PLASMIN IS A SPECIFIC STIMULUS OF THE 5-LIPOXYGENASE PATHWAY OF HUMANPERIPHERAL MONOCYTES

The objective of this study was to characterize the plasmin-induced st imulation of leukotriene (LT) B-4 biosynthesis in human peripheral mon ocytes (PM). Plasmin up to 175 X 10(-3) CTA U/ml triggers a concentrat ion-dependent release of 5-lipoxygenase-derived LTB(4) while release o f the cyclooxygenase products thromboxane (TX) B-2 and prostaglandin ( PG) E(2) remained unaffected. The stimulatory effect appeared to be sp ecific in as much as 1) it was found in PM, but not in polymorphonucle ar neutrophils (PMN), 2) it requires the lysine binding sites of plasm in molecule since it was inhibited by the lysine analogues 6-aminohexa noic acid (6-AHA) and trans-4(aminomethyl)cyclohexane-1-carboxylic aci d (t-AMCA), 3) the intact catalytic center of plasmin is required sinc e neither plasminogen nor catalytic center-blocked plasmin share the s timulatory effect of active plasmin, 4) other serine proteases such as alpha-chymotrypsin, human neutrophil elastase and cathepsin G did not stimulate release of detectable amounts of LTB(4) from PM. In additio n, catalytic center-blocked plasmin antagonized the stimulatory effect of active plasmin. Plasmin-mediated monocyte activation apparently pr oceeds via a pertussis toxin-sensitive G protein. Plasmin did not incr ease inositol (1,4,5) trisphosphate levels, but a time- and concentrat ion-dependent stimulation of cyclic GMP formation was observed. The da ta show that plasmin is a specific stimulus for human peripheral monoc ytes. Plasmin may be an important link between the coagulation cascade and inflammatory reactions.