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首页> 外文期刊>American Journal of Physiology >Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-beta on tropoelastin mRNA in lung fibroblasts.
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Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-beta on tropoelastin mRNA in lung fibroblasts.

机译：中性粒细胞弹性蛋白酶引发的EGFR / MEK / ERK信号传导抵消了自分泌TGF-β对肺成纤维细胞原弹性蛋白mRNA的稳定作用。

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摘要

Neutrophil elastase (NE) plays an important role in emphysema, a pulmonary disease associated with excessive elastolysis and ineffective repair of interstitial elastin. Besides its direct elastolytic activity, NE releases soluble epidermal growth factor receptor (EGFR) ligands and initiates EGFR/MEK/ERK signaling to downregulate tropoelastin mRNA in neonatal rat lung fibroblasts (DiCamillo SJ, Carreras I, Panchenko MV, Stone PJ, Nugent MA, Foster JA, and Panchenko MP. J Biol Chem 277: 18938-18946, 2002). We now report that NE downregulates tropoelastin mRNA in the rat fetal lung fibroblast line RFL-6. The tropoelastin mRNA downregulation is preceded by release of EGF-like and TGF-alpha-like polypeptides and requires EGFR/MEK/ERK signaling, because it is prevented by the EGFR inhibitor AG1478 and the MEK/ERK uncoupler U0126. Tropoelastin expression in RFL-6 fibroblasts is governed by autocrine TGF-beta signaling, because TGF-beta type I receptor kinase inhibitor or TGF-beta neutralizing antibody dramatically decreases tropoelastin mRNA and protein levels. Half-life of tropoelastin mRNA in RFL-6 cells is >24 h, but it is decreased to approximately 8 h by addition of TGF-beta neutralizing antibody, EGF, TGF-alpha, or NE. Tropoelastin mRNA destabilization by NE, EGF, or TGF-alpha is abolished by AG1478 or U0126. EGF-dependent tropoelastin mRNA downregulation is reversed upon ligand withdrawal, whereas chronic EGF treatment leads to persistent downregulation of tropoelastin mRNA and protein levels and decreases insoluble elastin deposition. We conclude that NE-initiated EGFR/MEK/ERK signaling cascade overrides the autocrine TGF-beta signaling on tropoelastin mRNA stability and, therefore, decreases the elastogenic response in RFL-6 fibroblasts. We hypothesize that persistent EGFR/MEK/ERK signaling could impede the TGF-beta-induced elastogenesis/elastin repair in the chronically inflamed, elastase/anti-elastase imbalanced lung in emphysema.
机译：中性粒细胞弹性蛋白酶（NE）在肺气肿中起着重要作用，肺气肿是一种与过度弹性分解和间质弹性蛋白修复无效有关的肺部疾病。除了具有直接的弹性分解活性外，NE还释放可溶性表皮生长因子受体（EGFR）配体并启动EGFR / MEK / ERK信号，从而下调新生大鼠肺成纤维细胞中的原弹性蛋白mRNA（DiCamillo SJ，Carreras I，Panchenko MV，Stone PJ，Nugent MA， Foster JA和Panchenko MP.J Biol Chem 277：18938-18946，2002）。现在，我们报告NE下调大鼠胎儿肺成纤维细胞系RFL-6中的原弹性蛋白mRNA。原弹性蛋白mRNA下调之前是释放EGF类和TGF-α类多肽，并且需要EGFR / MEK / ERK信号传导，因为它被EGFR抑制剂AG1478和MEK / ERK解偶联剂U0126阻止。 RFL-6成纤维细胞中滋养弹性蛋白的表达受自分泌TGF-beta信号的支配，因为TGF-beta I型受体激酶抑制剂或TGF-beta中和抗体会极大地降低原弹性蛋白的mRNA和蛋白质水平。原弹性蛋白mRNA在RFL-6细胞中的半衰期> 24小时，但通过添加TGF-β中和抗体，EGF，TGF-α或NE可将其降低至约8小时。 AG1478或U0126消除了NE，EGF或TGF-α对Tropoelastin mRNA造成的不稳定作用。依赖于EGF的原弹性蛋白mRNA的下调在配体撤离时被逆转，而长期的EGF治疗导致原弹性蛋白mRNA和蛋白水平的持续下调并减少不溶性弹性蛋白沉积。我们得出结论，NE启动的EGFR / MEK / ERK信号级联在原弹性蛋白mRNA稳定性上覆盖了自分泌TGF-β信号，因此降低了RFL-6成纤维细胞的弹性反应。我们假设持续的EGFR / MEK / ERK信号传导可能会阻碍肺气肿的慢性发炎，弹性蛋白酶/抗弹性蛋白酶失衡的TGF-β诱导的弹性生成/弹性蛋白修复。

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