IL10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways.
IL10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways.
复制标题
IL10通过IL10-IL10R-STAT3和IL10-AKT-MTOR途径在肥厚疤痕成纤维细胞中抑制饥饿诱导的自噬。
DOI：
10.1038/cddis.2016.44
复制
发表时间：
2016-03-10
影响因子：
9
通讯作者：
Hu D
中科院分区：
文献类型：
--
作者：
Shi J;Wang H;Guan H;Shi S;Li Y;Wu X;Li N;Yang C;Bai X;Cai W;Yang F;Wang X;Su L;Zheng Z;Hu D
增生性瘢痕（HS）是一种严重的皮肤纤维化疾病，其特征是细胞过度增生和细胞外基质（ECM）成分沉积。自噬是细胞维持、分化、发育和稳态所必需的严格调节的生理过程。先前的研究表明，IL 10在预防和减少HS形成方面具有潜在的治疗益处。然而，没有研究检查IL 10介导的自噬过程中的病理过程中的HS形成。在这里，我们研究了IL 10对饥饿诱导的自噬的影响，并研究了饥饿条件下IL 10介导的HS衍生成纤维细胞（HSFs）自噬抑制的分子机制。免疫染色和PCR分析显示，IL 10受体的特异性组分IL 10 α链（IL 10 R α）在HSF中表达。透射电子显微镜和western blot分析显示，IL 10抑制饥饿诱导的自噬，并以剂量依赖的方式诱导HSF中p-AKT和p-STAT 3的表达。使用特异性抑制剂（分别为IL 10 RB、LY 294002、雷帕霉素和隐丹参酮）阻断IL 10 R、p-AKT、p-mTOR和p-STAT 3表明，IL 10通过IL 10 R α介导的STAT 3激活（IL 10 R-STAT 3途径）和直接激活AKT-mTOR途径抑制自噬。值得注意的是，这些结果表明，IL 10介导的自噬抑制是由STAT 3、AKT和mTOR之间的串扰促进的;换句话说，IL 10-IL 10 R-STAT 3和IL 10-AKT-mTOR途径。最后，结果还表明，mTOR-p70 S6 K是这两种途径会聚在一起以诱导饥饿HSF中IL 10介导的自噬抑制的分子。总之，本文报道的发现阐明了IL 10介导的自噬抑制的分子机制，并表明IL 10是治疗HS的潜在治疗剂。
Hypertrophic scar (HS) is a serious skin fibrotic disease characterized by excessive hypercellularity and extracellular matrix (ECM) component deposition. Autophagy is a tightly regulated physiological process essential for cellular maintenance, differentiation, development, and homeostasis. Previous studies show that IL10 has potential therapeutic benefits in terms of preventing and reducing HS formation. However, no studies have examined IL10-mediated autophagy during the pathological process of HS formation. Here, we examined the effect of IL10 on starvation-induced autophagy and investigated the molecular mechanism underlying IL10-mediated inhibition of autophagy in HS-derived fibroblasts (HSFs) under starvation conditions. Immunostaining and PCR analysis revealed that a specific component of the IL10 receptor, IL10 alpha-chain (IL10Rα), is expressed in HSFs. Transmission electron microscopy and western blot analysis revealed that IL10 inhibited starvation-induced autophagy and induced the expression of p-AKT and p-STAT3 in HSFs in a dose-dependent manner. Blocking IL10R, p-AKT, p-mTOR, and p-STAT3 using specific inhibitors (IL10RB, LY294002, rapamycin, and cryptotanshinone, respectively) showed that IL10 inhibited autophagy via IL10Rα-mediated activation of STAT3 (the IL10R-STAT3 pathway) and by directly activating the AKT-mTOR pathway. Notably, these results suggest that IL10-mediated inhibition of autophagy is facilitated by the cross talk between STAT3, AKT, and mTOR; in other words, the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways. Finally, the results also indicate that mTOR-p70S6K is the molecule upon which these two pathways converge to induce IL10-mediated inhibition of autophagy in starved HSFs. In summary, the findings reported herein shed light on the molecular mechanism underlying IL10-mediated inhibition of autophagy and suggest that IL10 is a potential therapeutic agent for the treatment of HS.