Role of the lipopolysaccharide (LPS)-binding protein/CD14 pathway in LPS induction of tissue factor expression in monocytic cells.

Abstract

Endotoxic shock is associated with a coagulopathy, organ failure, and death. Tissue factor (TF) expression by monocytes exposed to bacterial endotoxin (lipopolysaccharide [LPS]) may mediate the coagulopathy and contribute to the high mortality of this disease. We examined the role of the LPS-binding protein (LBP)/CD14 receptor pathway in the LPS induction of TF expression in human monocytic THP-1 cells and peripheral blood monocytes. In THP-1 cells, the threshold concentration of LPS required to induce TF activity in serum-free medium was reduced 20-fold by purified LBP, which also enhanced TF mRNA synthesis. Similarly, monocytes cultured in the presence of serum were induced to S eptic shock syndrome, mediated by bacterial endotoxin (lipopolysaccharide [LPS]), is often associated with the development of coagulation disorders including microvascular thrombosis and disseminated intravascular coagulation.12 The pathophysiology of septic coagulopathy is intimately linked to the expression of the cellular procoagulant tissue factor (TF). In animal models, disseminated intravascular coagulation is induced by administration of either LPS or TF and is prevented by anti-TF antibodies.3 ' 4 Moreover, inhibition of TF activity in a baboon model of lethal septic shock using a monoclonal antibody attenuates the coagulopathy and protects against lethality, indicating that TF is a mediator of fatal bacteremic shock. 5Monocytes are the only circulating cell type that can be induced to express TF. 6 These cells may therefore represent the primary source of TF within the vasculature of patients with sepsis.2 In patients with meningococcal infection increased monocyte TF expression directly correlates with mortality.7 Experimental studies with leopine, 8 murine, 9 and porcine 10 models of septic shock indicate that monocytes from septic groups consistently express higher levels of TF activity than monocytes from control groups. Moreover, monocytes from rabbits pretreated with endotoxin are thrombogenic and produce pulmonary emboli and death when infused intravenously into untreated rabbits. 11TF expression is induced on the surface of human peripheral blood monocytes by exposure to LPS in

Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock

“…The CD14-mediated activation of peritoneal macrophages by heat-killed Staphylococcus aureus bacteria, LTA, cell wall PGN, or mycobacterial lipoproteins is not enhanced by LBP (345,357,478,524). In the presence of LBP, LPS induced an enhanced intracellular killing and secretion of TNF-␣ and NO by murine macrophages (68), increased adherence of human PMN to endothelial cells (590), LBP and CD14 release by HepG2 human hepatoma cells (383), and release of tissue factor by THP-1 cells in vitro (500), whereas the addition of anti-LBP or anti-CD14 antibodies abrogated the effect of LBP (154,500,590). Application of anti-LBP antibodies together with LPS protected D-galactosamine-sensitized mice from death (155, 156, 307a).…”

Lysophosphatidic Acid Induction of Tissue Factor Expression in Aortic Smooth Muscle Cells

“…However, LPS-induced TF expression was dependent on LPS-binding protein and the CD14 receptor. 47,48 In addition, MCP-1 induced TF by way of a Gi-coupled, unidentified MCP-1 receptor 49 in SMCs. We speculate that LPA induction of TF in SMCs may be dependent on Gi-protein-coupled Edg-2 or Edg-7, because these 2 receptors have recently been detected in vascular SMCs.…”

An accompanying genetic severe deficiency of tissue factor protects mice with a protein C deficiency from lethal endotoxemia

“…The interactions between these systems are profoundly displayed in sepsis/endotoxemia, wherein pathogenic challenge up-regulates tissue factor (TF) on monocytes 1 and endothelial cells, 2 that not only leads to a hypercoagulation potential, but also provides several proteases (eg, thrombin) that are capable of signaling the inflammatory response through interaction with cellular receptors. 3 The resulting inflammatory mediators downregulate anticoagulant activated protein C (aPC) generation and inhibit fibrinolysis, thus enhancing the hypercoagulable state.…”