骨髓间充质干细胞下调 CCl4 诱导的大鼠肝纤维化中 IL17A 依赖的 IL6/STAT3 信号通路。
Bone marrow derived-mesenchymal stem cells downregulate IL17A dependent IL6/STAT3 signaling pathway in CCl4-induced rat liver fibrosis.
机构信息
Department of Biology and Biotechnologies, Faculty of Science & Technology, AL-Neelain University, Khartoum, Sudan.
Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt.
出版信息
PLoS One. 2018 Oct 22;13(10):e0206130. doi: 10.1371/journal.pone.0206130. eCollection 2018.
Therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) has been reported in several animal models of liver fibrosis. Interleukin (IL) 17A, IL6 and Stat3 have been described to play crucial roles in chronic liver injury. However, the modulatory effect of MSCs on these markers was controversial in different diseases. BM-MSCs might activate the IL6/STAT3 signaling pathway and promote cell invasion in hepatocellular carcinoma, but the immunomodulatory role of BM-MSCs on IL17A/IL6/STAT3 was not fully elucidated in liver fibrosis. In the present study, we evaluated the capacity of the BM-MSCs in the modulation of cytokines milieu and signal transducers, based on unique inflammatory genes Il17a and Il17f and their receptors Il17rc and their effect on the IL6/STAT3 pathway in CCl4-induced liver fibrosis in rats. A single dose of BM-MSCs was administered to the group with induced liver fibrosis, and the genes and proteins of interest were evaluated along six weeks after treatment. Our results showed a significant downregulation of Il17a, Il17ra, il17f and Il17rc genes. In accordance, BM-MSCs administration declined IL17, IL2 and IL6 serum proteins and downregulated IL17A and IL17RA proteins in liver tissue. Interestingly, BM-MSCs downregulated both Stat3 mRNA expression and p-STAT3, while Stat5a gene was downregulated and p-STAT5 protein was elevated. Also P-SMAD3 and TGFβR2 proteins were downregulated in response to BM-MSCs treatment. Collectively, we suggest that BM-MSCs might play an immunomodulatory role in the treatment of liver fibrosis through downregulation of IL17A affecting IL6/STAT3 signaling pathway.
骨髓间充质干细胞(BM-MSCs)在几种肝纤维化动物模型中的治疗潜力已被报道。白细胞介素(IL)17A、IL6 和 Stat3 已被描述为在慢性肝损伤中发挥关键作用。然而,MSCs 对这些标志物的调节作用在不同疾病中存在争议。BM-MSCs 可能在肝细胞癌中激活 IL6/STAT3 信号通路并促进细胞侵袭,但 BM-MSCs 对肝纤维化中 IL17A/IL6/STAT3 的免疫调节作用尚未完全阐明。在本研究中,我们评估了 BM-MSCs 调节细胞因子环境和信号转导物的能力,基于独特的炎症基因 Il17a 和 Il17f 及其受体 Il17rc,以及它们对 CCl4 诱导的大鼠肝纤维化中 IL6/STAT3 途径的影响。在诱导肝纤维化的组中单次给予 BM-MSCs,治疗后 6 周评估感兴趣的基因和蛋白。我们的结果显示 Il17a、Il17ra、il17f 和 Il17rc 基因的表达显著下调。相应地,BM-MSCs 给药后血清中 IL17、IL2 和 IL6 蛋白减少,肝组织中 IL17A 和 IL17RA 蛋白减少。有趣的是,BM-MSCs 下调 Stat3 mRNA 表达和 p-STAT3,而 Stat5a 基因下调和 p-STAT5 蛋白上调。此外,BM-MSCs 治疗后 P-SMAD3 和 TGFβR2 蛋白也下调。总之,我们认为 BM-MSCs 通过下调影响 IL6/STAT3 信号通路的 IL17A 可能在肝纤维化的治疗中发挥免疫调节作用。