title: Monocyte-macrophage release of IL-1 is inhibited by type-1 plasminogen activator inhibitors.
abstract: Interleukin-1 (IL-1) release from monocyte-macrophages (Mo) appears dependent on pericellular proteolysis mediated by plasmin. Thus plasminogen activator inhibitors (PAI) which bind the serine proteases responsible for the conversion of plasminogen to plasmin, may inhibit IL-1 release from Mo. We have examined the effect of purified PAI from a hepatoma cell line Hep G2, on IL-1 release from Mo with secondary effects on lymphocyte proliferation in vitro. Fast acting inhibitors of both urokinase (u-PA) and tissue plasminogen activator (two chain t-PA) were noted in harvest fluids of Hep G2 cells. These inhibitors were stable at pH 3 but lost activity at 45 degrees C. They were SDS-stable and migrated with Mr53 and 104 kDa. These properties conformed to characteristics of type-1 plasminogen activator inhibitor (PAI-1). Partially purified PAI-1 added to human Mo cultured on 125I fibrin layer both in the presence and absence of plasminogen inhibited secretion of IL-1 by Mo in response to LPS. This effect, however, did not correlate with the inhibition of plasminogen dependent fibrinolysis. This suggested a degree of sequestration and inaccessibility of membrane bound u-PA of LPS activated Mo to PAI-1. PAI-1, in addition, inhibited mitogen stimulated peripheral blood mononuclear cell (PBMC) proliferation at similar concentration ranges. This effect was abrogated by the addition of specific antisera to PAI-1. PAI-1 may be released as part of an acute phase response. In addition to influencing fibrinolysis, PAI-1 may constitute a negative feedback pathway on Mo IL-1 release and subsequent immune activation in vivo.
authors.affiliation: Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.
authors.forename: S C
authors.initials: SC
authors.lastname: Robson
authors.forename: R
authors.initials: R
authors.lastname: Saunders
authors.forename: R E
authors.initials: RE
authors.lastname: Kirsch
mesh_terms: D000210:Acute-Phase Reaction / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D017395:Plasminogen Activator Inhibitor 1 / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1