title: Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1 beta, IL-6 and plasminogen activator inhibitors from monocytes in vitro.
abstract: Disseminated intravascular coagulation, characterized by circulating fibrin(ogen) degradation products (FDP), is associated with both acute and chronic inflammatory conditions. Since the association of FDP with monocytes could influence the release of cytokines and other regulatory proteins with significant clinical ramifications, we have studied cytokine synthesis and release following the interaction of D-dimer (DD), a terminal degradation product of fibrin, with human monocytes in vitro. Adherent peripheral blood monocytes were incubated with purified DD for 24 and 48 h and secreted or cell-associated IL-1 beta and IL-6 antigen levels and activity determined. DD (50 micrograms/ml) boosted the secretion of IL-1 beta antigen from median control levels of 659 pg/ml to 2704 pg/ml and that of IL-6 antigen from 806 pg/ml to > 3000 pg/ml at 48 h (P < 0.05). Similar increases in extracellular biologically active IL-1 and IL-6 were observed. Although DD increased cell associated IL-1 beta antigen levels from median values of 188 to 1600 pg/106 cells and IL-6 antigen from 660 to 2215 pg/106 cells (P < 0.05), cell-associated IL-1 functional activity decreased from control levels of 98 inhibitor units/ml to 65 units/ml for cells exposed to DD. Secreted plasminogen activator inhibitor (PAI) bioactivity and PAI type 2 antigen levels were significantly increased following exposure of monocytes to DD. This may explain the decreased cell associated IL-1 activity observed in our study as PAI are known to inhibit biologically active membrane bound IL-1. Our finding that DD enhances monocyte release of biologically active cytokines suggests the presence of positive feedback pathways for fibrinogen synthesis by hepatocytes. Furthermore, the association of monocytes with DD may potentiate localized coagulation processes by subsequent alterations in pericellular proteolysis.
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: E G
authors.initials: EG
authors.lastname: Shephard
authors.forename: R E
authors.initials: RE
authors.lastname: Kirsch
mesh_terms: D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D005338:Fibrin Fibrinogen Degradation Products / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007378:Interleukins / Q000097:blood*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D015849:Plasminogen Inactivators / Q000097:blood*
chemical_list: D000933:Antifibrinolytic Agents; D005338:Fibrin Fibrinogen Degradation Products; D007375:Interleukin-1; D015850:Interleukin-6; D007378:Interleukins; D015849:Plasminogen Inactivators; C036309:fibrin fragment D