Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal.
PLoS One. 2013 Jun 24;8(6):e67607. doi: 10.1371/journal.pone.0067607. Print 2013.
The glycoprotein 130 (gp130) dependent family of cytokines comprises interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (LIF), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1) and oncostatin M (OSM). These cytokines share the membrane gp130 as a common signal transducer. Recently, it was demonstrated that IL-6 promotes, whereas LIF inhibits fetal lung branching. Thus, in this study, the effects on fetal lung morphogenesis of the other classical members of the gp130-type cytokines (IL-11, CLC, CNTF, CT-1 and OSM) were investigated. We also provide the first description of these cytokines and their common gp130 receptor protein expression patterns during rat lung development. Fetal rat lung explants were cultured in vitro with increasing concentrations of IL-11, CLC, CNTF, CT-1 and OSM. Treated lung explants were morphometrically analyzed and assessed for MAPK, PI3K/AKT and STAT3 signaling modifications. IL-11, which similarly to IL-6 acts through a gp130 homodimer receptor, significantly stimulated lung growth via p38 phosphorylation. On the other hand, CLC, CNTF, CT-1 and OSM, whose receptors are gp130 heterodimers, inhibited lung growth acting in different signal-transducing pathways. Thus, the present study demonstrated that although cytokines of the gp130 family share a common signal transducer, there are specific biological activities for each cytokine on lung development. Indeed, cytokine signaling through gp130 homodimers stimulate, whereas cytokine signaling through gp130 heterodimers inhibit lung branching.
糖蛋白 130（gp130）依赖性细胞因子家族包括白细胞介素 6（IL-6）、白细胞介素 11（IL-11）、白血病抑制因子（LIF）、心脏营养素样细胞因子（CLC）、睫状神经营养因子（CNTF）、心脏营养素-1（CT-1）和肿瘤坏死因子 M（OSM）。这些细胞因子共享膜 gp130 作为共同的信号转导器。最近，研究表明 IL-6 促进胎儿肺分支，而 LIF 抑制胎儿肺分支。因此，在这项研究中，研究了 gp130 型细胞因子的其他经典成员（IL-11、CLC、CNTF、CT-1 和 OSM）对胎儿肺形态发生的影响。我们还首次描述了这些细胞因子及其在大鼠肺发育过程中的共同 gp130 受体蛋白表达模式。将胎鼠肺外植体在体外与不断增加浓度的 IL-11、CLC、CNTF、CT-1 和 OSM 一起培养。对处理后的肺外植体进行形态计量学分析，并评估 MAPK、PI3K/AKT 和 STAT3 信号转导的改变。IL-11 与 IL-6 相似，通过 gp130 同源二聚体受体发挥作用，通过 p38 磷酸化显著刺激肺生长。另一方面，CLC、CNTF、CT-1 和 OSM 的受体是 gp130 异源二聚体，通过不同的信号转导途径抑制肺生长。因此，本研究表明，尽管 gp130 家族的细胞因子共享共同的信号转导器，但它们对肺发育具有特定的生物学活性。事实上，通过 gp130 同源二聚体的细胞因子信号转导刺激，而通过 gp130 异源二聚体的细胞因子信号转导抑制肺分支。
