IL-28A/IL-10Rβ 轴通过调节 HSP70-1 的表达，通过 eNOS/AKT 信号和 AP-1/NF-κB/MMP-2 网络促进血管生成。

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research Pub Date : 2024-08-09 DOI:10.1016/j.jare.2024.08.013

Jun-Hui Song , Byungdoo Hwang , Sung Lyea Park , Hoon Kim , Soontag Jung , Changsun Choi , Hwan Myung Lee , Seok-Joong Yun , Yung Hyun Choi , Eun-Jong Cha , Cam Patterson , Wun-Jae Kim , Sung-Kwon Moon

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引用次数: 0

摘要

导言：血管生成在肿瘤进展和炎症性疾病的发展中起着重要作用。IL-28A在血管生成中的作用及其精确调控机制仍很少被阐明：我们报告了IL-28A在生理性血管生成中的新型调控作用。研究旨在阐明IL-28A介导的血管生成的调控机制，并确定与IL-28A诱导的血管生成反应相关的关键基因：为了了解IL-28A对血管生成的影响，应用HUVECs进行增殖、迁移、侵袭、管形成、免疫印迹和EMSA。通过 NGS 分析了 IL-28A 处理后 HUVECs 的基因表达变化。利用 PCR 和 siRNA 敲除技术评估了 HSP70-1 和 IL-10Rβ 在 IL-28A 诱导的血管生成反应中的功能作用。通过主动脉环体外试验、Matrigel塞体内试验以及使用HSP70-1基因敲除和转基因小鼠模型的免疫化学方法进行了动物实验。在后肢缺血模型中证实了IL-28A对血管生成的功效：结果：HUVECs的自分泌/旁分泌作用调节了IL-28A蛋白的表达。外源性 IL-28A 通过 eNOS/AKT 和 ERK1/2 信号传导增加了 HUVECs 的增殖。IL-28A通过诱导AP-1/NF-κB/MMP-2网络促进了HUVECs的迁移、侵袭和毛细血管管的形成，这与eNOS/AKT和ERK1/2信号有关。主动脉环和 Matrigel 栓实验证实了 IL-28A 诱导血管生成潜能的功效。利用生物信息学方法确定了HSP70-1是IL-28A介导的血管生成效应基因。敲除HSP70-1可消除IL-28A处理的HUVECs的血管生成反应和eNOS/AKT信号传导。在HSP70-1缺陷小鼠和HSP70-1转基因小鼠中，IL-28A诱导的微血管发芽形成得到了验证。注射 IL-28A 加快了后肢缺血小鼠的血流恢复。最后，IL-10Rβ基因的消减阻碍了IL-28A刺激HUVECs的血管生成反应和eNOS/AKT信号转导：结论：HSP70-1通过eNOS/AKT信号和AP-1/NF-κB/MMP-2网络驱动IL-28A/IL-10Rβ轴促进血管生成。

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IL-28A/IL-10Rβ axis promotes angiogenesis via eNOS/AKT signaling and AP-1/NF-κB/MMP-2 network by regulating HSP70-1 expression

Introduction

Angiogenesis plays a significant role in the development of tumor progression and inflammatory diseases. The role of IL-28A in angiogenesis and its precise regulatory mechanisms remain rarely elucidated.

Objectives

We report the novel regulatory role of IL-28A in physiological angiogenesis. The study aimed to elucidate the regulatory mechanisms involved in IL-28A-mediated angiogenesis and identify key genes associated with IL-28A-induced angiogenic responses.

Methods

To know the effect of IL-28A on angiogenesis, HUVECs were applied to perform proliferation, migration, invasion, tube formation, immunoblot, and EMSA. Gene expression changes in HUVECs following IL-28A treatment were analyzed by NGS. The functional role of HSP70-1 and IL-10Rβ in IL-28A-induced angiogenic responses was evaluated using PCR and siRNA knockdown. Animal studies were conducted by aortic ring ex vivo assays, Matrigel plug in vivo assays, and immunochemistry using HSP70-1 knockout and transgenic mice models. The efficacy of IL-28A in angiogenesis was confirmed in a hind-limb ischemia model.

Results

Autocrine/paracrine actions in HUVECs regulated IL-28A protein expression. Exogenous IL-28A increased the proliferation of HUVECs via eNOS/AKT and ERK1/2 signaling. IL-28A treatment promoted migration, invasion, and capillary tube formation of HUVECs through induction of the AP-1/NF-κB/MMP-2 network, which was associated with eNOS/AKT and ERK1/2 signaling. The efficacy of IL-28A-induced angiogenic potential was confirmed by aortic ring and Matrigel plug assay. HSP70-1 was identified as an IL-28A-mediated angiogenic effector gene using bioinformatics. Knockdown of HSP70-1 abolished angiogenic responses and eNOS/AKT signaling in IL-28A-treated HUVECs. IL-28A-induced microvessel sprouting formation was testified in HSP70-1-deficient and HSP70-1 transgenic mice. Flow recovery in hind-limb ischemia mice was accelerated by IL-28A injection. Finally, ablation of the IL-10Rβ gene impeded the angiogenic responses and eNOS/AKT signaling stimulated by IL-28A in HUVECs.

Conclusion

HSP70-1 drives the progression of angiogenesis by the IL-28A/IL-10Rβ axis via eNOS/AKT signaling and the AP-1/NF-κB/MMP-2 network.

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来源期刊

Journal of Advanced Research Multidisciplinary-Multidisciplinary

CiteScore

21.60

自引率

0.90%

发文量

280

审稿时长

12 weeks

期刊介绍： Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences. The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.