Gupta Kamlesh K, Xu Zhi, Castellino Francis J, Ploplis Victoria A
W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, 46556, United States.
W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, 46556, United States; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, United States.
Biochem Biophys Res Commun. 2016 Aug 26;477(3):503-8. doi: 10.1016/j.bbrc.2016.06.065. Epub 2016 Jun 15.
While inflammation is often associated with increased Plasminogen Activator Inhibitor-1 (PAI-1), the functional consequences of PAI-1 in inflammation have yet to be fully determined. The aim of this study was to establish the in vivo relevance of PAI-1 in inflammation. A mouse model of systemic inflammation was employed in wild-type (WT) and PAI-1 deficient (PAI-1(-/-)) mice. Mice survival, macrophage infiltration into the lungs, and plasma levels of pro-inflammatory cytokines were assessed after lipopolysaccharide (LPS) infusion. In vitro experiments were conducted to examine changes in LPS-induced inflammatory responses after PAI-1 exposure. PAI-1 was shown to regulate inflammation, in vivo, and affect macrophage infiltration into lungs. Further, PAI-1 activated macrophages, and increased pro-inflammatory cytokines at both the mRNA and protein levels in these cells. The effect of PAI-1 on macrophage activation was dose-dependent and LPS-independent. Proteolytic inhibitory activity and Lipoprotein Receptor-related Protein (LRP) and vitronectin (VN) binding functions, were not involved in PAI-1-mediated activation of macrophages. However, the effect of PAI-1 on macrophage activation was partially blocked by a TLR4 neutralizing antibody. Furthermore, PAI-1-induced Tumor Necrosis Factor-alpha (TNF-α) and Macrophage Inflammatory Protein-2 (MIP-2) expression was reduced in TLR4(-/-) macrophages compared to WT macrophages. These results demonstrate that PAI-1 is involved in the regulation of host inflammatory responses through Toll-like Receptor-4 (TLR4)-mediated macrophage activation.
虽然炎症通常与纤溶酶原激活物抑制剂-1（PAI-1）水平升高有关，但PAI-1在炎症中的功能后果尚未完全确定。本研究的目的是确定PAI-1在炎症中的体内相关性。在野生型（WT）和PAI-1缺陷型（PAI-1(-/-)）小鼠中采用全身炎症小鼠模型。在注射脂多糖（LPS）后评估小鼠存活率、巨噬细胞向肺部的浸润以及促炎细胞因子的血浆水平。进行体外实验以检查PAI-1暴露后LPS诱导的炎症反应的变化。结果表明，PAI-1在体内调节炎症，并影响巨噬细胞向肺部的浸润。此外，PAI-1激活巨噬细胞，并在这些细胞的mRNA和蛋白质水平上增加促炎细胞因子。PAI-1对巨噬细胞激活的作用是剂量依赖性的且不依赖于LPS。蛋白水解抑制活性以及脂蛋白受体相关蛋白（LRP）和玻连蛋白（VN）结合功能均不参与PAI-1介导的巨噬细胞激活。然而，PAI-1对巨噬细胞激活的作用被TLR4中和抗体部分阻断。此外，与WT巨噬细胞相比，PAI-1诱导的肿瘤坏死因子-α（TNF-α）和巨噬细胞炎性蛋白-2（MIP-2）在TLR4(-/-)巨噬细胞中的表达降低。这些结果表明，PAI-1通过Toll样受体-4（TLR4）介导的巨噬细胞激活参与宿主炎症反应的调节。
