X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis
X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis
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DOI：
10.1165/rcmb.2012-0224oc
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发表时间：
2013-07-01
影响因子：
6.4
通讯作者：
Horowitz, Jeffrey C.
中科院分区：
文献类型：
--
作者：
Ajayi, Iyabode O.;Sisson, Thomas H.;Horowitz, Jeffrey C.
特发性肺纤维化（IPF）的一个特征是成纤维细胞灶内耐凋亡成纤维细胞的积累，但其耐凋亡的机制尚不清楚。细胞凋亡抑制剂（IAP）蛋白家族成员X连锁细胞凋亡抑制剂（XIAP）的作用已由先前的研究表明，（1）XIAP定位于IPF组织中的成纤维细胞病灶，（2）前列腺素E-2抑制XIAP表达，同时增加成纤维细胞对细胞凋亡的敏感性。基于这些观察结果，我们假设XIAP将受到促纤维化介质转化生长因子（TGF）β-1和内皮素（ET）-1的调节，并且XIAP增加将有助于IPF成纤维细胞的凋亡抵抗。为了解决这些假设，我们检查了XIAP表达在正常和IPF成纤维细胞在基线和正常成纤维细胞治疗后与TGF-β 1或ET-1。使用功能性XIAP拮抗剂和siRNA沉默来检查XIAP在成纤维细胞对Fas介导的细胞凋亡的易感性的调节中的作用。与之前的报告一致，与正常肺成纤维细胞相比，IPF肺组织的成纤维细胞对细胞凋亡的抗性增加。与正常成纤维细胞相比，IPF成纤维细胞具有显著但不均匀的基础XIAP表达增加。此外，TGF-β 1和ET-1诱导XIAP蛋白在正常成纤维细胞中表达。抑制或沉默XIAP增强了肺成纤维细胞对Fas介导的凋亡的敏感性，而在没有Fas激活的情况下不引起凋亡。总的来说，这些发现支持XIAP在IPF成纤维细胞的抗凋亡表型中的机制作用。
The accumulation of apoptosis-resistant fibroblasts within fibro-blastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (XIAP) has been suggested by prior studies showing that (1) XIAP is localized to fibroblastic foci in IPF tissue and (2) prostaglandin E-2 suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor (TGF)beta-1 and endothelin (ET)-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-beta 1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-b1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fas-mediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.