Leukotriene formation by peripheral monocytes in contact-activated human blood

Weide, Ingo; Simmet, Thomas

doi:10.1016/0049-3848(93)90093-4

Cited by 9 publications

(8 citation statements)

References 11 publications

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“…Further experiments with isolated cells confirmed that plasmin-mediated activation of the 5-lipoxygenase pathway in monocytes but not in neutrophils, which similarly possess all the enzymes necessary to generate leukotrienes via the 5-lipoxygenase pathway [116]. Evidence for the pathophysiological relevance of these findings came from experiments showing selective activation of leukotriene biosynthesis both in clamped umbilical vessel segments still filled with autologous blood immediately after delivery as well as in fresh human thrombus specimens obtained by therapeutic thrombectomy [113].…”

Section: Plasmin-mediated Biosynthesis Of Lipid Mediators By Monocytesmentioning

confidence: 75%

“…Thrombin generated by the coagulation cascade however, stimulates only the cyclooxygenase pathway and, thus, the synthesis of prostanoids, but had no effect on the 5-lipoxygenase pathway [112]. Unexpectedly, supplementation experiments with autologous cells showed that contact-mediated activation of the 5-lipoxygenase pathway in coagulated human whole blood takes place in monocytes, but not in neutrophils, suggesting a cell-specific activation mechanism [113]. Monocyte activation in contact-stimulated blood could be inhibited by different lysine analogues, a 2 -antiplasmin and aprotinin, and it was amplified by the plasminogen activators urokinase and streptokinase.…”

Section: Plasmin-mediated Biosynthesis Of Lipid Mediators By Monocytesmentioning

confidence: 90%

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Novel aspects and new roles for the serine protease plasmin

Syrovets

Simmet

2004

Cellular and Molecular Life Sciences (CMLS)

137

149

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The serine protease plasmin is distributed throughout the human body in the form of the zymogen plasminogen. The plasminogen activation system is mostly recognized for its fibrinolytic activity but is also upregulated in chronic inflammatory diseases, including atherosclerosis and arthritis. Plasmin can bind to a variety of cells, including monocytes, through low-affinity binding sites and triggers aggregation of neutrophils, platelet degranulation and arachidonate release from endothelial cells. In monocytes, plasmin elicits full-scale proinflammatory activation, including lipid mediator release, chemotaxis and cytokine expression, as well as induction of other proinflammatory genes. The effects of plasmin are specific, require the active catalytic center and can be antagonized by lysine analogues, implying binding of the plasmin molecule to the cell membrane through its lysine binding sites. In view of the upregulation of the fibrinolytic genes in chronic inflammatory diseases, cell activation by plasmin is likely to play a major pathophysiological role, a view that is further supported by data from transgenic mice.

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Section: Plasmin-mediated Biosynthesis Of Lipid Mediators By Monocytesmentioning

confidence: 75%

Section: Plasmin-mediated Biosynthesis Of Lipid Mediators By Monocytesmentioning

confidence: 90%

Novel aspects and new roles for the serine protease plasmin

Syrovets

Simmet

2004

Cellular and Molecular Life Sciences (CMLS)

137

149

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“…Con-sistent with its activation of p38 MAPK, plasmin induced MCP-1 release from primary monocytes, similar to that triggered by LPS. Local contact activation leading to plasmin generation occurs in inflammatory reactions (7,66). Therefore, plasmin-induced expression of MCP-1 could have important implications for the recruitment of immunocompetent cells, such as additional monocytes, but also T lymphocytes and NK cells (20 -22).…”

Section: Discussionmentioning

confidence: 99%

The Serine Protease Plasmin Triggers Expression of MCP-1 and CD40 in Human Primary Monocytes via Activation of p38 MAPK and Janus Kinase (JAK)/STAT Signaling Pathways

