管液中存在的可溶性炎症介质可以防止囊状气道分支。此外，LPS处理导致局部产生介质，抑制气道分支和FGF-10的表达在LPS抗性的C.C3-Tlr 4Lpsd/J胎鼠肺外植体。直接的NF-κB活化和活化NF-κB的炎性细胞因子（IL-1β和TNF-α）均降低FGF-10的表达，而通过其他炎性途径传递信号的趋化因子则无影响。FGF-10启动子的突变分析未能鉴定直接抑制NF-κ B介导的FGF-10所需的遗传元件。相反，NF-κB活化似乎干扰了Sp 1对FGF-10表达的正常刺激。染色质免疫沉淀和核免疫共沉淀研究表明NF-κB的RelA亚基和Sp1在FGF-10启动子处物理相互作用。这些发现表明，通过NF-κB的炎症信号通过干扰对肺形态发生至关重要的转录机制来破坏胎儿肺间充质中FGF-10的正常表达。
Bronchopulmonary dysplasia (BPD) is a frequent complication of preterm birth. This chronic lung disease results from arrested saccular airway development and is most common in infants exposed to inflammatory stimuli. In experimental models, inflammation inhibits expression of fibroblast growth factor-10 (FGF-10) and impairs epithelial–mesenchymal interactions during lung development; however, the mechanisms connecting inflammatory signaling with reduced growth factor expression are not yet understood. In this study we found that soluble inflammatory mediators present in tracheal fluid from preterm infants can prevent saccular airway branching. In addition, LPS treatment led to local production of mediators that inhibited airway branching and FGF-10 expression in LPS-resistant C.C3-Tlr4Lpsd/J fetal mouse lung explants. Both direct NF-κB activation and inflammatory cytokines (IL-1β and TNF-α) that activate NF-κB reduced FGF-10 expression, whereas chemokines that signal via other inflammatory pathways had no effect. Mutational analysis of the FGF-10 promoter failed to identify genetic elements required for direct NF-κB–mediated FGF-10 inhibition. Instead, NF-κB activation appeared to interfere with the normal stimulation of FGF-10 expression by Sp1. Chromatin immunoprecipitation and nuclear coimmunoprecipitation studies demonstrated that the RelA subunit of NF-κB and Sp1 physically interact at the FGF-10 promoter. These findings indicate that inflammatory signaling through NF-κB disrupts the normal expression of FGF-10 in fetal lung mesenchyme by interfering with the transcriptional machinery critical for lung morphogenesis.
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