Idiopathic pulmonary fibrosis fibroblasts become resistant to Fas ligand-dependent apoptosis via the alteration of decoy receptor 3.
Idiopathic pulmonary fibrosis fibroblasts become resistant to Fas ligand-dependent apoptosis via the alteration of decoy receptor 3.
复制标题
DOI：
10.1002/path.4749
复制
发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Nho RS
中科院分区：
文献类型：
--
作者：
Im J;Kim K;Hergert P;Nho RS
特发性肺纤维化（IPF）是一种病因不明的不可逆致死性肺部疾病。IPF患者的肺成纤维细胞表达不适当的高Akt活性，保护它们响应于诱导骨化的I型胶原基质。已知Fas配体FasL在IPF患者的肺组织中增加，与IPF的进展有关。结合至FasL从而随后抑制FasL/Fas依赖性凋亡途径的诱饵受体3（DcR 3）的表达在各种人类疾病中频繁改变。然而，DcR 3在IPF成纤维细胞中调节其活力的作用尚未得到研究。我们发现，增强的DcR 3表达存在于胶原基质上的大多数IPF成纤维细胞中，从而保护IPF成纤维细胞免受FasL诱导的凋亡。异常高的Akt活性抑制GSK-3β功能，从而在细胞核中积累活化T细胞的核因子c1（NFATc 1），增加IPF成纤维细胞中DcR 3的表达。这种改变保护IPF细胞免受胶原蛋白上FasL诱导的凋亡。然而，Akt或NFATc 1的抑制降低了DcR 3 mRNA和蛋白水平，这使IPF成纤维细胞对FasL介导的凋亡敏感。此外，增强的DcR 3和NFATc 1表达主要存在于源自IPF患者的肺组织的成纤维细胞病灶中的肌成纤维细胞中。我们的研究结果表明，当IPF细胞与胶原基质相互作用时，异常激活的Akt通过GSK-3β/NFATc 1增加DcR 3的表达，并保护IPF细胞免受FasL依赖性凋亡途径的影响。这些发现表明，抑制DcR 3功能可能是一种有效的方法，可使IPF成纤维细胞对FasL敏感，从而限制肺纤维化的进展。
Idiopathic pulmonary fibrosis (IPF) is an irreversible lethal lung disease with an unknown aetiology. IPF patient’s lung fibroblasts express inappropriately high Akt activity, protecting them in response to an apoptosis-inducing type I collagen matrix. FasL, a ligand for Fas, is known to be increased in the lung tissues of patients with IPF, implicated with the progression of IPF. Expression of Decoy Receptor3 (DcR3) which binds to FasL, thereby subsequently suppressing the FasL/Fas-dependent apoptotic pathway is frequently altered in various human disease. However, the role of DcR3 in IPF fibroblasts in regulating their viability has not been examined. We found that enhanced DcR3 expression exists in the majority of IPF fibroblasts on collagen matrices, resulting in the protection of IPF fibroblasts from FasL-induced apoptosis. Abnormally high Akt activity suppresses GSK-3β function, thereby accumulating the nuclear factor of activated T-cells c1 (NFATc1) in the nucleus, increasing DcR3 expression in IPF fibroblasts. This alteration protects IPF cells from FasL-induced apoptosis on collagen. However, the inhibition of Akt or NFATc1 decreases DcR3 mRNA and protein levels, which sensitizes IPF fibroblasts to FasL-mediated apoptosis. Furthermore, enhanced DcR3 and NFATc1 expression is mainly present in myofibroblasts in the fibroblastic foci of lung tissues derived from IPF patients. Our results showed that when IPF cells interacted with collagen matrix, aberrantly activated Akt increased DcR3 expression via GSK-3β/NFATc1 and protected IPF cells from the FasL-dependent apoptotic pathway. These findings suggest that the inhibition of DcR3 function may be an effective approach for sensitizing IPF fibroblasts in response to FasL, limiting the progression of lung fibrosis.