Plasmin is a potent and specific chemoattractant for human peripheral monocytes acting via a cyclic guanosine monophosphate-dependent pathway.
We have previously reported that the serine protease plasmin generated during contact activation of human plasma triggers biosynthesis of leukotrienes (LTs) in human peripheral monocytes (PMs), but not in polymorphonuclear neutrophils (PMNs). We now show that purified plasmin acts as a potent chemoattractant on human monocytes, but not on PMNs. Human plasmin or plasminogen activated with urokinase, but not active site-blocked plasmin or plasminogen, elicited monocyte migration across polycarbonate membranes. Similarly, stimulation of monocytes with plasmin, but not with active site-blocked plasmin or plasminogen, induced actin polymerization. As assessed by checkerboard analysis, the plasmin-mediated monocyte locomotion was a true chemotaxis. The plasmin-induced chemotactic response was inhibited by the lysine analog trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA), which prevents binding of plasmin/ogen to the appropriate membrane binding sites. In addition, active site-blocked plasmin inhibited monocyte migration triggered by active plasmin. Further, plasmin-induced monocyte chemotaxis was inhibited by pertussis toxin (PTX) and 1-O-hexadecyl-2-O-methyl-rac-glycerol (HMG) and chelerythrine, two structurally unrelated inhibitors of protein kinase C (PKC). Plasmin, but not active site-blocked plasmin or plasminogen, triggered formation of cyclic guanosine monophosphate (cGMP) in monocytes. LY83583, an inhibitor of soluble guanylyl cyclase, inhibited both plasmin-induced cGMP formation and the chemotactic response. The latter effect could be antagonized by 8-bromo-cGMP. In addition, KT5823 and (Rp)-8-(p-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate [(Rp)-8-pCPT-cGMPs], two structurally unrelated inhibitors of cGMP-dependent protein kinase, inhibited plasmin-mediated monocyte chemotaxis. Thus, beyond being a stimulus for lipid mediator release, plasmin is a potent and specific chemoattractant for human monocytes acting via a cGMP-dependent mechanism. Therefore, plasmin represents a proinflammatory activator for human monocytes.
Syrovets
T
T
Department of Pharmacology and Toxicology, Ruhr University, Bochum, Germany.
Tippler
B
B
Rieks
M
M
Simmet
T
T
D000470:Alkaloids / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D053119:Benzophenanthridines; D001665:Binding Sites / Q000187:drug effects; D002227:Carbazoles; D002630:Chemotactic Factors / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005341:Fibrinolysin / Q000494:pharmacology*; D005995:Glyceryl Ethers / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D007211:Indoles; D008239:Lysine / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D009928:Organ Specificity; D037342:Pertussis Toxin; D010617:Phenanthridines / Q000494:pharmacology; D010958:Plasminogen / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013873:Thionucleotides / Q000494:pharmacology; D014148:Tranexamic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D000470:Alkaloids; D000634:Aminoquinolines; D053119:Benzophenanthridines; D002227:Carbazoles; D002630:Chemotactic Factors; D004791:Enzyme Inhibitors; D005995:Glyceryl Ethers; D007211:Indoles; D010617:Phenanthridines; D013873:Thionucleotides; D010566:Virulence Factors, Bordetella; C059039:1-O-hexadecyl-2-O-methylglycerol; C062699:tranexamic acid isobenzedrine ester; C073601:KT 5823; C016276:8-bromocyclic GMP; D009240:N-Formylmethionine Leucyl-Phenylalanine; D014148:Tranexamic Acid; D010958:Plasminogen; C041715:6-anilino-5,8-quinolinedione; C016299:chelerythrine; D037342:Pertussis Toxin; D011493:Protein Kinase C; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D008239:Lysine