Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, University of Adam Mickiewicz, Poznan, Poland.
Cytokine Growth Factor Rev. 2011 Aug;22(4):211-9. doi: 10.1016/j.cytogfr.2011.06.003. Epub 2011 Jul 12.
Inflammation participates importantly in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of atherosclerosis. Recruitment of blood leukocytes to the injured vascular endothelium characterizes the initiation and progression of atherosclerosis and involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity. The pro-inflammatory cytokine, interferon (IFN)-γ derived from T cells, is vital for both innate and adaptive immunity and is also expressed at high levels in atherosclerotic lesions. As such IFN-γ plays a crucial role in the pathology of atherosclerosis through activation of signal transducer and activator of transcription (STAT) 1. Toll-like receptors (TLRs) are innate immune pattern recognition receptors (PRRs) expressed on a variety of cells, and thus initiate and sustain the inflammatory response in atherosclerosis. More recent studies have revealed that STAT1 is involved in the signaling events mediated by TLR4, leading to increased expression of several pro-inflammatory and pro-atherogenic mediators. By upregulating members of the Suppressors Of Cytokine Signaling (SOCS) family that regulate cellular responsiveness to immune signals, IFNγ and TLR4-activated pathways have also shown to inhibit IL-6 STAT3-dependent anti-inflammatory signaling and potentially shift IL-6 to a STAT1 activating pro-inflammatory cytokine. Consequently, STAT1 has been identified as a point of convergence for the cross-talk between the pro-atherogenic IFN-γ, TLR4 and IL-6 activated pathways in immune as well as vascular cells, as such amplifying pro-inflammatory signals. This results in augmented smooth muscle cell (SMC) and leukocyte migration, leukocyte to endothelial cell (EC) adhesion and foam cell formation, and could encompass a novel mechanism involved in the initiation and progression of atherosclerosis. Therefore, application of small inhibitory compounds that specifically interact with the SH2-phosphotyrosine pocket of STAT1, proposed here as a novel working mechanism for the known STAT1 inhibitor fludarabine, could be a promising tool in the development of a therapeutical strategy for atherosclerosis.
炎症在宿主防御感染因子和损伤方面起着重要作用，但它也促成了动脉粥样硬化的病理生理学。血液白细胞募集到受损的血管内皮是动脉粥样硬化起始和进展的特征，涉及许多炎症介质，这些介质由固有免疫和适应性免疫的细胞调节。源自 T 细胞的促炎细胞因子干扰素 (IFN)-γ 对固有免疫和适应性免疫至关重要，在动脉粥样硬化病变中也高表达。因此，IFN-γ 通过激活信号转导和转录激活因子 (STAT)1 在动脉粥样硬化的病理学中发挥关键作用。Toll 样受体 (TLR) 是固有免疫模式识别受体 (PRR)，在多种细胞上表达，因此在动脉粥样硬化中启动和维持炎症反应。最近的研究表明，STAT1 参与 TLR4 介导的信号事件，导致几种促炎和促动脉粥样硬化介质的表达增加。通过上调调节细胞对免疫信号反应性的细胞因子信号转导抑制因子 (SOCS) 家族成员，IFNγ 和 TLR4 激活途径也显示出抑制 IL-6 STAT3 依赖性抗炎信号的作用，并可能使 IL-6 向 STAT1 激活的促炎细胞因子转变。因此，STAT1 已被确定为促动脉粥样硬化 IFN-γ、TLR4 和 IL-6 激活途径在免疫和血管细胞之间交叉对话的交汇点，从而放大促炎信号。这导致平滑肌细胞 (SMC) 和白细胞迁移、白细胞与内皮细胞 (EC) 黏附和泡沫细胞形成增加，并可能包含一个涉及动脉粥样硬化起始和进展的新机制。因此，应用专门与 STAT1 的 SH2-磷酸酪氨酸口袋相互作用的小分子抑制剂，如本文提出的已知 STAT1 抑制剂氟达拉滨的一种新作用机制，可能成为动脉粥样硬化治疗策略开发的有前途的工具。
