Biomedical subjects

N Mackman

Publications and source records attributed to N Mackman.

At least 55 records · Page 3Linked to original sources

PubMed1998

Transcriptional regulation of the tissue factor gene by progestins in human endometrial stromal cells.

Decidualization of estradiol (E2)-primed human endometrial cells (HESCs) by progesterone is associated with elevated levels of tissue factor (TF), the primary initiator of hemostasis. Similarly, in cultured human HESCs, the synthetic progestin, medroxyprogesterone acetate (MPA), enhances TF protein and messenger ribonucleic acid (mRNA) levels. Although ineffective alone, E2 potentiates this progestin enhancement of TF expression by HESCs. The current study examines mechanisms underlying MPA enhancement of TF mRNA expression in HESCs. In the presence of the transcription-blocking agent dichlororibofuranosylbenzimidazole, no significant differences were noted in the half-lives of TF mRNA isolated from HESCs treated with E2 alone or with E2 plus MPA. This indicates that MPA-enhanced TF mRNA levels do not reflect changes in the stability of the TF message. To test the effect of progestin on TF promoter activity and to ascertain the mechanism of promoter regulation, primary or first passaged HESCs were transfected with TF promoter constructs spanning the regions -2106 to +121 (TFp(-2106)), -278 to +121 (TFp(-278)), and -111 to +14 (TFp(-111)) bp upstream of the transcription start site. MPA was found to enhance TF transcription by 20-fold in HESCs transfected with TFp(-2106) after correcting for transfection efficiencies with a beta-galactosidase reporter plasmid. Interestingly, levels of E2- plus MPA-stimulated transcription were significantly increased using TFp(-278) compared to TFp(-2106), suggesting that the region between -2106 and -278 bp may contain an inhibitory element. In addition, rates of MPA-stimulated transcription using TFp(-111) were significantly reduced compared to values obtained using TFp(-2106) and were even further reduced compared to values obtained using TFp(-278). This suggests that regulatory elements in the -111 bp region of the TF promoter are necessary for progestin-mediated regulation of the TF gene in HESCs, but are not sufficient to account for maximal rates of TF gene transcription. Our results also demonstrated that induction of steady state TF mRNA by MPA was abolished by treating cells with E2 plus MPA in conjunction with the protein synthesis inhibitor cycloheximide. In light of the absence of a complete progesterone or estrogen response element in the published 5'-sequence of the TF promoter, our results suggest that progestin-enhanced transcription of TF mRNA in stromal cells may be mediated by an uncharacterized protein intermediate(s).

Cells, Cultured↗

PubMed1998

Binding of human single chain urokinase to Chinese Hamster Ovary cells and cloning of hamster u-PAR.

The plasminogen activator, urokinase (u-PA), interacts with the u-PA receptor (u-PAR) which results in enhanced plasminogen activation on cell surfaces. The u-PAR is comprised of three homologous domains of approximately 90 amino acids, defined by the pattern of disulfide bonds. Domain 1 (amino acids 1-87) binds the ligand. Within this domain, Y57, and a site between residues 47 and 53, have been suggested as ligand contact points. Intradomain interactions also contribute to the interaction of u-PA and u-PAR. The interaction of u-PA with its receptor exhibits some species specificity. Previous studies have shown that human u-PA does not bind to the murine u-PAR and murine u-PA does not recognize human u-PAR. However, human u-PA does interact with bovine cells with high affinity. To further examine the interaction of the human ligand with the u-PAR of a different species, we characterized the binding of human 125I single chain u-PA (scu-PA) to hamster cells. Chinese Hamster Ovary (CHO) cells bound human scu-PA with high affinity and capacity (Kd = 1.13 +/- 0.8 nM; Bmax = 5.45 +/- 0.98 x 10(4) sites/cell). In ligand blotting with human 125I-scu-PA, major bands migrating with apparent Mr's of 74, 49 and 38 kDa were observed. The cDNA of hamster u-PAR was cloned and a single 1.4 kb mRNA species identified in Northern blots of CHO cell RNA. For comparison, we also cloned u-PAR cDNA from human THP-1 cells. Our human sequence was identical to those published for U937 and endothelial cells. These sequences were aligned with the published sequences for the murine, bovine and rat u-PAR's to obtain a consensus sequence for five species. The cysteine residues could be aligned for all species. Y57, which has been suggested as a ligand contact point was also conserved across species. In addition, 5 of the 7 amino acids between amino acids 47 and 53 were conserved in all species. Gly283, the most likely glycosyl-phosphatidyl inositol attachment site, was also conserved in all species. The conservation of these amino acid residues across all five species, attests to their importance in u-PAR function. In addition, the results of our studies suggest that the hamster may be a useful small animal model for studies of human urokinase function.

