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

Abstract

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.

Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus–induced arthritis

“…Plasmin(ogen) is not essential for inflammatory cell migration, but it seems to play a critical role in normal functioning, especially bacterial clearance and necrotic tissue removal. In vitro studies have shown that plasmin is a potent and selective stimulus for human peripheral monocytes (33,34). For instance, plasmin has been shown to release macrophage-derived IL-1 and to activate transforming growth factor ␤ (35).…”

Elevated levels of leukotriene B4 and leukotriene E4 in bronchoalveolar lavage fluid from patients with scleroderma lung disease

“…We recently showed that 5-LOX is overexpressed in the skin of patients with SSc compared with the skin of normal controls, and that skin fibroblasts from patients with SSc generate more LTB 4 than do those from normal subjects (37). There are also several hypothetical stimuli that have been shown to contribute to the pathogenesis of SSc and might be responsible for 5-LOX stimulation in vivo, including transforming growth factor ␤ and the coagulation/fibrinolysis cascade (38,39).…”

Plasmin Induces In Vivo Monocyte Recruitment through Protease-Activated Receptor-1–, MEK/ERK-, and CCR2-Mediated Signaling

“…It has been shown that Pla is able to activate monocytes and trigger the release of lipid mediators, cytokines, and chemokines in vitro (16,18,19). Owing to the importance of cytokines and chemokines to cell migration, we investigated pleural levels of the cytokines IL-1b, IL-6, and TNF-a and the chemokines MCP-1 (CCL2), KC/CXCL1, and MIP-2 (CXCL2) during Pla-induced mononuclear traffic into the pleural cavity.…”

“…Plasmin stimulates expression of cytokines (TNF-a, IL-6, IL-1a/b, CD40), chemokines (MCP-1/CCL2), tissue factors, and the release of lipid mediators and chemotaxis in purified monocytes (16)(17)(18)(19). Some of these effects are followed by the activation of the transcription factors NF-kB and AP-1 (16)(17)(18)(19).…”

“…Some of these effects are followed by the activation of the transcription factors NF-kB and AP-1 (16)(17)(18)(19). Pla also triggers multiple signaling pathways such as JAK/STAT, p38 MAPK, and ERK1/2 (18)(19)(20) and it has been shown to activate protease-activated receptor-1 (PAR-1) in fibroblasts (21,22).…”