Tgf-β1 inhibits Cftr biogenesis and prevents functional rescue of ΔF508-Cftr in primary differentiated human bronchial epithelial cells.
Tgf-β1 inhibits Cftr biogenesis and prevents functional rescue of ΔF508-Cftr in primary differentiated human bronchial epithelial cells.
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DOI：
10.1371/journal.pone.0063167
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Swiatecka-Urban A
中科院分区：
文献类型：
--
作者：
Snodgrass SM;Cihil KM;Cornuet PK;Myerburg MM;Swiatecka-Urban A
CFTR 是一种完整的跨膜糖蛋白和 cAMP 激活的 Cl− 通道。 CFTR 基因突变会导致囊性纤维化 (CF)——一种常染色体隐性遗传疾病，大部分发病率和死亡率是由气道感染、炎症和纤维化引起的。 CFTR 基因中最常见的疾病相关突变——Phe508 (ΔF508) 缺失会导致 CFTR 生物合成加工缺陷。纠正缺陷并将 ΔF508-CFTR 递送至细胞表面作为一种疾病缓解疗法备受期待。在早期临床试验中，与培养细胞中的有希望的结果相比，这种方法对 CF 患者的效果要差得多。虽然临床试验中未能确定ΔF508-CFTR挽救失败的原因，但可以考虑体内存在干扰挽救的因素。细胞因子 TGF-β1 在 CF 患者中经常升高。 TGF-β1 在不同的疾病模型和遗传背景中具有多效性，但关于 TGF-β1 对人气道上皮细胞 CFTR 的影响知之甚少。此外，还没有已发表的研究检验 TGF-β1 对 ΔF508-CFTR 功能拯救的影响。在这里，我们发现 TGF-β1 通过降低非 CF 个体的原代分化人支气管上皮 (HBE) 细胞中的 mRNA 水平和蛋白质丰度来抑制 CFTR 生物发生。 TGF-β1 抑制 CFTR 生物发生，而不损害 HBE 细胞的上皮表型或完整性。 TGF-β1 还抑制生物发生并损害来自 ΔF508 突变纯合患者的 HBE 细胞中 ΔF508-CFTR 的功能拯救。我们的数据表明，TGF-β1 信号传导的激活可能会抑制非 CF 个体的 CFTR 功能，并可能干扰旨在纠正 CF 患者中 ΔF508-CFTR 加工缺陷的治疗。
CFTR is an integral transmembrane glycoprotein and a cAMP-activated Cl− channel. Mutations in the CFTR gene lead to Cystic Fibrosis (CF)–an autosomal recessive disease with majority of the morbidity and mortality resulting from airway infection, inflammation, and fibrosis. The most common disease-associated mutation in the CFTR gene–deletion of Phe508 (ΔF508) leads to a biosynthetic processing defect of CFTR. Correction of the defect and delivery of ΔF508-CFTR to the cell surface has been highly anticipated as a disease modifying therapy. Compared to promising results in cultured cell this approach was much less effective in CF patients in an early clinical trial. Although the cause of failure to rescue ΔF508-CFTR in the clinical trial has not been determined, presence of factor(s) that interfere with the rescue in vivo could be considered. The cytokine TGF-β1 is frequently elevated in CF patients. TGF-β1 has pleiotropic effects in different disease models and genetic backgrounds and little is known about TGF-β1 effects on CFTR in human airway epithelial cells. Moreover, there are no published studies examining TGF-β1 effects on the functional rescue of ΔF508-CFTR. Here we found that TGF-β1 inhibits CFTR biogenesis by reducing mRNA levels and protein abundance in primary differentiated human bronchial epithelial (HBE) cells from non-CF individuals. TGF-β1 inhibits CFTR biogenesis without compromising the epithelial phenotype or integrity of HBE cells. TGF-β1 also inhibits biogenesis and impairs the functional rescue of ΔF508-CFTR in HBE cells from patients homozygous for the ΔF508 mutation. Our data indicate that activation of TGF-β1 signaling may inhibit CFTR function in non-CF individuals and may interfere with therapies directed at correcting the processing defect of ΔF508-CFTR in CF patients.
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影响因子：
3.1
作者：
Harris, William T.;Muhlebach, Marianne S.;Oster, Robert A.;Knowles, Michael R.;Clancy, J. P.;Noah, Terry L.
通讯作者：
Noah, Terry L.
影响因子：
10
作者：
Hilliard, Tom N.;Regamey, Nicolas;Davies, Jane C.
通讯作者：
Davies, Jane C.
DOI：
10.1152/ajpcell.1994.267.5.c1398
发表时间：
1994-11-01
影响因子：
5.5
作者：
BESANCON, F;PRZEWLOCKI, G;EDELMAN, A
通讯作者：
EDELMAN, A
影响因子：
5.2
作者：
Cutting GR
通讯作者：
Cutting GR
影响因子：
10
作者：
Clancy JP;Rowe SM;Accurso FJ;Aitken ML;Amin RS;Ashlock MA;Ballmann M;Boyle MP;Bronsveld I;Campbell PW;De Boeck K;Donaldson SH;Dorkin HL;Dunitz JM;Durie PR;Jain M;Leonard A;McCoy KS;Moss RB;Pilewski JM;Rosenbluth DB;Rubenstein RC;Schechter MS;Botfield M;Ordoñez CL;Spencer-Green GT;Vernillet L;Wisseh S;Yen K;Konstan MW
通讯作者：
Konstan MW