Synergistic Induction of Tissue Factor by Coagulation Factor Xa and TNF: Evidence for Involvement of Negative Regulatory Signaling Cascades

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 34; pp. 12077 - 12082
• Main Authors: Hezi-Yamit, Ayala, Wong, Paul W, Bien-Ly, Nga, Komuves, Laszlo G, Prasad, K S Srinivasa, Phillips, David R, Sinha, Uma
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23-08-2005; National Acad Sciences
• Subjects: Agonists; Biological Sciences; Blood Coagulation - physiology; CD40 Ligand - metabolism; Coagulation; Cytokines; DNA Primers; E-Selectin - metabolism; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - physiology; Enzymes; Factor Xa - metabolism; Fluorescent Antibody Technique; Gene Expression Regulation; Human umbilical vein endothelial cells; Humans; Immunoblotting; Interleukin-1 - metabolism; Lead; Phosphatases; Phosphorylation; Receptors; Reverse Transcriptase Polymerase Chain Reaction; Signal transduction; Signal Transduction - physiology; Thromboplastin - metabolism; Tissues; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0504526102

Enzymes of the blood coagulation pathway enhance the inflammatory response leading to endothelial dysfunction, accounting, in part, for the vascular complications occurring in sepsis and cardiovascular disease. The responses of endothelial cell activation include induction of the expression of tissue factor (TF), a membrane glycoprotein that promotes thrombosis, and of E-selectin, a cell adhesion molecule that promotes inflammation. In this report, we demonstrate synergistic interactions between the coagulation factor Xa (fXa) and the proinflammatory cytokines TNF, IL-1β, and CD40L, leading to enhanced expression of TF and E-selectin in endothelial cells. A detailed analysis of the molecular pathways that could account for this activity of fXa showed that fXa inhibited the cytokine-induced expression of dual specificity phosphatases, MAP kinase phosphatase-L, -4, -5, and -7, blocking a negative regulatory effect on c-Jun N-terminal kinase. The synergistic interaction between fXa and TNF was also involved in the inhibition of A20 and IκBα expression in the IκB kinase-NF-κB pathway. The data indicate that inhibition of negative regulatory signaling accounts for the amplification of cytokine-induced endothelial cell activation by fXa.