Amino Acid Sequence↗

PubMed1997

Role of cyclic AMP response element-binding protein in cyclic AMP inhibition of NF-kappaB-mediated transcription.

The NF-kappaB family of transcription factors regulates the inducible expression of a variety of genes. Recently, we showed that elevation of intracellular cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytes and endothelial cells without preventing nuclear translocation of NF-kappaB complexes. The present study examined the molecular mechanism of this inhibition. We hypothesized that activation of the protein kinase A signaling pathway may inhibit NF-kappaB-mediated transcription by phosphorylating proteins, such as cAMP response element-binding protein (CREB), which compete for limiting amounts of the coactivator CBP. Here, we show that the amino-terminal region (amino acids 1-450) of CBP specifically interacts with the carboxyl-terminal region (amino acids 286-551) of NF-kappaB p65 (RelA) both in vitro and in vivo. Functional studies using human endothelial cells demonstrated that overexpression of CBP rescued cAMP inhibition of NF-kappaB-mediated transcription and transcription mediated by a chimeric protein, GAL4-p65(286-551), which contained the GAL4 DNA binding domain fused to the carboxyl-terminal region of p65 (amino acids 286-551). In contrast, overexpression of CREB inhibited GAL4-p65(286-551)-mediated transcription. These results suggest that activation of the protein kinase A pathway inhibits NF-kappaB transcription by phosphorylating CREB, which competes with p65 for limiting amounts of CBP.

Calcium-Binding Proteins↗

PubMed1997

Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-kappaB transcription factors.

Biosynthesis of tumor necrosis factor-alpha (TNF-alpha) is predominantly by cells of the monocytic lineage. This study examined the role of various cis-acting regulatory elements in the lipopolysaccharide (LPS) induction of the human TNF-alpha promoter in cells of monocytic lineage. Functional analysis of monocytic THP-1 cells transfected with plasmids containing various lengths of TNF-alpha promoter localized enhancer elements in a region (-182 to -37 base pairs (bp)) that were required for optimal transcription of the TNF-alpha gene in response to LPS. Two regions were identified: region I (-182 to -162 bp) contained an overlapping Sp1/Egr-1 site, and region II (-119 to -88) contained CRE and NF-kappaB (designated kappaB3) sites. In unstimulated THP-1, CRE-binding protein and, to a lesser extent, c-Jun complexes were found to bind to the CRE site. LPS stimulation increased the binding of c-Jun-containing complexes. In addition, LPS stimulation induced the binding of cognate nuclear factors to the Egr-1 and kappaB3 sites, which were identified as Egr-1 and p50/p65, respectively. The CRE and kappaB3 sites in region II together conferred strong LPS responsiveness to a heterologous promoter, whereas individually they failed to provide transcriptional activation. Furthermore, increasing the spacing between the CRE and the kappaB3 sites completely abolished LPS induction, suggesting a cooperative interaction between c-Jun complexes and p50/p65. These studies indicate that maximal LPS induction of the TNF-alpha promoter is mediated by concerted participation of at least two separate cis-acting regulatory elements.

Activating Transcription Factor 2↗

PubMed1997

Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system.

