Toll-like receptor 5 tunes hepatic and pancreatic stellate cells activation.

IF 3.3 Q2 GASTROENTEROLOGY & HEPATOLOGY
Pietro Di Fazio, Sophia Mielke, Isabell T Böhm, Malte Buchholz, Sami Matrood, Detlef Schuppan, Thaddeus Wissniowski
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引用次数: 0

Abstract

Objective: Stellate cells are responsible for liver and pancreas fibrosis and strictly correlate with tumourigenesis. Although their activation is reversible, an exacerbated signalling triggers chronic fibrosis. Toll-like receptors (TLRs) modulate stellate cells transition. TLR5 transduces the signal deriving by the binding to bacterial flagellin from invading mobile bacteria.

Design: Human hepatic and pancreatic stellate cells were activated by the administration of transforming growth factor-beta (TGF-β). TLR5 was transiently knocked down by short-interference RNA transfection. Reverse Transcription-quantitativePCR and western blot were performed to analyse the transcript and protein level of TLR5 and the transition players. Fluorescence microscopy was performed to identify these targets in spheroids and in the sections of murine fibrotic liver.

Results: TGF-β-activated human hepatic and pancreatic stellate cells showed an increase of TLR5 expression. TLR5 knockdown blocked the activation of those stellate cells. Furthermore, TLR5 busted during murine liver fibrosis and co-localised with the inducible Collagen I. Flagellin suppressed TLR5, COL1A1 and ACTA2 expression after the administration of TGF-β. Instead, the antagonist of TLR5 did not block the effect of TGF-β. Wortmannin, a specific AKT inhibitor, induced TLR5 but not COL1A1 and ACTA2 transcript and protein level.

Conclusion: TGF-β-mediated activation of hepatic and pancreatic stellate cells requires the over-expression of TLR5. Instead, its autonomous signalling inhibits the activation of the stellate cells, thus prompting a signalling through different regulatory pathways.

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toll样受体5调节肝脏和胰腺星状细胞的激活。
目的:星状细胞与肝、胰腺纤维化有关,与肿瘤发生密切相关。尽管它们的激活是可逆的,但信号加剧会引发慢性纤维化。toll样受体(TLRs)调节星状细胞的转变。TLR5转导入侵的移动细菌与细菌鞭毛蛋白结合产生的信号。设计:通过转化生长因子-β (TGF-β)激活人肝脏和胰腺星状细胞。短干扰RNA转染可短暂敲低TLR5。采用逆转录-定量pcr和western blot方法分析TLR5及其过渡基因的转录和蛋白水平。荧光显微镜在小鼠纤维化肝的球体和切片中鉴定这些靶标。结果:TGF-β激活的人肝、胰星状细胞TLR5表达升高。TLR5敲低阻断了这些星状细胞的激活。此外,TLR5在小鼠肝纤维化过程中被破坏,并与诱导型胶原共定位。鞭毛蛋白在给药TGF-β后抑制TLR5、COL1A1和ACTA2的表达。相反,TLR5拮抗剂不能阻断TGF-β的作用。Wortmannin是一种特异性AKT抑制剂,可诱导TLR5,但不影响COL1A1和ACTA2的转录和蛋白水平。结论:TGF-β介导的肝、胰腺星状细胞活化需要TLR5过表达。相反,它的自主信号抑制星状细胞的激活,从而促使信号通过不同的调节途径。
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来源期刊
BMJ Open Gastroenterology
BMJ Open Gastroenterology GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
5.90
自引率
3.20%
发文量
68
审稿时长
2 weeks
期刊介绍: BMJ Open Gastroenterology is an online-only, peer-reviewed, open access gastroenterology journal, dedicated to publishing high-quality medical research from all disciplines and therapeutic areas of gastroenterology. It is the open access companion journal of Gut and is co-owned by the British Society of Gastroenterology. The journal publishes all research study types, from study protocols to phase I trials to meta-analyses, including small or specialist studies. Publishing procedures are built around continuous publication, publishing research online as soon as the article is ready.
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