Calcipotriol abrogates TGF-β1/pSmad3-mediated collagen 1 synthesis in pancreatic stellate cells by downregulating RUNX1

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY Toxicology and applied pharmacology Pub Date : 2024-08-28 DOI:10.1016/j.taap.2024.117078

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Abstract

RUNX1 with CBFβ functions as an activator or repressor of critical mediators regulating cellular function. The aims of this study were to clarify the role of RUNX1 on regulating TGF-β1-induced COL1 synthesis and the mechanism of calcipotriol (Cal) on antagonizing COL1 synthesis in PSCs. RT-qPCR and Western Blot for determining the mRNAs and proteins of RUNX1 and COL1A1/1A2 in rat PSC line (RP-2 cell). Luciferase activities driven by RUNX1 or COL1A1 or COL1A2 promoter, co-immunoprecipitation and immunoblotting for pSmad3/RUNX1 or CBFβ/RUNX1, and knockdown or upregulation of Smad3 and RUNX1 were used. RUNX1 production was regulated by TGF-β1/pSmad3 signaling pathway in RP-2 cells. RUNX1 formed a coactivator with CBFβ in TGF-β1-treated RP-2 cells to regulate the transcriptions of COL1A1/1A2 mRNAs under a fashion of pSmad3/RUNX1/CBFβ complex. However, Cal effectively abrogated the levels of COL1A1/1A2 transcripts in TGF-β1-treated RP-2 cells by downregulating RUNX1 production and hindering the formation of pSmad3/RUNX1/CBFβ complexes. This study suggests that RUNX1 may be a promising antifibrotic target for the treatment of chronic pancreatitis.

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钙泊三醇通过下调 RUNX1 可抑制 TGF-β1/pSmad3 介导的胰腺星状细胞胶原蛋白 1 的合成。

RUNX1与CBFβ共同作为调控细胞功能的关键介质的激活剂或抑制剂，以阐明RUNX1对TGF-β1诱导的COL1合成的调控作用以及钙泊三醇（Cal）拮抗PSCs中COL1合成的机制。通过 RT-qPCR 和 Western Blot 检测大鼠 PSC 株系（RP-2 细胞）中 RUNX1 和 COL1A1/1A2 的 mRNA 和蛋白。采用 RUNX1 或 COL1A1 或 COL1A2 启动子驱动荧光素酶活性、共免疫沉淀和免疫印迹检测 pSmad3/RUNX1 或 CBFβ/RUNX1，以及敲除或上调 Smad3 和 RUNX1。在RP-2细胞中，RUNX1的产生受TGF-β1/pSmad3信号通路的调控。在TGF-β1处理的RP-2细胞中，RUNX1与CBFβ形成共激活因子，在pSmad3/RUNX1/CBFβ复合物的作用下调控COL1A1/1A2 mRNA的转录。然而，Cal通过下调RUNX1的产生和阻碍pSmad3/RUNX1/CBFβ复合物的形成，有效地降低了TGF-β1处理的RP-2细胞中COL1A1/1A2转录本的水平。这项研究表明，RUNX1可能是治疗慢性胰腺炎的一个很有前景的抗纤维化靶点。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.