Szelag Malgorzata, Piaszyk-Borychowska Anna, Plens-Galaska Martyna, Wesoly Joanna, Bluyssen Hans A R
Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
Oncotarget. 2016 Jul 26;7(30):48788-48812. doi: 10.18632/oncotarget.9195.
Key factors contributing to early stages of atherosclerosis and plaque development include the pro-inflammatory cytokines Interferon (IFN)α, IFNγ and Interleukin (IL)-6 and Toll-like receptor 4 (TLR4) stimuli. Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT) and Interferon Regulatory Factor (IRF) families. In particular, STAT1, 2 and 3; IRF1 and 8 have recently been recognized as prominent modulators of inflammation, especially in immune and vascular cells during atherosclerosis. Moreover, inflammation-mediated activation of these STATs and IRFs coordinates a platform for synergistic amplification leading to pro-atherogenic responses.Searches for STAT3-targeting compounds, exploring the pTyr-SH2 interaction area of STAT3, yielded many small molecules including natural products. Only a few inhibitors for other STATs, but none for IRFs, are described. Promising results for several STAT3 inhibitors in recent clinical trials predicts STAT3-inhibiting strategies may find their way to the clinic. However, many of these inhibitors do not seem STAT-specific, display toxicity and are not very potent. This illustrates the need for better models, and screening and validation tools for novel STAT and IRF inhibitors.This review presents a summary of these findings. It postulates STAT1, STAT2 and STAT3 and IRF1 and IRF8 as interesting therapeutic targets and targeted inhibition could be a potential treatment strategy in CVDs. In addition, it proposes a pipeline approach that combines comparative in silico docking of STAT-SH2 and IRF-DBD models with in vitro STAT and IRF activation inhibition validation, as a novel tool to screen multi-million compound libraries and identify specific inhibitors for STATs and IRFs.
促成动脉粥样硬化早期阶段和斑块形成的关键因素包括促炎细胞因子干扰素（IFN）α、IFNγ和白细胞介素（IL）-6以及Toll样受体4（TLR4）刺激。它们共同触发信号转导和转录激活因子（STAT）以及干扰素调节因子（IRF）家族的激活。特别是，STAT1、2和3；IRF1和8最近被认为是炎症的重要调节因子，尤其是在动脉粥样硬化过程中的免疫和血管细胞中。此外，炎症介导的这些STAT和IRF的激活协调了一个协同放大的平台，导致促动脉粥样硬化反应。针对STAT3靶向化合物的研究，探索STAT3的磷酸化酪氨酸- SH2相互作用区域，产生了许多小分子，包括天然产物。仅描述了几种针对其他STAT的抑制剂，但没有针对IRF的抑制剂。最近临床试验中几种STAT3抑制剂的 promising 结果表明，STAT3抑制策略可能会进入临床。然而，这些抑制剂中的许多似乎不是STAT特异性的，具有毒性且效力不强。这说明了需要更好的模型以及用于新型STAT和IRF抑制剂的筛选和验证工具。本综述总结了这些发现。它假设STAT1、STAT2和STAT3以及IRF1和IRF8是有趣的治疗靶点，靶向抑制可能是心血管疾病的一种潜在治疗策略。此外，它提出了一种流水线方法，将STAT - SH2和IRF - DBD模型的比较计算机对接与体外STAT和IRF激活抑制验证相结合，作为筛选数百万化合物库并鉴定STAT和IRF特异性抑制剂的新型工具。
