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The serine protease plasmin triggers proinflammatory gene induction in human macrophages – characterization of signaling pathways
Author(s) -
Li Qun,
Laumonnier Yves,
Syrovets Tatiana,
Simmet Thomas
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a278-a
Subject(s) - proinflammatory cytokine , plasmin , microbiology and biotechnology , signal transduction , mapk/erk pathway , phosphorylation , serine protease , chemistry , biology , inflammation , protease , biochemistry , immunology , enzyme
Contact activation in inflamed tissues induces generation of the serine protease plasmin. Here we demonstrate that plasmin activates macrophages, key regulators of the inflammatory response. The plasmin‐mediated stimulation of macrophages leads to cytokine induction, which depends on the proteolytic activity of the enzyme and proceeds via a receptor complex composed at least of annexin A2 and S100A10. Down‐regulation of the expression of either annexin A2 or S100A10 by antisense oligodeoxynucleotides abolished the plasmin‐induced expression of proinflammatory cytokines, whereas that by the positive control LPS remained unaffected. Further downstream, plasmin activates JAK signaling resulting in STAT3 activation, Akt‐dependent NF‐κB activation, and phosphorylation of the p38 MAPK and ERK1/2. By activation of these signaling pathways plasmin induces the expression and release of the proinflammatory cytokines TNF‐α and IL‐ 6. Pharmacological inhibitors of JAK, p38 and NF‐κB revealed that these signaling pathways are indispensable for the plasmin‐mediated induction of the TNF‐α and IL‐6 genes. By contrast, activation of the ERK1/2 appears to be essential only for the expression of the IL‐6 gene. In conclusion, our data show that the serine protease plasmin is a potent proinflammatory activator of human macrophages acting via the annexin A2 heterotetramer and multiple downstream signaling pathways. Thus, plasmin generated at the sites of inflammation will profoundly affect macrophage function.