VEGF has been proposed to participate in normal and pathological vessel formation. Surprisingly, lack of only a single VEGF allele resulted in embryonic lethality due to abnormal formation of intra- and extra-embryonic vessels. Homozygous VEGF-deficient embryos, generated by tetraploid aggregation, revealed an even more severe defect in vessel formation. These results (1) suggest a tight regulation of early vessel development by VEGF and, indirectly, the presence of other VEGF-like molecules; (2) reveal an unprecedented lethal phenotype associated with heterozygous deficiency of an autosomal gene, and (3) demonstrate that tetraploid aggregation was a valid and the only method to study the phenotype of the homozyogous VEGF-deficient embryos. The dominant and strict dose-dependent role of VEGF in vivo renders this molecule a desirable therapeutic target for promoting or preventing angiogenesis. Tissue factor (TF) is the principal cellular initiator of coagulation and its deregulated expression has been related to thrombogenesis in sepsis, cancer, and inflammation. However, TF appears to be also involved in a variety of non-hemostatic functions including inflammation, cancer, brain function, immune response, and tumor-associated angiogenesis. Surprisingly, TF deficiency resulted in embryonic lethality due to abnormal extra-embryonic vessel development and defective vitelloembryonic circulation. The abnormal yolk sac vasculature is reminiscent of that observed in embryos lacking VEGF, possibly suggesting that both gene functions are interconnected. These targeting studies extend the recently documented role of TF in tumor-associated angiogenesis and warrant further study of its role in angiogenesis during other pathological disorders. The plasminogen system, via its triggers, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), has been implicated in thrombosis, arterial neointima formation, and atherosclerosis. Studies in mice with targeted gene inactivation of t-PA, u-PA, PAI-1, the urokinase receptor (u-PAR), and plasminogen (Plg) revealed (1) that deficiency of t-PA or u-PA increase the susceptibility to thrombosis associated with inflammation and that combined deficiency of t-PA:u-PA or deficiency of Plg induces severe spontaneous thrombosis; (2) that vascular injury-induced neointima formation is reduced in mice lacking u-PA-mediated plasmin proteolysis, unaltered in t-PA- or u-PAR-deficient mice and accelerated in PAI-1-deficient mice, but that it can be reverted by adenoviral PAI-1 gene transfer; and (3) that atherosclerosis in mice doubly deficient in apolipoprotein E (apoE) and PAI-1 is reduced after 10 weeks of cholesterol-rich diet. Thus, the plasminogen system significantly affects thrombosis, restenosis, and atherosclerosis.

Animals↗

PubMed1997

Shear stress induction of the tissue factor gene.

Using flow channel, we report that the application of a laminar shear stress induced a transient increase of tissue factor (TF) procoagulant activity in human umbilical vein endothelial cells (HUVEC), which was accompanied by a rapid and transient induction of the TF mRNA in the HUVEC. Functional analysis of the 2.2 kb TF 5' promoter indicated that a GC-rich region containing three copies each of the EGR-1 and Sp1 sites was required for induction. Mutation of the Sp1 sites, but not the EGR-1 sites, attenuated the response of TF promoter to shear stress. Thus, Sp1 is a newly defined shear stress responsive element. Electrophoretic mobility shift assays showed there was no increase in binding of nuclear extracts from sheared cells to an Sp1 consensus site. In contrast, immunoblotting of these nuclear extracts with antibody against transcription factor Sp1 demonstrated that shear stress increased the phosphorylation of Sp1. We also showed that shear stress, like the phosphatase inhibitor okadaic acid, increased the transcriptional activity of Sp1. These findings suggest that the shear stress induction of TF gene expression is mediated through an increased Sp1 transcriptional activity with a concomitant hyperphosphorylation of Sp1.

Endothelium, Vascular↗

PubMed1997

Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein.

Nuclear factor-kappa B (NF-kappa B)/Rel transcription factors may be involved in atherosclerosis, as is suggested by the presence of activated NF-kappa B in human atherosclerotic lesions. The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the NF-kappa B system in human THP-1 monocytic cells as well as adherent monocytes. Our results demonstrate that short-term incubation of these cells with oxLDL activated p50/p65 containing NF-kappa B dimers and induced the expression of the target gene IL-8. This activation of NF-kappa B was inhibited by the antioxidant and H2O2 scavenger pyrrolidine dithiocarbamate and the proteasome inhibitor PSI. The oxLDL-induced NF-kappa B activation was accompanied by an initial depletion of I kappa B-alpha followed by a slight transient increase in the level of this inhibitor protein. In contrast, long-term treatment with oxLDL prevented the lipopolysaccharide-induced depletion of I kappa B-alpha, accompanied by an inhibition of both NF-kappa B activation and the expression of tumor necrosis factor-alpha and interleukin-1 beta genes. These observations provide additional evidence that oxLDL is a potent modulator of gene expression and suggest that (dys)regulation of NF-kappa B/Rel is likely to play an important role in atherogenesis.

Antioxidants↗

PubMed1997

Regulation of the tissue factor gene in human monocytic cells. Role of AP-1, NF-kappa B/Rel, and Sp1 proteins in uninduced and lipopolysaccharide-induced expression.

