TNF-α sensitizes normal and fibrotic human lung fibroblasts to Fas-induced apoptosis
TNF-α sensitizes normal and fibrotic human lung fibroblasts to Fas-induced apoptosis
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DOI：
10.1165/rcmb.2005-0155oc
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发表时间：
2006-03-01
影响因子：
6.4
通讯作者：
Riches, DWH
中科院分区：
文献类型：
--
作者：
Frankel, SK;Cosgrove, GP;Riches, DWH
特发性肺纤维化/普通型间质性肺炎（IIFP/UIP）中成纤维细胞和肌成纤维细胞的肺蓄积与（1）纤维细胞循环池迁移增加，（2）细胞增殖和（3）细胞凋亡抗性有关。肺成纤维细胞生理性凋亡的机制还不清楚。使用正常和纤维化的人肺成纤维细胞和人肺成纤维细胞系MRC-5，我们研究了促炎细胞因子TNF-α对Fas诱导的细胞凋亡的调节。和IFN-γ。在此，我们发现肺成纤维细胞和肌成纤维细胞对Fas诱导的细胞凋亡的基础抵抗力被TNF-α的敏化作用所克服。IFN-γ对Fas诱导的细胞凋亡不敏感，但与TNF-α表现出协同活性。在MRC-5细胞和来自正常和纤维化人肺的成纤维细胞和肌成纤维细胞中观察到TNF-α的致敏作用，表明这代表参与Fas诱导的细胞凋亡的保守机制。致敏的机制定位在衔接蛋白，FADD，Fas的胞质结构域的招聘水平。总的来说，这些发现表明成纤维细胞凋亡涉及两个步骤，致敏和诱导，IPF/UIP中的肺部炎症不足可能通过降低对凋亡的致敏性而有利于成纤维细胞蓄积。
Pulmonary accumulation of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis/usual interstitial pneumonia (lIFP/UIP) has been linked to (1) increased migration of a circulating pool of fibrocytes, (2) cell proliferation, and (3) resistance to apoptosis. The mechanism of physiologic apoptosis of lung fibroblasts is poorly understood. Using normal and fibrotic human lung fibroblasts and the human lung fibroblast cell line, MRC-5, we examined the regulation of Fas-induced apoptosis by the proinflammatory cytokines TNF-alpha. and IFN-gamma. Herein, we show that the basal resistance of lung fibroblasts and myofibroblasts to Fas-induced apoptosis is overcome by sensitization with TNF-alpha. IFN-gamma did not sensitize cells to Fas-induced apoptosis, but exhibited synergistic activity with TNF-alpha. Sensitization by TNF-alpha was observed in MRC-5 cells and in fibroblasts and myofibroblasts from normal and fibrotic human lung, suggesting that this represents a conserved mechanism to engage Fas-induced apoptosis. The mechanism of sensitization was localized at the level of recruitment of the adapter protein, FADD, to the cytoplasmic domain of Fas. Collectively, these findings suggest that fibroblast apoptosis involves two steps, sensitization and induction, and that inadequate pulmonary inflammation in IPF/UIP may favor fibroblast accumulation by reducing sensitization to apoptosis.