scholarly journals Pyrrolidine dithiocarbamate abrogates tissue factor (TF) expression by endothelial cells: evidence implicating nuclear factor-kappa B in TF induction by diverse agonists

Blood ◽  
1995 ◽  
Vol 86 (2) ◽  
pp. 436-443 ◽  
Author(s):  
CL Orthner ◽  
GM Rodgers ◽  
LA Fitzgerald
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Nuclear Factor Kappa B ◽  
Transcriptional Level ◽  
Pyrrolidine Dithiocarbamate ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Nf Kappa B ◽  
Nuclear Factor Kappa ◽  
Tf Gene

Tissue factor (TF), a 46-kD glycoprotein receptor for coagulation factors VII and VIIa, is expressed on the surface of endothelial cells in response to a variety of agonists and is thought to play an important role in initiating the thrombosis associated with inflammation during infection, sepsis, and organ transplant rejection. The induction of TF activity by lipopolysaccharide (LPS) is regulated, at least partially, at a transcriptional level and an LPS response element containing two activator protein-1 sites and a nuclear factor- kappa B (NF kappa B)-like site has been localized to the 5′ flanking region of the TF gene by transfection studies of TF promoter/reporter gene constructs. We have examined the effect of pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of the NF kappa B pathway on the expression of the endogenous TF gene in human umbilical vein endothelial cells (HUVEC). Preincubation of HUVEC for 60 minutes with PDTC inhibited LPS induction of TF activity on the cell surface in a dose-dependent manner, with 50% inhibition occurring at 10 mumol/L PDTC and 100% inhibition at higher concentrations (> or = 100 mumol/L). Furthermore, PDTC inhibited TF expression in response to tumor necrosis factor-alpha, interleukin-1 beta, and phorbol 12-myristate 13-acetate. The effect of PDTC was at the mRNA level, as seen by the complete abrogation of the large increase in TF mRNA observed in LPS-treated HUVEC. These results suggest that endothelial cell activation by diverse agonists initiates intracellular signaling events that converge upon a common pathway involving NF kappa B and, furthermore, that NF kappa B activation is an obligatory step induction of TF.

scholarly journals Lipopolysaccharide-mediated transcriptional activation of the human tissue factor gene in THP-1 monocytic cells requires both activator protein 1 and nuclear factor kappa B binding sites.

1991 ◽  
Vol 174 (6) ◽  
pp. 1517-1526 ◽  
Author(s):  
N Mackman ◽  
K Brand ◽  
T S Edgington
Keyword(s):  
Tissue Factor ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Nuclear Factor Kappa B ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Nf Kappa B ◽  
Monocytic Cells ◽  
Activator Protein ◽  
Nuclear Factor Kappa

Lipopolysaccharide (LPS) activation of cells of monocytic lineage leads to rapid and transient expression of a set of inflammatory gene products, including tissue factor (TF). This transmembrane receptor is the major cellular initiator of the blood coagulation cascades, and induced expression of TF is postulated to play a role in inflammation. Functional studies using transfected THP-1 monocytic cells revealed the presence of a 56-bp LPS response element (LRE) within the TF promoter that conferred LPS responsiveness to a heterologous promoter. LPS stimulation of these cells activated proteins that bound to nucleotide sequences within the LRE resembling consensus binding sites for activator protein 1 (AP-1) and nuclear factor kappa B (NF-kappa B). Induction of the TF gene may represent a prototypic example of gene activation in monocytic cells by assembly of transcription factor complexes, and may clarify the role of AP-1 and NF-kappa B in the regulation of other LPS-responsive genes.

scholarly journals Alisol B 23-Acetate Inhibits IgE/Ag-Mediated Mast Cell Activation and Allergic Reaction

2018 ◽  
Vol 19 (12) ◽  
pp. 4092 ◽  
Author(s):  
Chen Shao ◽  
Bingjie Fu ◽  
Ning Ji ◽  
Shunli Pan ◽  
Xiaoxia Zhao ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Allergic Reaction ◽  
Nuclear Factor Kappa B ◽  
Immunoglobulin E ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa

Alisol B 23-acetate (AB23A), a natural triterpenoid, has been reported to exert hepatoprotective and antitumor activities. Aiming to investigate the anti-inflammatory activity, this study examined the effect of AB23A on mast cells and allergic reaction. AB23A inhibited the degranulation of mast cells stimulated by immunoglobulin E/antigen (IgE/Ag), and also decreased the synthesis of leukotriene C4 (LTC4), production of interlukin-6 (IL-6), and expression of cyclooxygenase-2 (COX-2) in a concentration-dependent manner with no significant cytotoxicity in bone marrow-derived mast cells (BMMCs). AB23A inhibited spleen tyrosine kinase (Syk) and the downstream signaling molecules including phospholipase Cγ (PLCγ), serine-threonine protein kinase/inhibitor of nuclear factor kappa-B kinase/nuclear factor kappa-B (Akt/IKK/NF-κB), and mitogen-activated protein kinases/cytosolic phospholipase A2 (MAPK/cPLA2). Furthermore, AB23A blocked mobilization of Ca2+. Similar results were obtained in other mast cell lines Rat basophilic leukemia (RBL)-2H3 cells and a human mast cell line (HMC-1). In addition, AB23A attenuated allergic responses in an acute allergy animal model, passive cutaneous anaphylaxis (PCA). Taken together, this study suggests that AB23A inhibits the activation of mast cells and ameliorates allergic reaction, and may become a lead compound for the treatment of mast cell-mediated allergic diseases.

