Overproduction of collagen and diminished SOCS1 expression are causally linked in fibroblasts from idiopathic pulmonary fibrosis.
Overproduction of collagen and diminished SOCS1 expression are causally linked in fibroblasts from idiopathic pulmonary fibrosis.
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DOI：
10.1016/j.bbrc.2006.12.128
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发表时间：
2007-02
影响因子：
3.1
通讯作者：
Hiroyasu Shoda;A. Yokoyama;Ryouhei Nishino;Taku Nakashima;N. Ishikawa;Y. Haruta;N. Hattori;T. Naka;N. Kohno
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文献类型：
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作者：
Hiroyasu Shoda;A. Yokoyama;Ryouhei Nishino;Taku Nakashima;N. Ishikawa;Y. Haruta;N. Hattori;T. Naka;N. Kohno
特发性肺纤维化（IPF）是一种慢性、进行性且常常致命的肺部疾病，其病理学特征是实质纤维化。为了研究 IPF 中成纤维细胞的特征，我们从 IPF 肺部获得了 8 个成纤维细胞系，从正常肺部获得了 8 个成纤维细胞系。我们发现，与正常肺的成纤维细胞相比，IPF 的成纤维细胞自发产生更多的 I 型胶原蛋白，并且 SOCS1 的表达水平更低。通过使用小鼠成纤维细胞，我们证明了它们之间的因果关系：成纤维细胞中SOCS1的缺乏导致胶原蛋白产生增加，而SOCS1的过度表达则抑制胶原蛋白的产生。即使在 SOCS1 缺陷的成纤维细胞中，IFN-γ 也能抑制自发胶原蛋白的产生，表明 IFN-γ 的抑制作用不依赖于 SOCS1。相反，IFN-γ抑制野生型成纤维细胞中IL-4诱导的胶原蛋白产生的增加，但不抑制SOCS1缺陷的成纤维细胞，表明在这种情况下IFN-γ仅通过SOCS1发挥作用。 IFN-γ刺激后，IPF成纤维细胞表达的SOCS1 mRNA量与正常成纤维细胞相当。因此，在 IPF 成纤维细胞中，IFN-γ 刺激后 SOCS1 增加的程度显着更高。 IPF 成纤维细胞中 IFN-γ 抑制胶原蛋白生成的程度也大于正常成纤维细胞。这些结果表明，IPF 成纤维细胞中胶原蛋白的过量产生与 SOCS1 表达减少有关，并且由于 SOCS1 表达减少，IPF 成纤维细胞更容易受到 IFN-γ 的影响。
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal pulmonary disorder, and its pathology is characterized by parenchymal fibrosis. To investigate the characteristics of fibroblasts in IPF, we obtained eight fibroblast cell lines from lungs with IPF and eight lines from normal lungs. We found that the fibroblasts from IPF spontaneously produced higher amounts of type I collagen and had lower expression levels of SOCS1 than fibroblasts from normal lung. By using mouse fibroblasts, we demonstrated the causal relationship between them: the deficiency of SOCS1 in fibroblasts resulted in increased collagen production, whereas overexpression of SOCS1 suppressed collagen production. IFN-γ suppressed spontaneous collagen production even in SOCS1-deficient fibroblasts, indicating that IFN-γ inhibition is SOCS1-independent. In contrast, IFN-γ suppressed the increase of collagen production induced by IL-4 in wild type fibroblasts but not SOCS1-deficient fibroblasts, suggesting IFN-γ acted exclusively via SOCS1 in this case. Following IFN-γ stimulation, the amount of SOCS1 mRNA expressed by IPF fibroblasts was comparable to that of normal fibroblasts. Thus, the extent of SOCS1 increase after stimulation by IFN-γ was significantly higher in IPF fibroblasts. The extent to which IFN-γ inhibited collagen production was also larger in IPF fibroblasts than in normal fibroblasts. These results suggest that the exaggerated production of collagen observed in fibroblasts from IPF is causally related to the diminished expression of SOCS1, and IPF fibroblasts are more susceptible to IFN-γ because of decreased expression of SOCS1.