Cellular immune and cytokine pathways resulting in tissue factor expression and relevance to septic shock.
Cells of monocyte lineage serve as effector cells in the cellular immune response. In addition, they respond to LPS and cytokines with activation and expression of inflammatory effector gene products similar to those elicited by the antigen driven response. The response to antigen proceeds at the T helper cell level through two independent forms of cellular collaboration, contact and lymphokine. We review the control of expression of the Tissue Factor (TF) gene and the function of the TF protein. The enhanced initiation of transcription of the TF gene appears to require engagement of a 56 bp LPS Response Element, an enhancer that is engaged by both AP-1 type heterodimeric complexes as well as NF kappa B like heterodimeric complexes. Dissociation of NF kappa B from Ig kappa B by cytokine and LPS stimulation, and possibly activated T cells, may represent a common pathway to induction of the TF and other inflammatory genes. Enhancement of expression of TF is observed upon adhesion of Mo to endothelial cells and extracellular matrix proteins, as well as upon engagement of leukocyte integrins. The biological effects that follow from expression of TF by vascular cells have been resolved by analysis of function aided by the use of recombinant full length TF and truncated surface domain of TF. The rules of assembly of the cognate ligands of TF, namely the zymogen plasma factors VII and the serine protease factor VIIa, with the soluble surface domain of TF in free solution, in the presence of phospholipid surfaces and cell surface and of the anchored TF molecule have been described. It is evident that assembly of the surface domain of TF with VIIa to form the binary TF.VIIa complex induces a significant increase in the Kcat of the catalytic domain of VIIa for small peptidyl substrates and more profoundly for protein substrate. This provides substantial evidence for an allosteric effect on the catalytic cleft of VIIa that is imparted by binding to TF, its cognate catalytic cofactor. It is also evident that the TF.VIIa complex is proteolytically active and can activate the zymogen plasma factor X to the serine protease Xa in free solution, inferring that extended substrate recognition by induced structural loci of the TF.VIIa complex are created from either or both proteins to constitute a new recognition structure. It is also evident that association of X with charged phospholipid surfaces enhances the proteolytic activation of this zymogen by increasing recognition and susceptibility of the sessile peptide bond deduced from the markedly decreased Km and increased Kcat.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037.
T S
TS
Edgington
N
N
Mackman
S T
ST
Fan
W
W
Ruf
D000818:Animals; D001777:Blood Coagulation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000502:physiology*; D004211:Disseminated Intravascular Coagulation / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology; D004789:Enzyme Activation; D005167:Factor VII / Q000378:metabolism; D015942:Factor VIIa / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007111:Immunity, Cellular; D008051:Lipid Bilayers / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008213:Lymphocyte Activation; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology / Q000503:physiopathology*; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic
D016207:Cytokines; D008051:Lipid Bilayers; D008070:Lipopolysaccharides; D008563:Membrane Lipids; D016328:NF-kappa B; D005167:Factor VII; D013925:Thromboplastin; D015942:Factor VIIa