Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial cells (EC) are primary cellular targets for the actions of pro-inflammatory cytokines such as tumor necrosis factor (TNF). We have studied the signaling pathways used by TNF that lead to new gene expression (endothelial cell activation) or apoptosis (endothelial cell injury). Both responses are initiated by ligand binding to TNFR-I (the p55 receptor). TNF initiates transcription of the E-selectin gene by activation of the transcription factors NF-kappa B and c-Jun/ATF-2. NF-kappa B is activated following degradation of I kappa B alpha and I kappa B-beta. Activation of c-Jun/ATF-2 involves new c-Jun synthesis, and more importantly, phosphorylation of the amino terminus of c-Jun by Jun N-terminal kinase (JNK). Studies in transiently transfected human umbilical vein endothelial cells have revealed that NF-kappa B activation is initiated through the adaptor protein TRAF-2. The activation of JNK also depends upon TRAF-2 and probably involves a kinase cascade initiated by the small G proteins Rac-1 and/or cdc-42. Normally, TNF does not injure human EC. However, TNF can cause apoptosis of EC when cells are co-treated with either the protein synthesis inhibitor cycloheximide (CHX) or the lipid mediator ceramide (cer). The pathways leading to apoptosis following treatment with TNF + CHX and TNF + cer are different since only TNF + CHX is blocked by the caspase inhibitors crmA protein or the peptide zVAD.fmk while only TNF + cer is blocked by the anti apoptotic proteins Bcl-2, Bcl-XL or Al. Both pathways may be inhibited by the anti-apoptotic protein A-20. TNF does not cause the liberation of cer in EC, perhaps because of limited expression of neutral sphingomyelinase-activating adaptor protein FAN. These observations suggest that TNF normally acts as an activator of EC but may change from an activator to a killer of EC when combined with agents that release ceramide, such as u.v. irradiation or cytotoxic drugs, or with ceramide mimetics such as lipopolysaccharide. The activation and injury of endothelial cells induced by TNF and other proinflammatory cytokines may underlie the local effects of these mediators in vivo.
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PMID:Activation and injury of endothelial cells by cytokines. 976 10

Human protein C is a natural anticoagulant factor, and a recombinant activated form of the molecule (rhAPC) is completing clinical evaluation for treatment of severe sepsis. Because of the pathophysiologic role of endothelial dysfunction in severe inflammatory disease and sepsis, we explored the possibility that rhAPC might directly modulate endothelial function, independent of its anticoagulant activity. Using broad transcriptional profiling, we show that rhAPC directly modulates patterns of endothelial cell gene expression clustering into anti-inflammatory and cell survival pathways. rhAPC directly suppressed expression of p50 and p52 NFkappaB subunits, resulting in a functional decrease in NFkappaB binding at target sites. Further, rhAPC blocked expression of downstream NFkappaB regulated genes following tumor necrosis factor alpha induction, including dose-dependent suppression of cell adhesion expression and functional binding of intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin. Further, rhAPC modulated several genes in the endothelial apoptosis pathway, including the Bcl-2 homologue protein and inhibitor of apoptosis protein. These pathway changes resulted in the ability of rhAPC to inhibit the induction of apoptosis by the potent inducer, staurosporine. This new mechanistic understanding of endothelial regulation and the modulation of tumor necrosis factor-induced endothelial dysfunction creates a novel link between coagulation, inflammation, and cell death and provides insight into the molecular basis for the efficacy of APC in systemic inflammation and sepsis.
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PMID:Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. 1127 52

