Plasmin Triggers Cytokine Induction in Human Monocyte-Derived Macrophages

Publisher Website
Google Scholar
Abstract
Objective— 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. Methods and Results— 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-κB 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-α and IL-6. Inhibitors of JAK, p38, and NF-κB revealed that these signaling pathways are indispensable for the plasmin-mediated tumor necrosis factor-α and IL-6 induction. By contrast, the extracellular signal-regulated kinase 1/2 activation is essential only for the IL-6 e... Plasmin, but not catalytically blocked plasmin, induces cytokines such as TNF-α and IL-6 in human monocyte-derived macrophages. The plasmin-induced signaling utilizes the annexin A2 heterotetramer as receptor that triggers downstream signaling via JAK/STAT, Akt-dependent NF-κB activation, as well as ERK1/2 and the p38 MAPK, leading to proinflammatory gene induction.

This publication has 31 references indexed in Scilit: