Role of the lipopolysaccharide (LPS)-binding protein/CD14 pathway in LPS induction of tissue factor expression in monocytic cells.
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 express TF antigen at LPS concentrations 100 times lower than monocytes cultured in serum-free medium. An anti-LBP monoclonal antibody indicated that this effect was dependent on the presence of LBP in serum. LPS/LBP induction of TF activity and TF antigen expression in these monocytic cells were also inhibited by an anti-CD14 monoclonal antibody, indicating a requirement for the CD14 receptor. Thus, we suggest that low levels of LPS (5 to 100 pg/mL) present during sepsis induce TF expression in monocytes via the LBP/CD14-dependent pathway.
Steinemann
S
S
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037.
Ulevitch
R J
RJ
Mackman
N
N
D000209:Acute-Phase Proteins / Q000502:physiology*; D015703:Antigens, CD / Q000502:physiology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D004731:Endotoxins / Q000502:physiology; D004926:Escherichia coli; D006801:Humans; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins; D009000:Monocytes / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002352:Carrier Proteins; D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D013925:Thromboplastin; D000099231:Lipopolysaccharide-Binding Protein; C044101:endotoxin, Escherichia coli