Implants of collagen-fibronectin gels containing Bcl-2-transduced human umbilical vein endothelial cells (Bcl-2-HUVECs) induce the formation of human endothelial cell (EC)/murine vascular smooth muscle cell (VSMC) chimeric vessels in immunodeficient mice. Microfil casting of the vasculature 60 d after implantation reveals highly branched microvascular networks within the implants that connect with and induce remodeling of conduit vessels arising from the abdominal wall circulation. Approximately 85% of vessels within the implants are lined by Bcl-2-positive human ECs expressing VEGFR1, VEGFR2, and Tie-2, but not integrin alpha(v)beta(3). The human ECs are seated on a well formed human laminin/collagen IV-positive basement membrane, and are surrounded by mouse VSMCs expressing SM-alpha actin, SM myosin, SM22alpha, and calponin, all markers of contractile function. Transmission electron microscopy identified well formed EC-EC junctions, chimeric arterioles with concentric layers of contractile VSMC, chimeric capillaries surrounded by pericytes, and chimeric venules. Bcl-2-HUVEC-lined vessels retain 70-kDa FITC-dextran, but not 3-kDa dextran; local histamine rapidly induces leak of 70-kDa FITC-dextran or India ink. As in skin, TNF induces E-selectin and vascular cell adhesion molecule 1 only on venular ECs, whereas intercellular adhesion molecule-1 is up-regulated on all human ECs. Bcl-2-HUVEC implants are able to engraft within and increase perfusion of ischemic mouse gastrocnemius muscle after femoral artery ligation. These studies show that cultured Bcl-2-HUVECs can differentiate into arterial, venular, and capillary-like ECs when implanted in vivo, and induce arteriogenic remodeling of the local mouse vessels. Our results support the utility of differentiated EC transplantation to treat tissue ischemia.
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PMID:Induction, differentiation, and remodeling of blood vessels after transplantation of Bcl-2-transduced endothelial cells. 1562 6

Although hypoxia stimulates the expression of vascular endothelial growth factor (VEGF), little is known of the role or mechanism by which VEGF functions after ischemia and reperfusion (I/R) injury. In this report, we first evaluated the expression of VEGF in a mouse model of liver warm ischemia. We found that the expression of VEGF increased after ischemia but peaked between 2 and 6 hours after reperfusion. Mice were treated with a neutralizing anti-mouse VEGF antiserum (anti-VEGF) or control serum daily from day -1 (1 day before the initiation of ischemia). Treatment with anti-VEGF significantly reduced serum glutaminic pyruvic transaminase levels and reduced histological evidence of hepatocellular damage compared with controls. Anti-VEGF also markedly decreased T-cell, macrophage, and neutrophil accumulation within livers and reduced the frequency of intrahepatic apoptotic terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells. Moreover, there was a reduction in the expression of pro-inflammatory cytokines (tumor necrosis factor-alpha and interferon-gamma), chemokines (interferon-inducible protein-10 and monocyte chemoattractant protein-1) and adhesion molecules (E-selectin) in parallel with enhanced expression of anti-apoptotic genes (Bcl-2/Bcl-xl and heme oxygenase-1) in anti-VEGF-treated animals. In conclusion, hypoxia-inducible VEGF expression by hepatocytes modulates leukocyte trafficking and leukocyte-induced injury in a mouse liver model of warm I/R injury, demonstrating the importance of endogenous VEGF production in the pathophysiology of hepatic I/R injury.
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PMID:Vascular endothelial growth factor antagonist modulates leukocyte trafficking and protects mouse livers against ischemia/reperfusion injury. 1643 82

