Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin 300071, China.
Department of Internal Medicine, Wangdingdi Hospital, Tianjin 300071, China.
World J Gastroenterol. 2022 Oct 14;28(38):5573-5588. doi: 10.3748/wjg.v28.i38.5573.
Ischemia-reperfusion injury (IRI) is a major risk associated with liver surgery and transplantation, and its pathological mechanism is complex. Interleukin-1 receptor antagonist (IL-1ra) can protect the liver from IRI. However, the regulatory mechanism of IL-1ra expression is still unclear.
To identify the mechanism that could protect the liver in the early stage of IRI.
To screen the key genes in hepatic IRI, we performed RNA sequencing and gene enrichment analysis on liver tissue from mice with hepatic IRI. Subsequently, we verified the expression and effect of IL-1ra in hepatic IRI. We also used promoter mutagenesis and chromatin immunoprecipitation assay to search for the transcriptional regulatory sites of hypoxia-inducible factor (HIF)-1α. Finally, to explore the protective mechanism of ischemic preconditioning (IP), we examined the expression of HIF-1α and IL-1ra after IP.
We identified IL-1ra as a key regulator in hepatic IRI. The expression of IL-1ra was significantly upregulated after hepatic IRI both and . Furthermore, we found that HIF-1α regulated transcription in response to hypoxia. Increased HIF-1α accumulation promoted IL-1ra expression, whereas inhibition of HIF-1α exhibited the opposite effect. We also confirmed a predominant role for hypoxia response element in the regulation of transcription by HIF-1α activation. Of note, we demonstrated that IP protects against hepatic IRI by inducing IL-1ra expression, which is mediated through HIF-1α.
We demonstrated that ischemia or hypoxia leads to increased expression of IL-1ra through HIF-1α. Importantly, IP protects the liver from IRI the HIF-1α-IL-1ra pathway.
缺血再灌注损伤（IRI）是与肝外科和肝移植相关的主要风险因素，其病理机制复杂。白介素-1 受体拮抗剂（IL-1ra）可保护肝脏免受 IRI 损伤。然而，IL-1ra 表达的调控机制尚不清楚。
确定在 IRI 早期阶段可保护肝脏的机制。
为筛选肝 IRI 中的关键基因，我们对肝 IRI 小鼠的肝组织进行了 RNA 测序和基因富集分析。随后，我们验证了 IL-1ra 在肝 IRI 中的表达和作用。我们还使用启动子诱变和染色质免疫沉淀实验来寻找缺氧诱导因子（HIF）-1α的转录调控位点。最后，为探讨缺血预处理（IP）的保护机制，我们检测了 IP 后 HIF-1α 和 IL-1ra 的表达。
我们发现 IL-1ra 是肝 IRI 的关键调节因子。肝 IRI 后 和 时，IL-1ra 的表达均显著上调。此外，我们发现 HIF-1α 可在缺氧时调节 的转录。HIF-1α 积累增加可促进 IL-1ra 表达，而抑制 HIF-1α 则呈现相反效果。我们还证实，缺氧反应元件在 HIF-1α 激活调控 的转录中起主要作用。值得注意的是，我们证实 IP 通过诱导 IL-1ra 表达来保护肝脏免受 IRI 损伤，而 IL-1ra 的表达是通过 HIF-1α 介导的。
我们证明，缺血或缺氧会通过 HIF-1α 导致 IL-1ra 的表达增加。重要的是，IP 通过 HIF-1α-IL-1ra 通路来保护肝脏免受 IRI。
