The effect of plasmin-derived fibrinogen fragments on the biosynthesis of fibrinogen was investigated in cultured monolayers ofrat hepatocytes. Incubating the cells with several concentrations of either fibrinogen or fibrin fragment D or E had no effect on the synthesis and secretion of fibrinogen by these cells. However, if the fragments were incubated with isolated peripheral blood leukocytes, they caused these cells to secrete a factor that when added to the hepatocytes caused an increase in fibrinogen synthesis 4-to 6-fold over controls. Moreover, the hepatocyte-stimulating factor also affected the production of several other proteins produced by the hepatocyte. These results demonstrate that both fragments D and E can stimulate hepatic fibrinogen synthesis via an indirect leukocyte-mediated pathway.When fibrinogen or fibrin is acted upon by plasmin, a series of well-defined proteolytic cleavages occur that ultimately result in the formation of two different molecular species that come from different parts of the molecule. The fragments are designated E, which is derived from the amino-terminal region of the molecule and has a Mr of 40,000, and D, which is derived from the carboxy-terminal region and has a Mr of 80,000 (1, 2). Slightly more than a decade ago, Barnhardt et al (3) infused fibrinolytic fragments into dogs and found a significant increase in fibrinogen synthesis as judged by an increased immunofluorescence of liver slices taken several hours after the infusion. The observation that some of the plasminolytic fragments derived from fibrinogen or fibrin maybe involved in the regulation of fibrinogen synthesis was suggestive of a novel regulatory pathway that could be an important part of the inflammatory response.A number of reports has appeared (4-8) which seem to verify and expand the study of Barnhardt et al.-that is, they suggest that either fibrinogen degradation products or fibrin degradation products (FDP or fdp, respectively) play an important role in regulating fibrinogen synthesis. On the other hand, several other studies (9)(10)(11)(12) have been unable to demonstrate any effects of FDP on fibrinogen production. Unfortunately there is no consistent explanation for these conflicting observations. Thus, whether FDP play any significant role in regulating fi--brinogen is still unresolved.In this report we have characterized a role that FDP play in regulating fibrinogen synthesis by exposing cultured hepatocytes to purified fragments offibrinogen and fibrin. We provide evidence that the fragments, do not stimulate fibrinogen synthesis by direct interaction with the hepatocyte. However, the fragments do affect fibrinogen synthesis by stimulating leukocytes to produce a potent hepatocyte-stimulating factor (HSF), which then acts on the hepatocytes to increase fibrinogen synthesis. We also demonstrate that both fragments are equally potent in causing the production of HSF. These results show the pathway by which FDP stimulate fibrinogen production. MATERIALS AND METHODSPreparation of R...