Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2.
Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2.
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氧化还原敏感的 MAPK 和 Notch3 调节成纤维细胞分化和活化：ERK1/2 的双重作用
DOI：
10.18632/oncotarget.9667
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发表时间：
2016-07-12
期刊：
影响因子：
--
通讯作者：
Zhu JH
中科院分区：
文献类型：
--
作者：
Lai JM;Zhang X;Liu FF;Yang R;Li SY;Zhu LB;Zou M;Cheng WH;Zhu JH
肌成纤维转化以α-平滑肌肌动蛋白响应于TGF-β1等促纤维化因子而上调为特征，被认为是导致纤维化的主要事件。肌成纤维细胞分化与特发性肺纤维化及其治疗之间的机制基础尚不清楚。在本研究中，我们研究了MAPK、Notch和活性氧（ROS）在基础水平和TGF-β1诱导的肺成纤维细胞IMR-90分化过程中的作用。我们的研究结果表明，ros依赖的p38、JNK1/2和Notch3的激活促进了基础和TGF-β1诱导的细胞外基质蛋白的分化和表达。与此形成鲜明对比的是，ERK1/2受到ROS的抑制，对分化有抑制作用，但对细胞外基质蛋白的表达有微弱的促进作用。TGF-β1诱导Notch3表达依赖于p38和JNK1/2。有趣的是，Notch3也位于ERK1/2的下游，提示ERK1/2在肺功能中的复杂作用。我们的研究结果表明，在IPF的病理进展过程中，ros介导的优势从抑制性ERK1/2转向刺激性p38、JNK1/2和Notch3。因此，靶向ERK1/2信号的激活和p38、JNK1/2和Notch3的抑制可能具有抗肺纤维化的临床潜力。
Myofibroblastic transformation, characterized by upregulation of α-smooth muscle actin in response to profibrotic agents such as TGF-β1, is considered as a major event leading to fibrosis. The mechanistic basis linking myofibroblast differentiation to idiopathic pulmonary fibrosis and the disease treatment remain elusive. In this study, we studied roles of MAPK, Notch, and reactive oxygen species (ROS) during the differentiation of IMR-90 lung fibroblasts at basal level and induced by TGF-β1. Our results demonstrated that ROS-dependent activation of p38, JNK1/2 and Notch3 promoted basal and TGF-β1-induced differentiation and expression of extracellular matrix proteins. In stark contrast, ERK1/2 was suppressed by ROS and exhibited an inhibitory effect on the differentiation but showed a weak promotion on the expression of extracellular matrix proteins. TGF-β1-induced Notch3 expression depended on p38 and JNK1/2. Interestingly, Notch3 was also downstream of ERK1/2, suggesting a complex role of ERK1/2 in lung function. Our results suggest a novel ROS-mediated shift of dominance from the inhibitory ERK1/2 to the stimulatory p38, JNK1/2 and Notch3 during the pathological progression of IPF. Thus, targeting ERK1/2 signaling for activation and p38, JNK1/2 and Notch3 for inhibition may be of clinical potential against lung fibrosis.
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DOI：
10.1165/ajrcmb/5.2.155
发表时间：
1991-08-01
影响因子：
6.4
作者：
KHALIL, N;OCONNOR, RN;GREENBERG, AH
通讯作者：
GREENBERG, AH
影响因子：
1.2
作者：
Cai, Yan;Kimura, Shioko
通讯作者：
Kimura, Shioko
影响因子：
3.9
作者：
Gauldie, J.;Bonniaud, P.;Kolb, M.
通讯作者：
Kolb, M.
DOI：
10.1186/cc6983
发表时间：
2008
期刊：
Critical care (London, England)
影响因子：
--
作者：
Li LF;Liao SK;Huang CC;Hung MJ;Quinn DA
通讯作者：
Quinn DA
影响因子：
3.7
作者：
Lim, Min Jin;Ahn, Jiyeon;Song, Jie-Young
通讯作者：
Song, Jie-Young