Plasmin triggers cytokine induction in human monocyte-derived macrophages.
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.


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.
Li
Qun
Q
Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Helmholtzstr. 20, D-89081 Ulm, Germany.
Laumonnier
Yves
Y
Syrovets
Tatiana
T
Simmet
Thomas
T
D021581:Active Transport, Cell Nucleus; D017306:Annexin A2 / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099248:S100 Calcium Binding Protein A10
D017306:Annexin A2; D048049:Extracellular Signal-Regulated MAP Kinases; D005341:Fibrinolysin; D015850:Interleukin-6; D053612:Janus Kinases; D016328:NF-kappa B; D051058:Oncogene Protein v-akt; D012333:RNA, Messenger; D009418:S100 Proteins; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099248:S100 Calcium Binding Protein A10; C472822:ANXA2 protein, human; C508600:IL6 protein, human