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

Disseminated intravascular coagulation, characterized by circulating f ibrin(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 regulato ry proteins with significant clinical ramifications, we have studied c ytokine synthesis and release following the interaction of D-dimer (DD ), a terminal degradation product of fibrin, with human monocytes in v itro. Adherent peripheral blood monocytes were incubated with purified DD for 24 and 48 h and secreted or cell-associated IL-I beta and IL-6 antigen levels and activity determined. DD (50 mu g/ml) boosted the s ecretion 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<O.05). Similar increases in extracellular biologically acti ve IL-1 and IL-6 were observed. Although DD increased cell associated ILI 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<O.05), cell-associa ted IL-1 functional activity decreased from control levels of 98 inhib itor units/ml to 65 units/ml for cells exposed to DD. Secreted plasmin ogen activator inhibitor (PAI) bioactivity and PAI type 2 antigen leve ls 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-l. Our finding that DD enhances monocyte release of biologic ally active cytokines suggests the presence of positive feedback pathw ays for fibrinogen synthesis by hepatocytes. Furthermore, the associat ion of monocytes with DD may potentiate localized coagulation processe s by subsequent alterations in pericellular proteolysis.