scholarly journals Inhibition of protein kinase C beta phosphorylation activates nuclear factor-kappa B and improves postischemic recovery in type 1 diabetes

2020 ◽  
Vol 245 (9) ◽  
pp. 785-796
Author(s):  
Satyanarayana Alleboina ◽  
Thomas Wong ◽  
Madhu V Singh ◽  
Ayotunde O Dokun
Keyword(s):  
Endothelial Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
High Glucose ◽  
Nuclear Factor Kappa B ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Kinase C ◽  
Protein Kinase C Beta

Peripheral artery disease (PAD) is a major health problem and is caused by atherosclerosis in arteries outside the heart leading to impaired blood flow. The presence of diabetes significantly increases the likelihood of having worse outcomes in PAD, and the molecular mechanisms involved are poorly understood. Hyperglycemia in diabetes activates the nuclear factor-kappa B (NF-κB) pathway, and chronic inflammation in diabetes is associated with vascular complications. Ischemia also activates NF-κB signaling that is important for perfusion recovery in experimental PAD. We hypothesized that prolonged exposure of endothelial cells to high glucose in diabetes impairs ischemic activation of the NF-κB pathway and contributes to poor perfusion recovery in experimental PAD. We assessed the effect of high glucose and ischemia on canonical and non-canonical NF-κB activation in endothelial cells and found both conditions activate both pathways. However, exposure of endothelial cells to high glucose impairs ischemia-induced activation of the canonical NF-κB pathway but not the non-canonical pathway. We probed an array of antibodies against signaling proteins in the NF-κB pathway to identify proteins whose phosphorylation status are altered in endothelial cells exposed to high glucose. Protein kinase C beta (PKCβ) was among the proteins identified, and its role in impaired ischemia-induced activation of NF-κB during hyperglycemia has not been previously described. Inhibition of PKCβ improves ischemia-induced NF-κB activation in vitroand in vivo. It also improves perfusion recovery in diabetic mice following experimental PAD. Thus, in diabetes, PKCβ phosphorylation contributes to impaired ischemic activation of NF-κB and likely a mechanism contributing to poor PAD outcomes. Impact statement Diabetes worsens the outcomes of peripheral arterial disease (PAD) likely in part through inducing chronic inflammation. However, in PAD, recovery requires the nuclear factor-kappa B (NF-κB) activation, a known contributor to inflammation. Our study shows that individually, both ischemia and high glucose activate the canonical and non-canonical arms of the NF-κB pathways. We show for the first time that prolonged high glucose specifically impairs ischemia-induced activation of the canonical NF-κB pathway through activation of protein kinase C beta (PKCβ). Accordingly, inhibition of PKCβ restores the ischemia-induced NF-κB activity both in vitroin endothelial cells and in vivoin hind limbs of type 1 diabetic mice and improves perfusion recovery after experimental PAD. Thus, this study provides a mechanistic insight into how diabetes contributes to poor outcomes in PAD and a potential translational approach to improve PAD outcomes.

Linoleic acid-stimulated vascular adhesion molecule-1 expression in endothelial cells depends on nuclear factor-[kappa ]B activation

Metabolism ◽  
2002 ◽  
Vol 51 (3) ◽  
pp. 327-333 ◽  
Author(s):  
Wolfgang Dichtl ◽  
Mikko P.S. Ares ◽  
Audrey Niemann J[ouml ]nson ◽  
Stefan Jovinge ◽  
Otmar Pachinger ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Linoleic Acid ◽  
Adhesion Molecule ◽  
Nuclear Factor Kappa B ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Vascular Adhesion

Activated Platelets Induce Tissue Factor Expression on Human Umbilical Vein Endothelial Cells by Ligation of CD40

1998 ◽  
Vol 80 (12) ◽  
pp. 1008-1041 ◽  
Author(s):  
Matthias Kalbas ◽  
Antje Willuweit ◽  
Volker Henn ◽  
Richard Kroczek ◽  
Gert Müller-Berghaus ◽  
...  
Keyword(s):  
Wound Healing ◽  
Endothelial Cells ◽  
Tissue Factor ◽  
Vascular Endothelial Cells ◽  
Tissue Injury ◽  
Pyrrolidine Dithiocarbamate ◽  
Type I ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Activated Platelets

SummaryCD40 is a type I member of the tumour necrosis factor (TNF) receptor superfamily of proteins, and is present on a wide variety of cells including vascular endothelial cells. Ligation of this receptor on endothelial cells is known to increase expression of inflammatory adhesion molecules. We have recently demonstrated that platelets express the ligand of CD40 (CD154) within seconds of exposure to agonist, and interact with endothelial cells to participate directly in the induction of an inflammatory response. Here we show that activated platelets induce tissue factor (TF) expression on endothelial cells in a CD40/CD154-dependent manner, and that the magnitude of this response can equal that induced by TNFα. Moreover, CD40 ligation on endothelial cells downregulates the expression of thrombomodulin. We also show that CD40-mediated TF expression is less sensitive to inhibition with the oxidative radical scavenger pyrrolidine dithiocarbamate than is that mediated by TNFα, indicating that CD40 has a distinct signalling pathway. Tissue factor is a cell membrane protein which functions as the main trigger of the extrinsic pathway of blood coagulation, and its expression on endothelial cells is implicated in wound healing and angiogenesis. Since platelets are among the first cells involved in haemostasis following tissue injury, our data showing that ligation of CD40 by CD154 induces a procoagulant phenotype on vascular endothelial cells suggests that platelets may play an important role in the induction of wound healing.

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