Tissue factor (TF) expression by peripheral blood monocytes during sepsis initiates intravascular thrombosis. Bacterial lipopolysaccharide (LPS) rapidly induces TF gene transcription in monocytes. The human TF promoter contains binding sites for the transcription factors AP-1, c-Rel/p65, Egr-1, and Sp1. NF-kappa B/Rel proteins have been shown to physically interact with both AP-1 and Sp1 proteins. In this study, we investigated the role of these transcription factors in uninduced and LPS-induced TF gene expression in human monocytic THP-1 cells. Deletional analysis indicated that five Sp1 sites mediated basal expression in uninduced cells. The two AP-1 sites bound c-Fos/c-Jun heterodimers in both unstimulated and LPS-stimulated cells. Maximal LPS induction of the TF promoter required the two AP-1 sites and the kappa B site within the LPS response element. Disruption of the conserved spacing between the proximal AP-1 site and the kappa B site abolished LPS induction. Replacement of the two AP-1 sites with intrinsically bent DNA partially restored LPS induction, suggesting an additional structural role for the AP-1 sites. Synergistic transactivation of the LPS response element in Drosophila Schneider cells by coexpression of c-Fos, c-Jun, c-Rel, and p65 or c-Jun and p65 required the transactivation domains of c-Jun and p65. These data indicated that c-Fos/c-Jun, c-Rel/p65, and Sp1 regulate TF gene expression in human monocytic cells.

Animals↗

PubMed1997

The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B.

The natural occurring pigment curcumin, a major component of the spice tumeric, has been described to have antioxidative, anti-tumorpromoting, anti-thrombotic and anti-inflammatory properties. It appears, that the pleiotropic effects of curcumin are at least partly due to inhibition of the transcription factors NF-kappa B and AP-1. This study investigates the effect of curcumin on the TNF alpha induced expression of endothelial Tissue Factor (TF), the central mediator of coagulation known to be controlled by AP-1 and NF-kappa B. When bovine aortic endothelial cells (BAEC) were preincubated in the presence of curcumin, TNF alpha induced TF gene transcription and expression were reduced. Transient transfection studies with TF-promoter plasmids revealed that both, NF-kappa B and AP-1 dependent TF expression, were reduced by curcumin action. The observed inhibitions were due to distinct mechanisms. Curcumin inhibited TNF alpha induced I kappa B alpha degradation and the nuclear import of NF-kappa B. In contrast, inhibition of AP-1 was due to a direct interaction of curcumin with AP-1-binding to its DNA binding motif. Thus, curcumin inhibits NF-kappa B and AP-1 by two different mechanisms and reduces expression of endothelial genes controlled by both transcription factors in vitro.

Animals↗

PubMed1997

Regulation of the tissue factor gene.

Tissue factor is a cellular receptor that initiates blood coagulation. The TF gene is constitutively expressed in some extravascular cell types and is inducibly expressed in several vascular cell types, including monocytes, vascular endothelial cells and vascular smooth muscle cells. Functional studies indicate that Sp1 controls basal TF gene expression. A distal enhancer (-227 to -172) containing two AP-1 sites and an NF-kappa B site mediates induction of the human TF promoter in monocytic cells and endothelial cells. Similarly, two AP-1 sites (-220 to -200) regulate induction of the murine TF promoter in fibroblast-like cells. In contrast, proximal enhancers in the human TF (-109 to -59) and rat (-103 to -80) TF promoters containing Egr-1 and Sp1 sites mediate induction in epithelial-like cells and vascular smooth muscle cells, respectively. These results suggest that cell type-specific pathways regulate TF gene expression.

Animals↗

PubMed1996

Requirement of receptor-bound urokinase-type plasminogen activator for integrin alphavbeta5-directed cell migration.

The urokinase plasminogen activator (uPA) interacts with its cell surface receptor (uPAR), providing an inducible, localized cell surface proteolytic activity, thereby promoting cellular invasion. Evidence is provided for a novel function of cell surface-associated uPA.uPAR. Specifically, induction of cell surface expression of uPA. uPAR by growth factors or phorbol ester was necessary for vitronectin-dependent carcinoma cell migration, an event mediated by integrin alphavbeta5. Cell migration on vitronectin was blocked with either a soluble form of uPAR, an antibody that disrupts uPA binding to uPAR, or a monoclonal antibody to alphavbeta5. Moreover, plasminogen activator inhibitor type 2 blocked this migration event but did not affect adhesion, suggesting a direct role for uPA enzyme activity in this process and that migration but not adhesion of these cells is regulated by uPA.uPAR. Growth factor-mediated induction of uPA.uPAR on the carcinoma cell surface promotes a specific motility event mediated by integrin alphavbeta5, since cells transfected with the beta3 integrin subunit expressed alphavbeta3 and migrated on vitronectin independently of growth factors or uPA.uPAR expression. This relationship between alphavbeta5 and the uPA.uPAR system has significant implications for regulation of motility events associated with development, angiogenesis, and tumor metastasis.

