Anti-fibrotic actions of interleukin-10 against hypertrophic scarring by activation of PI3K/AKT and STAT3 signaling pathways in scar-forming fibroblasts.
Anti-fibrotic actions of interleukin-10 against hypertrophic scarring by activation of PI3K/AKT and STAT3 signaling pathways in scar-forming fibroblasts.
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Interleukin-10 通过激活疤痕成纤维细胞中的 PI3K/AKT 和 STAT3 信号通路来对抗肥厚性疤痕形成的抗纤维化作用
DOI：
10.1371/journal.pone.0098228
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Shi J;Li J;Guan H;Cai W;Bai X;Fang X;Hu X;Wang Y;Wang H;Zheng Z;Su L;Hu D;Zhu X
背景增生性瘢痕（hypertrophic scar，HS）是一种严重的皮肤纤维化疾病，是临床上的一大难题.白细胞介素-10（IL-10）已被确定为基于临床前试验的有前景的疤痕改善化合物。我们以前的工作表明，IL-10在转化生长因子（TGF）-β1刺激的成纤维细胞中具有抗纤维化作用，以及预防和减少瘢痕形成的潜在治疗益处。然而，对IL-10介导的抗纤维化和瘢痕改善作用的机制知之甚少。目的探讨白细胞介素10（IL-10）受体在人HS组织和原代HS成纤维细胞（HSFs）中的表达，探讨IL-10抗纤维化和改善瘢痕的分子机制。方法采用免疫组织化学、免疫荧光显微镜和聚合酶链反应技术检测HS组织和HSF中IL-10受体的表达。用IL-10、特异性磷脂酰肌醇3激酶（PI 3 K）抑制剂（LY 294002）或针对IL-10受体的功能阻断抗体（IL-10 RB）处理原代HSF。接下来，使用Western印迹分析来评估AKT和信号转导和转录激活因子（STAT）3的磷酸化状态的变化，以及纤维化相关蛋白的表达水平。结果HS组织和原发性HSFs的特征在于IL-10受体的表达和相对于正常对照的纤维化标记物的高表达。原代HSF表达IL-10受体，而IL-10诱导这些细胞中的AKT和STAT 3磷酸化。此外，LY 294002阻断AKT和STAT磷酸化，并且还上调IL-10处理的细胞中I型和III型胶原（Col 1和Col 3）和α-平滑肌肌动蛋白（α-SMA）的表达水平。类似地，IL-10 RB减少STAT 3/AKT磷酸化并阻断IL-10介导的HSF纤维化缓解。结论IL-10通过激活IL-10受体下游AKT和STAT 3的磷酸化，促进PI 3 K/AKT和STAT 3信号转导通路之间的相互作用，抑制纤维化。
Background The hypertrophic scar (HS) is a serious fibrotic skin condition and a major clinical problem. Interleukin-10 (IL-10) has been identified as a prospective scar-improving compound based on preclinical trials. Our previous work showed that IL-10 has anti-fibrotic effects in transforming growth factor (TGF)-β1-stimulated fibroblasts, as well as potential therapeutic benefits for the prevention and reduction of scar formation. However, relatively little is known about the mechanisms underlying IL-10-mediated anti-fibrotic and scar-improvement actions. Objective To explore the expression of the IL-10 receptor in human HS tissue and primary HS fibroblasts (HSFs), and the molecular mechanisms contributing to the anti-fibrotic and scar-improvement capabilities of IL-10. Methods Expression of the IL-10 receptor was assessed in HS tissue and HSFs by immunohistochemistry, immunofluorescence microscopy, and polymerase chain reaction analysis. Primary HSFs were treated with IL-10, a specific phosphatidylinositol 3 kinase (PI3K) inhibitor (LY294002) or a function-blocking antibody against the IL-10 receptor (IL-10RB). Next, Western blot analysis was used to evaluate changes in the phosphorylation status of AKT and signal transducers and activators of transcription (STAT) 3, as well as the expression levels of fibrosis-related proteins. Results HS tissue and primary HSFs were characterized by expression of the IL-10 receptor and by high expression of fibrotic markers relative to normal controls. Primary HSFs expressed the IL-10 receptor, while IL-10 induced AKT and STAT3 phosphorylation in these cells. In addition, LY294002 blocked AKT and STAT phosphorylation, and also up-regulated expression levels of type I and type III collagen (Col 1 and Col 3) and alpha-smooth muscle actin (α-SMA) in IL-10-treated cells. Similarly, IL-10RB reduced STAT3/AKT phosphorylation and blocked the IL-10-mediated mitigation of fibrosis in HSFs. Conclusion IL-10 apparently inhibits fibrosis by activating AKT and STAT3 phosphorylation downstream of the IL-10 receptor, and by facilitating crosstalk between the PI3K/AKT and STAT3 signal transduction pathways.
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DOI：
10.1016/j.bjps.2008.03.020
发表时间：
2008-01-01
影响因子：
2.7
作者：
Brown, B. C.;McKenna, S. P.;Bayat, A.
通讯作者：
Bayat, A.
影响因子：
7.3
作者：
Franke, Thomas F.
通讯作者：
Franke, Thomas F.
DOI：
10.1152/ajplung.2000.278.5.l914
发表时间：
2000-05-01
影响因子：
4.9
作者：
Arai, T;Abe, K;Hayashi, S
通讯作者：
Hayashi, S
影响因子：
5.7
作者：
Gauglitz, Gerd G.;Korting, Hans C.;Jeschke, Marc G.
通讯作者：
Jeschke, Marc G.
DOI：
10.1084/jem.170.6.2081
发表时间：
1989-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fiorentino DF;Bond MW;Mosmann TR
通讯作者：
Mosmann TR