Gli2 Mediated Activation of Hedgehog Signaling Attenuates Acute Pancreatitis via Balancing Inflammatory Cytokines in Mice
Gli2 Mediated Activation of Hedgehog Signaling Attenuates Acute Pancreatitis via Balancing Inflammatory Cytokines in Mice
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DOI：
10.1159/000491668
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Zhou, Xiangyu
中科院分区：
文献类型：
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作者：
Liu, Zhiqiang;Lai, Kun;Zhou, Xiangyu
背景/目的：炎症反应是急性胰腺炎（AP）病理进展的决定因素。以往的研究表明，刺猬（Hh）信号的激活是雨蛙素诱导AP的一个显着变化。然而，Hh信号传导和炎症之间的关系在很大程度上是模糊的。研究方法：采用雨蛙肽诱导AP小鼠模型，采用组织学染色和血清酶学检测方法评价AR的建立，Western blot检测AR蛋白水平、凋亡蛋白裂解和NE-κ B信号通路的激活情况。应用细胞因子芯片筛选炎性细胞因子，实时荧光定量PCR检测靶细胞因子的转录表达，酶联免疫吸附试验检测血清中靶细胞因子的水平。结果：Hh信号通路中的关键转录因子Gli 2在胰腺等组织中表达上调，是胰腺组织局部炎症和多器官系统性炎症反应的特征。炎症性NF-κ B通路是激活Hh信号传导所必需的，因为通过吡咯烷二硫代氨基甲酸酯阻断NF-κ B通路损害了Gli 2上调。Gli 2表达的调控相应地改变了NE-κ B通路的激活，以及雨蛙素诱导的AR中的细胞凋亡。此外，Gli 2上调改变了小鼠胰腺腺泡细胞中的细胞因子表达谱，主要是降低促炎细胞因子白细胞介素（1）-6、干扰素-γ和FasL。抗炎细胞因子IL-10被Gli 2过表达上调。Gli特异性抑制剂GANT 61对Gli 2的阻断加重了小鼠的AP，并改变了炎症细胞因子的平衡。结论：这项研究表明，在AP发展过程中，Hh激活是炎症反应的负反馈，限制了胰腺和其他组织的炎症损伤。因此，Hh信号的操纵应该有助于限制炎症和减轻AP损伤。(C)2018作者由S.发布Karger AG，巴塞尔。
Background/Aims: Inflammatory response is a determinant in the pathological progression of acute pancreatitis (AP). Previous studies have shown that the activation of hedgehog (Hh) signaling is a remarkable change in caerulein-induced AP. However, the relationship between Hh signaling and inflammation is largely ambiguous. Methods: The AP mouse model was induced by injection of cerulein, and histological staining and serum enzymology assays were used to evaluate the establishment of AR Western blot assay was used to determine the protein levels, cleavage of apoptotic proteins, and activation of the NE-kappa B signaling pathway. Cytokine array was used to screen inflammatory cytokines, and target cytokines' transcriptional expression and serum levels were examined by real-time PCR and enzyme-linked immunosorbent assay, respectively. Results:The key transcriptional factor in Hh signaling, Gli2, was upregulated in the pancreas and other tissues during the process of AP, and it seems to be a characteristic feature of local inflammation in pancreatic tissue and systemic inflammatory response in multiple organs. The inflammatory NF-kappa B pathway is required for the activation of Hh signaling, as blockade of the NF-kappa B pathway by pyrrolidine dithiocarbamate impaired the Gli2 upregulation. Manipulation of Gli2 expression altered the activation of the NE-kappa B pathway correspondingly, as well as the cell apoptosis in cerulein-induced AR Moreover, Gli2 upregulation changed the cytokine expression profile in mouse pancreatic acinar cells, mainly decreasing the pro-inflammatory cytokines interleukin (1)-6, interferon-gamma, and FasL. The anti-inflammatory cytokine IL-10 was upregulated by Gli2 overexpression. Interdiction of Gli2 by the Gli-specific inhibitor GANT61 exacerbated AP in mice and altered the balance of inflammatory cytokines. Conclusions: This study indicates that Hh activation during AP development is a negative feedback of the inflammatory response, restricting inflammatory injury to the pancreas and other tissues. Thus, manipulation of Hh signaling should shed light on limiting inflammation and alleviating AP damage. (C) 2018 The Author(s) Published by S. Karger AG, Basel.