Cell Movement↗

PubMed1996

Role of tissue factor in embryonic blood vessel development.

Tissue factor, a member of the cytokine-receptor superfamily and high-affinity receptor and cofactor for plasma factor VII/VIIa (ref. 1), is the primary cellular initiator of blood coagulation. It is involved in thrombosis and inflammation associated with sepsis, atherosclerosis and cancer, and can participate in other cellular processes including intracellular signalling, metastasis, tumor-associated angiogenesis, and embryogenesis. Here we report that inactivation of the tissue factor gene (TF) results in abnormal circulation from yolk sac to embryo beyond embryonic day 8.5, leading to embryo wasting and death. Vitelline vessels from null mice were deficient in smooth-muscle alpha-actin-expressing mesenchymal cells, which participate in organization of the vessel wall. This implies that tissue factor has a role in blood vessel development.

Animals↗

PubMed1996

Elevated cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytic cells and endothelial cells.

The NF-kappaB/Rel family of transcription factors regulates the inducible expression of many genes in activated human monocytes and endothelial cells. In this study, we examined the molecular mechanism by which agents that elevate intracellular cAMP inhibit the expression of the tumor necrosis factor alpha (TNFalpha), tissue factor, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1 genes. Both forskolin and dibutyryl cAMP, which elevate intracellular cAMP by independent mechanisms, inhibited TNFalpha and tissue factor expression at the level of transcription. Induction of NF-kappaB-dependent gene expression in transiently transfected human monocytic THP-1 cells and human umbilical vein endothelial cells was inhibited by elevated cAMP and by overexpression of the catalytic subunit of protein kinase A (PKA). Elevated cAMP did not prevent nuclear translocation of p50/p65 and c-Rel/p65 heterodimers, decrease nuclear translocation of p65, or significantly modify TNFalpha-induced phosphorylation of p65. Functional studies demonstrated that transcriptional activation of a plasmid containing multimerized kappaB sites by p65 was inhibited by agents that elevate cAMP and by overexpression of the catalytic subunit of PKA. This study indicates that activation of PKA reduces the induction of a distinct set of genes in monocytes and endothelial cells by inhibiting NF-kappaB-mediated transcription.

Biological Transport↗

PubMed1996

A benzothiophene-carboxamide is a potent inhibitor of IL-1beta induced VCAM-1 gene expression in human endothelial cells.

Vascular endothelial cells respond to cytokines such as IL-1 beta or TNF-alpha by undergoing a number of functional alterations. Among these alterations is the induction of cell surface adhesion molecules, including VCAM-1. In this report, we investigated the effects of a 3-alkoxybenzo[beta]thiophene-2-carboxamide (BZT) on the cytokine induction of VCAM-1 expression and activation of the transcription factor NF-kappa B in human endothelial cells. BZT blocked the IL-1 beta induced cell surface expression of VCAM-1 in human endothelial cells but did not prevent nuclear translocation of NF-kappa B. This study demonstrates that BZT is a potent inhibitor of VCAM-1 expression in human endothelial cells.

Base Sequence↗

PubMed1996

Transcriptional regulation of the tissue factor gene in human epithelial cells is mediated by Sp1 and EGR-1.

Tissue factor (TF) gene expression is rapidly induced in epithelial cells by phorbol 12-myristate 13-acetate and serum. We have shown that this induction is mediated by a novel serum response region (SRR) (-111 to +14 bp) within the human TF promoter. In this study, we characterized cis-acting genetic elements within the SRR that regulated basal and inducible expression of the TF gene in HeLa cells. Gel mobility shift assays using oligonucleotides spanning the entire SRR identified three 12-base pair (bp) motifs within subregions 1, 2, and 3 that bound constitutively expressed Sp1 and inducibly expressed EGR-1. Analysis of protein binding to these 12-bp motifs by competition with Sp1 and EGR-1 sites, mutation, and antibody supershift experiments indicated that they each contained distinct EGR-1 and Sp1 sites that overlapped by 6 bp. Functional studies using HeLa cells transfected with plasmids containing the wild-type TF promoter (-111 to +14 bp) or derivatives containing mutations in the three Sp1 and/or EGR-1 sites examined basal and inducible expression. The Sp1 sites mediated basal promoter activity, and both Sp1 and EGR-1 sites were required for maximal induction of the TF promoter by phorbol 12-myristate 13-acetate or serum. These data indicated that TF gene expression in HeLa cells was regulated by both Sp1 and EGR-1.

