Li Qun, Laumonnier Yves, Syrovets Tatiana, Simmet Thomas
Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Helmholtzstr. 20, D-89081 Ulm, Germany.
Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1383-9. doi: 10.1161/ATVBAHA.107.142901. Epub 2007 Apr 5.
Fibrinolytic activity is upregulated in atherosclerotic lesions, yet little is known about the role of plasmin in macrophage function. We postulated a direct effect of plasmin on human monocyte-derived macrophages.
Plasmin activates macrophages via the annexin A2 heterotetramer composed of annexin A2 and S100A10 with subsequent stimulation of Janus kinase JAK1/TYK2 signaling. JAK1/TYK2 leads to STAT3 activation, Akt-dependent NF-kappaB activation, and phosphorylation of extracellular signal-regulated kinase 1/2 and mitogen-activated kinase p38. These signaling pathways trigger nuclear translocation of STAT3 and p65 transcription factors and the induction of the proinflammatory cytokines tumor necrosis factor-alpha and IL-6. Inhibitors of JAK, p38, and NF-kappaB revealed that these signaling pathways are indispensable for the plasmin-mediated tumor necrosis factor-alpha and IL-6 induction. By contrast, the extracellular signal-regulated kinase 1/2 activation is essential only for the IL-6 expression. The activation clearly depends on the proteolytic activity of plasmin, which cleaves the A2 subunit of the annexin A2 heterotetramer. Downregulation of each of the receptor subunits by antisense oligodeoxynucleotides abolished the plasmin-induced expression of proinflammatory cytokines stressing the crucial role the annexin A2 heterotetramer.
Plasmin generated at sites of inflammation such as atherosclerotic lesions will trigger cytokine expression in human macrophages.
纤溶活性在动脉粥样硬化病变中上调，但关于纤溶酶在巨噬细胞功能中的作用知之甚少。我们推测纤溶酶对人单核细胞衍生的巨噬细胞有直接作用。
纤溶酶通过由膜联蛋白A2和S100A10组成的膜联蛋白A2异源四聚体激活巨噬细胞，随后刺激Janus激酶JAK1/TYK2信号通路。JAK1/TYK2导致信号转导和转录激活因子3（STAT3）活化、Akt依赖的核因子κB（NF-κB）活化以及细胞外信号调节激酶1/2（ERK1/2）和丝裂原活化蛋白激酶p38（p38 MAPK）的磷酸化。这些信号通路触发STAT3和p65转录因子的核转位以及促炎细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的诱导。JAK、p38和NF-κB的抑制剂表明，这些信号通路对于纤溶酶介导的TNF-α和IL-6诱导是不可或缺的。相比之下，ERK1/2活化仅对IL-6表达至关重要。这种活化明显依赖于纤溶酶的蛋白水解活性，纤溶酶可切割膜联蛋白A2异源四聚体的A2亚基。通过反义寡脱氧核苷酸下调每个受体亚基可消除纤溶酶诱导的促炎细胞因子表达，强调了膜联蛋白A2异源四聚体的关键作用。
在动脉粥样硬化病变等炎症部位产生的纤溶酶将触发人巨噬细胞中的细胞因子表达。
