Mechanism for nicotine-induced up-regulation of Wnt signaling in human alveolar interstitial fibroblasts.
Mechanism for nicotine-induced up-regulation of Wnt signaling in human alveolar interstitial fibroblasts.
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DOI：
10.3109/01902148.2010.490288
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发表时间：
2011-04
影响因子：
1.7
通讯作者：
Rehan VK
中科院分区：
文献类型：
--
作者：
Sakurai R;Cerny LM;Torday JS;Rehan VK
尼古丁暴露改变了正常的稳态肺上皮-间充质旁分泌信号通路，导致肺泡间质成纤维细胞（AIF）向肌成纤维细胞（MYF）转分化。由于AIF与MYF的表型分别由过氧化物酶体增殖物激活受体（PPAR）γ和Wingless/Int（Wnt）信号传导的表达决定，因此我们假设尼古丁诱导的AIF向MYF转分化的特征是下调PPARγ，上调Wnt信号传导途径。由于已知尼古丁可激活PKC信号传导，我们还假设在AIF中，尼古丁诱导的Wnt信号传导上调可能是由于PKC激活。用尼古丁（1 × 10 - 6 M）处理胚胎人肺成纤维细胞（WI 38细胞）30分钟或24小时，同时使用或不使用calphostin C（1 × 10 - 7）（一种泛PKC抑制剂）预处理30分钟。然后我们检测了PKC（p-PKC）和Wnt信号传导（p-GSK-3β、β-连环蛋白、LEF-1和纤连蛋白）的激活。此外，还检测了烟碱乙酰胆碱受体（nAChR）-α3和−α7的激活，以及PPARγ激动剂罗格列酮是否阻断尼古丁介导的Wnt激活。尼古丁刺激后，有明确的证据表明nAChR-α3和−α7上调，伴随着PKC和Wnt信号的激活，这进一步伴随着24 h时Wnt信号下游靶点表达的显著变化。尼古丁介导的Wnt激活几乎完全被calphostin C或RGZ预处理阻断，表明PKC激活和Wnt/PPARγ相互作用在尼古丁诱导的Wnt信号上调中起重要作用，因此AIF向MYF转分化，为尼古丁诱导的肺损伤提供了新的预防/治疗靶点。
Nicotine exposure alters normal homeostatic pulmonary epithelial-mesenchymal paracrine signaling pathways, resulting in alveolar interstitial fibroblast (AIF)-to-myofibroblast (MYF) transdifferentiation. Since the AIF vs MYF phenotype is determined by the expression of Peroxisome Proliferator-Activated Receptor (PPAR)γ and Wingless/Int (Wnt) signaling, respectively, we hypothesized that nicotine-induced AIF-to-MYF transdifferentiation is characterized by the down-regulation of PPARγ, and the up-regulation of the Wnt signaling pathway. As nicotine is known to activate PKC signaling, we also hypothesized that in AIFs, nicotine-induced up-regulation of Wnt signaling might be due to PKC activation. Embryonic human lung fibroblasts (WI38 cells) were treated with nicotine (1 × 10−6M) for either 30 minutes or 24 hours, with or without 30 minute pretreatment with calphostin C (1 × 10−7), a pan-PKC inhibitor. Then we examined the activation of PKC (p-PKC) and Wnt signaling (p-GSK-3β, β-catenin, LEF-1, and fibronectin). Furthermore, activation of nicotinic acetylcholine receptors (nAChR)-α3 and −α7, and whether a PPARγ agonist, Rosiglitazone, blocks nicotine-mediated Wnt activation were examined. Following nicotine stimulation, there was clear evidence for nAChR-α3 and −α7 up-regulation, accompanied by the activation of PKC and Wnt signaling, which was further accompanied by significant changes in the expression of the down-stream targets of Wnt signaling at 24h. Nicotine-mediated Wnt activation was almost completely blocked by pretreatment with either calphostin C or RGZ, indicating the central involvement of PKC activation and Wnt/PPARγ interaction in nicotine-induced up-regulation of Wnt signaling, and hence AIF-to-MYF transdifferentiation, providing novel preventive/therapeutic targets for nicotine-induced lung injury.
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DOI：
10.1152/ajplung.00417.2002
发表时间：
2003-08-01
影响因子：
4.9
作者：
Bogatkevich, GS;Tourkina, E;Ludwicka-Bradley, A
通讯作者：
Ludwicka-Bradley, A
DOI：
10.1152/ajplung.00050.2006
发表时间：
2007-02-01
影响因子：
4.9
作者：
Alejandre-Alcazar, Miguel A.;Kwapiszewska, Grazyna;Morty, Rory E.
通讯作者：
Morty, Rory E.
影响因子：
5.3
作者：
Liu, Jiajian;Wang, Hong;Farmer, Stephen R.
通讯作者：
Farmer, Stephen R.
影响因子：
3.1
作者：
CHEN, MF;KIMIZUKA, G;WANG, NS
通讯作者：
WANG, NS
DOI：
10.1152/ajplung.00358.2004
发表时间：
2005-10-01
影响因子：
4.9
作者：
Rehan, VK;Wang, Y;Torday, JS
通讯作者：
Torday, JS