Ischemia-reperfusion injury (IRI) contributes to early and late dysfunction of liver transplants. We have shown that sentinel Toll-like receptor-4 (TLR4) plays a key role in the activation of T cell immune responses during hepatic IRI. We have also documented that overexpression of heme oxygenase-1 (HO-1) exerts potent cytoprotective effects. This study analyzes how adenovirus (Ad)-based viral interleukin-10 (vIL-10) gene transfer affects TLR4 and HO-1 signaling in host innate and adaptive immunity during liver IRI. Using a partial lobar warm IRI model, groups of wild-type and HO-1(+/-) knockout (KO) mice were assessed for severity of hepatocellular damage after 90 min of warm ischemia followed by 6 hr of reperfusion. Both wild-type and HO-1 (+/-) KO mice treated with Ad-vIL-10 have shown improved hepatic function (serum glutamic-oxaloacetic transaminase levels), ameliorated histological signs of IRI (Suzuki's score), decreased neutrophil accumulation (myeloperoxidase activity), and depressed tumor necrosis factor-alpha/IL-1beta, IL-2/interferon-gamma, E-selectin, and macrophage inflammatory protein-2 expression. These effects were IL-10 dependent as treatment with neutralizing antibody re-created liver IRI. In contrast, untreated wild-type and HO-1 (+/-) KO mice, as well as wild-type and HO-1 (+/-) KO mice treated with Ad-beta-Gal, showed severe hepatocellular damage due to IRI. Unlike in controls, wild-type and HO-1 (+/-) KO mice treated with Ad-vIL-10 revealed markedly depressed TLR4 and NF-kappaB expression, along with increased HO-1 and Bcl-2/Bcl-x(L) expression, as compared with respective controls. Thus, vIL-10 gene transfer prevents hepatic IRI in association with depressed expression of innate TLR4, and adaptive Th1 cytokine/chemokine programs. The induction of antioxidant HO-1 and anti-apoptotic Bcl-2/Bcl-x(L) by vIL-10 exerts synergistic cytoprotective function against antigen-independent hepatic inflammatory response triggered by IRI.
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PMID:Viral interleukin-10 gene transfer prevents liver ischemia-reperfusion injury: Toll-like receptor-4 and heme oxygenase-1 signaling in innate and adaptive immunity. 1743 57

Regions of the arterial tree exposed to laminar flow, which exerts high shear stress, are protected from inflammation, endothelial cell (EC) death and atherosclerosis. TNFalpha activates NF-kappaB transcription factors, which potentially exert dual functions by inducing both proinflammatory and cytoprotective transcripts. We assessed whether laminar shear stress protects EC by modulating NF-kappaB function. Human umbilical vein EC (HUVEC) were cultured under shear stress (12 dynes/cm2 for 16 h) using a parallel-plate flow chamber or were maintained in static conditions. Comparative real-time PCR revealed that preshearing significantly alters transcriptional responses to TNFalpha by enhancing the expression of cytoprotective molecules (Bcl-2, MnSOD, GADD45beta, A1) and suppressing proinflammatory transcripts (E-selectin, VCAM-1, IL-8). We demonstrated using assays of nuclear localization, NF-kappaB subunit phosphorylation, DNA-binding, and transcriptional activity that NF-kappaB is activated by TNFalpha in presheared HUVEC. Furthermore, a specific inhibitor revealed that NF-kappaB is essential for the induction of cytoprotective transcripts in presheared EC. Finally, we observed that NF-kappaB can be activated in vascular endothelium exposed to laminar shear stress in NF-kappaB-luciferase reporter mice, thus validating our cell culture experiments. We conclude that shear stress primes EC for enhanced NF-kappaB-dependent cytoprotective responsiveness while attenuating proinflammatory activation. Thus modulation of NF-kappaB function may underlie the atheroprotective effects of laminar shear stress.
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PMID:Laminar shear stress acts as a switch to regulate divergent functions of NF-kappaB in endothelial cells. 1755 31

