Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs
Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs
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DOI：
10.1165/rcmb.2002-0262oc
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发表时间：
2003-10-01
影响因子：
6.4
通讯作者：
Knight, DA
中科院分区：
文献类型：
--
作者：
Moodley, YP;Misso, NLA;Knight, DA
成纤维细胞凋亡对纤维化的消退至关重要。然而，这些细胞发生凋亡的机制尚不清楚。由于白细胞介素(IL)-6和IL-11可能改变修复和重塑过程，我们假设它们可能在特发性肺纤维化（IPF）中发挥作用。我们利用3名IPF患者（IPF- fb）和3名无肺部疾病（normal-Fb）的肺原代成纤维细胞研究了这些细胞因子对fas诱导的细胞凋亡的影响。与正常- fb相比，IPF-Fb对fas诱导的细胞凋亡具有抵抗性（P < 0.01）。通过RNase保护实验，我们发现IL-6增强了fas诱导的正常fb细胞凋亡和Bax的表达，而抑制了IPF-Fb细胞凋亡和诱导Bcl-2的表达。Western blots密度测定显示，正常fb的Bcl-2/Bax比值为0.15 +/- 0.01，而IPF-Fb的Bcl-2/Bax比值为12.05 +/- 1.0。正常- fb中Bcl-2的上调和IPF-Fb中Bax的上调均依赖于stat -3。抑制细胞外信号调节激酶对正常fb无影响，但逆转了IL-6对IPF-Fb的抗凋亡作用。IL-11抑制fas诱导的细胞凋亡，增加正常fb和IPF-Fb中Bcl-2的表达。这些结果表明，IPF- fb中IL-6信号的改变可能会增强这些细胞对凋亡的抵抗力，并有助于IL-6在IPF中的促纤维化作用。
Fibroblast apoptosis is crucial to the resolution of fibrosis. However, the mechanisms by which these cells undergo apoptosis are not well known. Because interleukin (IL)-6 and IL-11 may alter repair and remodeling processes, we hypothesized that they may play a role in idiopathic pulmonary fibrosis (IPF). We investigated the effects of these cytokines on Fas-induced apoptosis using primary lung fibroblasts from three patients with IPF (IPF-Fb) and three subjects without lung disease (normal-Fb). IPF-Fb were resistant to Fas-induced apoptosis compared with normal-Fb (P < 0.01). Using RNase protection assays, we showed that IL-6 enhanced Fas-induced apoptosis and expression of Bax in normal-Fb, but inhibited apoptosis and induced expression of Bcl-2 in IPF-Fb. Densitometry of Western blots revealed a Bcl-2/Bax ratio 0.15 +/- 0.01 in normal-Fb compared with 12.05 +/- 1.0 in IPF-Fb. Upregulation of Bcl-2 in normal-Fb and Bax in IPF-Fb were both STAT-3-dependent. Inhibition of extracellular signal-regulated kinase had no effect in normal-Fb, but reversed the antiapoptotic effect of IL-6 in IPF-Fb. IL-11 inhibited Fas-induced apoptosis and increased Bcl-2 expression in both normal-Fb and IPF-Fb. These results suggest that altered IL-6 signaling in IPF-Fb may enhance the resistance of these cells to apoptosis and contribute to a profibrotic effect of IL-6 in IPF.