Base Sequence↗

PubMed1996

Proteasome inhibitors block VCAM-1 and ICAM-1 gene expression in endothelial cells without affecting nuclear translocation of nuclear factor-kappa B.

Endothelial cells play a major role in recruiting leukocytes to sites of inflammation. This is accomplished, at least in part, by up-regulation of cell surface adhesion molecules, including VCAM-1 and ICAM-1, in response to cytokines. In this report, we investigated the role of the proteasome complex in mediating the interleukin (IL)- 1 beta induction of VCAM-1 and ICAM-1 gene expression in human endothelial cells. We present evidence that a proteasome inhibitor, n-acetyl-leucinyl-leucinyl-norleucinal (norLEU), as well as specific protease inhibitors, n-tosyl-Lys-chloromethylketone and N-tosyl-Phe-chloromethylketone, blocked IL-1 beta induction of VCAM-1 and ICAM-1 promoter-driven reporter gene expression in stably transfected endothelial cells. These inhibitors also blocked cytokine induced cell surface expression of VCAM-1 and ICAM-1 by human umbilical vein endothelial cells. As expected, the protease inhibitors blocked the activation of nuclear factor (NF)-kappa B in response to IL-1 beta stimulation. In contrast, norLEU did not prevent IL-1 beta-induced nuclear translocation of NF-kappa B. The effects of norLEU were specific because it did not inhibit the IL-1 beta induction of plasminogen activator inhibitor type 1 gene expression. This study demonstrates that inhibition of the proteolytic activity of the proteasome blocks IL-1 beta induction of VCAM-1 and ICAM-1 gene expression in human endothelial cells.

Base Sequence↗

PubMed1996

Prothrombotic activation of pulmonary arterial endothelial cells in a patient with tuberculosis.

Activation of endothelial cells occurs in response to numerous physiological stimuli and results in the concerted expression of endothelial cell proteins that change the nonthrombogenic intimal surface of a vessel into a thrombogenic surface, with the subsequent development of local thrombosis. For example, both type 1 plasminogen activator inhibitor and tissue factor expression are mediated by endothelial cell stimulation in vitro; however, in contrast to type 1 plasminogen activator inhibitor, it has been difficult to detect tissue factor associated with endothelial cells in vivo. This case study describes the presence of both type 1 plasminogen activator inhibitor and tissue factor antigen associated with pulmonary arterial endothelial cells of a patient exhibiting a mycobacterial infection. The disease was associated with chronic hemoptysis and characterized by extensive tissue destruction and local thrombosis within the pulmonary artery. The data show that conditions occur in vivo in which local thrombosis is associated with increased levels of type 1 plasminogen activator inhibitor and tissue factor.

Arteries↗

PubMed1996

Expression of tissue factor is increased in astrocytes within the central nervous system during persistent infection with borna disease virus.

Persistent tolerant infection of rats with borna disease virus (BDV) results in a central nervous system (CNS) disease characterized by behavioral abnormalities. These disorders occur without inflammation and widespread cytolysis in the CNS. Therefore, mechanisms other than virally induced destruction of brain cells may explain the CNS disturbance caused by BDV. Previously, we have shown that astrocytes in the CNS express tissue factor (TF). TF functions as the primary cellular initiator of the coagulation protease cascades, resulting in the generation of the protease thrombin. Proteases and their inhibitors play important roles in the development and physiology of the CNS, and altered protease activity has been implicated in the pathophysiology of various neurological diseases. Here, we present evidence that TF expression in the brain is markedly increased during persistent infection with BDV. Persistent infection of cultured astrocytes with BDV also increased TF expression as a result of both increased transcription of the TF gene and stabilization of TF mRNA. We speculate that increased TF expression within the brain parenchyma may lead to increased protease activity in the CNS and contribute to virus-mediated CNS functional impairment by affecting neural cell interactions.

Animals↗