Plasmin triggers cytokine induction in human monocyte-derived macrophages.

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-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.

CONCLUSIONS:

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

• Authors: Qun Li, Yves Laumonnier, Tatiana Syrovets, Thomas Simmet
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 27 Issue 6 Pg. 1383-9 (Jun 2007) ISSN: 1524-4636 [Electronic] United States
• PMID: 17413040 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ANXA2 protein, human
• Annexin A2
• IL6 protein, human
• Interleukin-6
• NF-kappa B
• RNA, Messenger
• S100 Proteins
• S100 calcium binding protein A10
• STAT Transcription Factors
• Tumor Necrosis Factor-alpha
• Janus Kinases
• Oncogene Protein v-akt
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• Fibrinolysin

Topics

• Active Transport, Cell Nucleus
• Annexin A2 (metabolism)
• Atherosclerosis (metabolism)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibrinolysin (metabolism, pharmacology)
• Humans
• Inflammation (metabolism)
• Interleukin-6 (genetics, metabolism)
• Janus Kinases (metabolism)
• Macrophage Activation (drug effects)
• Macrophages (drug effects, metabolism)
• NF-kappa B (metabolism)
• Oncogene Protein v-akt (metabolism)
• Phosphorylation
• RNA, Messenger (metabolism)
• S100 Proteins (metabolism)
• STAT Transcription Factors (metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (metabolism)