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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1383.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Plasmin Triggers Cytokine Induction in Human Monocyte-Derived Macrophages

Qun Li; Yves Laumonnier; Tatiana Syrovets; Thomas Simmet

From the Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Germany.

Correspondence to Thomas Simmet, Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Helmholtzstr. 20, D-89081 Ulm, Germany. E-mail thomas.simmet{at}uni-ulm.de

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-B 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- and IL-6. Inhibitors of JAK, p38, and NF-B revealed that these signaling pathways are indispensable for the plasmin-mediated tumor necrosis factor- 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.

Conclusions— Plasmin generated at sites of inflammation such as atherosclerotic lesions will trigger cytokine expression in human macrophages.

Plasmin, but not catalytically blocked plasmin, induces cytokines such as TNF- 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-B activation, as well as ERK1/2 and the p38 MAPK, leading to proinflammatory gene induction.

Key Words: IL-6 • macrophage • plasmin • signaling • tumor necrosis factor-

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