Effects of KGF on alveolar epithelial cell transdifferentiation are mediated by JNK signaling
Effects of KGF on alveolar epithelial cell transdifferentiation are mediated by JNK signaling
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DOI：
10.1165/rcmb.2007-0172oc
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发表时间：
2008-02-01
影响因子：
6.4
通讯作者：
Borok, Zea
中科院分区：
文献类型：
--
作者：
Qiao, Renli;Yan, Weilhong;Borok, Zea
原代培养的大鼠肺泡上皮细胞（AEC）从II型（AT 2）向I型（AT 1）细胞样表型转分化，这一过程可以被角质细胞生长因子（KGF）阻止和逆转。微阵列分析显示，KGF的这些作用与丝裂原活化蛋白激酶（MAPK）通路中关键分子的上调有关。为了进一步探索三个关键MAPK的作用（即，细胞外信号相关激酶[ERK] 1/2、c-Jun N-末端激酶[JNK]和p38）介导KGF对AEC表型的作用，从第4天开始用KGF（10 ng/ml）处理在最小成分确定的无血清培养基（MDSF）中培养的原代大鼠AEC，间隔长达48小时。暴露于KGF激活所有三种MAPK、JNK、ERK 1/2和p38。JNK的抑制，但不是ERK 1/2或p38，废除的能力，KG F维持AT 2细胞表型，证明了板层膜蛋白（p180）的表达损失和增加的反应性与AT 1细胞特异性单克隆抗体VIIIB 2的培养第6天。JNK上游激酶JNKK 2的过表达增加了内源性c-Jun的活化，并与p180表达增加和AQP 5的废除相关，表明c-Jun的活化促进了AT 2细胞表型的保留。这些结果表明，保留的AT 2细胞表型的KGF涉及c-Jun，并建议激活c-Jun激酶可能是一个重要的决定因素，维持AT 2细胞表型。
Rat alveolar epithelial cells (AEC) in primary culture transdifferentiate from a type II (AT2) toward a type I (AT1) cell-like phenotype, a process that can be both prevented and reversed by keratinocyte growth factor (KGF). Microarray analysis revealed that these effects of KGF are associated with up-regulation of key molecules in the mitogen-activated protein kinase (MAPK) pathway. To further explore the role of three key MAPK (i.e., extracellular signal-related kinase [ERK] 1/2, c-Jun N-terminal kinase [JNK] and p38) in mediating effects of KGF on AEC phenotype, primary rat AEC cultivated in minimal defined serum-free medium (MDSF) were treated with KGF (10 ng/ml) from Day 4 for intervals up to 48 hours. Exposure to KGF activated all three MAPK, JNK, ERK 1/2, and p38. Inhibition of JNK, but not of ERK 1/2 or p38, abrogated the ability of KG F to maintain the AT2 cell phenotype, as evidenced by loss of expression of lamellar membrane protein (p180) and increased reactivity with the AT1 cell-specific monoclonal antibody VIIIB2 by Day 6 in culture. Overexpression of JNKK2, upstream kinase of JNK, increased activation of endogenous c-Jun in association with increased expression of p180 and abrogation of AQP5, suggesting that activation of c-Jun promotes retention of the AT2 cell phenotype. These results indicate that retention of the AT2 cell phenotype by KGF involves c-Jun and suggest that activation of c-Jun kinase may be an important determinant of maintenance of AT2 cell phenotype.