Burýšek

Syrovets

Simmet

2002

Journal of Biological Chemistry

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151

148

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The mechanism of proinflammatory activation of human monocytes by plasmin is unknown. Here we demonstrate that in human primary monocytes, plasmin stimulates mitogen-activated protein kinase (MAPK) signaling via phosphorylation of MAPK kinase 3/6 (MKK3/6) and p38 MAPK that triggers subsequent DNA binding of transcription factor activator protein-1 (AP-1). The AP-1 complex contained phosphorylated c-Jun and ATF2, and its DNA binding activity was blocked by the p38 MAPK inhibitor SB203580. In addition, plasmin elicits Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, as detected by phosphorylation of JAK1 tyrosine kinase and STAT1 and STAT3 proteins. Plasmin-induced DNA binding of STAT1 and STAT3 was blocked by SB203580 and AG490, inhibitors of p38 MAPK and JAK, respectively, but not by U0126, an inhibitor of MKK1/2. DNA binding of NF-B remained unaffected by any of these inhibitors. The plasmin-induced signaling led to expression of monocyte chemoattractant protein-1 (MCP-1) and CD40, which required activation of both p38 MAPK and JAK/ STAT signaling pathways. Additionally, signaling through both p38 MAPK and JAK is involved in the plasmin-mediated monocyte migration, whereas the formylmethionylleucylphenylalanine-induced chemotaxis remained unaffected. Taken together, our data demonstrate a novel function of the serine protease plasmin in a proinflammatory signaling network.

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“…TX generation in clotting human blood is mainly taking place in platelets via the cyclooxygenase pathway of arachidonic acid metabolism (5). LT formation, on the other hand, occurs via the 5-lipoxygenase pathway residing in polymorphonuclear leukocytes and peripheral monocytes (PM), but not in lymphocytes (6). By supplementation experiments it could be shown that during contact activation of human whole blood the 5-lipoxygenase pathway was Correspondence to: Dr. Thomas Simmet, Department of Pharmacology and Toxicology, Ruhr University, PO Box 102148, D-44721 Bochum, Germany -FAX Number: +49 234 7094 521 selectively stimulated in PM but not in polymorphonuclear neutrophils (PMN) (6).…”

Section: Introductionmentioning

confidence: 99%

Plasmin Is a Specific Stimulus of the 5-Lipoxygenase Pathway of Human Peripheral Monocytes

et al. 1996

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SummaryThe objective of this study was to characterize the plasmin-induced stimulation of leukotriene (LT) B4 biosynthesis in human peripheral monocytes (PM). Plasmin up to 175 × 10-3 CTA U/ml triggers a concentration-dependent release of 5-lipoxygenase-derived LTB4 while release of the cyclooxygenase products thromboxane (TX) B2 and prostaglandin (PG) E2 remained unaffected. The stimulatory effect appeared to be specific in as much as 1) it was found in PM, but not in polymorphonuclear neutrophils (PMN), 2) it requires the lysine binding sites of plasmin molecule since it was inhibited by the lysine analogues 6-aminohexanoic acid (6-AHA) and trans-4(aminometh-yl)cyclohexane-l-carboxylic acid (t-AMCA), 3) the intact catalytic center of plasmin is required since neither plasminogen nor catalytic center-blocked plasmin share the stimulatory effect of active plasmin, 4) other serine proteases such as a-chymotrypsin, human neutrophil elastase and cathepsin G did not stimulate release of detectable amounts of LTB4 from PM. In addition, catalytic center-blocked plasmin antagonized the stimulatory effect of active plasmin. Plasmin-mediated monocyte activation apparently proceeds via a pertussis toxin-sensitive G protein. Plasmin did not increase inositol (1,4,5) trisphosphate levels, but a time- and concentration-dependent stimulation of cyclic GMP formation was observed. The data show that plasmin is a specific stimulus for human peripheral monocytes. Plasmin may be an important link between the coagulation cascade and inflammatory reactions.

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Leukotriene formation by peripheral monocytes in contact-activated human blood

Cited by 9 publications

References 11 publications

Novel aspects and new roles for the serine protease plasmin

Novel aspects and new roles for the serine protease plasmin

The Serine Protease Plasmin Triggers Expression of MCP-1 and CD40 in Human Primary Monocytes via Activation of p38 MAPK and Janus Kinase (JAK)/STAT Signaling Pathways

Plasmin Is a Specific Stimulus of the 5-Lipoxygenase Pathway of Human Peripheral Monocytes

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