Atherosclerosis is a chronic inflammatory process with increased oxidative stress in vascular endothelium. Ginkgo biloba extract (GbE), extracted from Ginkgo biloba leaves, has commonly been used as a therapeutic agent for cardiovascular and neurological disorders. The aim of this study was to investigate how GbE protects vascular endothelial cells against the proatherosclerotic stressor oxidized low-density lipoprotein (oxLDL) in vitro. Human umbilical vein endothelial cells (HUVECs) were incubated with GbE (12.5-100 microg/ml) for 2 h and then incubated with oxLDL (150 microg/ml) for an additional 24 h. Subsequently, reactive oxygen species (ROS) generation, antioxidant enzyme activities, adhesion to monocytes, cell morphology, viability, and several apoptotic indexes were assessed. Our data show that ROS generation is an upstream signal in oxLDL-treated HUVECs. Cu,Zn-SOD, but not Mn-SOD, was inactivated by oxLDL. In addition, oxLDL diminished expression of endothelial NO synthase and enhanced expression of adhesion molecules (ICAM, VCAM, and E-selectin) and the adherence of monocytic THP-1 cells to HUVECs. Furthermore, oxLDL increased intracellular calcium, disturbed the balance of Bcl-2 family proteins, destabilized mitochondrial membrane potential, and triggered subsequent cytochrome c release into the cytosol and activation of caspase-3. These detrimental effects were ameliorated dose dependently by GbE (P < 0.05). Results from this study may provide insight into a possible molecular mechanism underlying GbE suppression of the oxLDL-mediated vascular endothelial dysfunction.
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PMID:Ginkgo biloba extract attenuates oxLDL-induced oxidative functional damages in endothelial cells. 1922 86

Burkholderia pseudomallei is the causative agent of melioidosis, and its infection usually affects patients' lungs. The organism is a facultative intracellular Gram-negative bacillus commonly found in soil and water in endemic tropical regions. Another closely related Burkholderia species found in soil and water is B. thailandensis. This bacterium is a non-pathogenic environmental saprophyte. B. pseudomallei is considerably more efficient than B. thailandensis in host cell invasion and adherence. A previous study by our group demonstrated that after successfully invading cells, there was no difference in the ability to survive and to replicate between both Burkholderia species in cultured A549 human lung epithelial cells. In this study, Human Affymetrix GeneChips were used to identify the difference in gene expression profiles of A549 cells after a 2-h exposure to B. pseudomallei and B. thailandensis. A total of 280 of 22,283 genes were expressed at higher levels in the B. pseudomallei-infected cells than in the B. thailandensis-infected cells, while 280 genes were expressed at lower levels in the B. pseudomallei-infected cells. Approximately 9% of these genes were involved in immune response and apoptosis. Those genes were further selected for gene expression analysis using reverse transcription PCR and/or real-time RT-PCR. The results of RT-PCR and real-time RT-PCR are in accordance with data from the microarray data in that bcl2 gene expression in the B. pseudomallei-infected cells was 2-fold higher than the level in the B. thailandensis-infected cells even though no apoptosis was seen in the infected cells. The levels of E-selectin, ICAM-1, IL-11, IRF-1, IL-6, IL-1beta and LIF genes expression in the B. pseudomallei-infected cells were 1.5-5 times lower than in the B. thailandensis-infected cells. However, both species stimulated the same level of IL-8 production from the tested epithelial cell line, and no difference in the ratio of adherent polymorphonuclear cells (PMNs) to infected A549 cells of both species was observed. Taken together, our results suggest that B. pseudomallei manipulates host response in favor of its survival in the host cell, which may explain the more virulent characteristics of B. pseudomallei when compared with B. thailandensis.
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PMID:Differential gene expression profiles of lung epithelial cells exposed to Burkholderia pseudomallei and Burkholderia thailandensis during the initial phase of infection. 1954 31

Macrophages play a critical role in the pathophysiology of liver ischemia and reperfusion (IR) injury (IRI). However, macrophages that overexpress antioxidant heme oxygenase-1 (HO-1) may exert profound anti-inflammatory functions. This study explores the cytoprotective effects and mechanisms of ex vivo modified HO-1-expressing bone marrow-derived macrophages (BMDMs) in well-defined mouse model of liver warm ischemia followed by reperfusion. Adoptive transfer of Ad-HO-1-transduced macrophages prevented IR-induced hepatocellular damage, as evidenced by depressed serum glutamic-oxaloacetic transaminase (sGOT) levels and preserved liver histology (Suzuki scores), compared to Ad-beta-gal controls. This beneficial effect was reversed following concomitant treatment with HO-1 siRNA. Ad-HO-1-transfected macrophages significantly decreased local neutrophil accumulation, TNF-alpha/IL-1beta, IFN-gamma/E-selectin, and IP-10/MCP-1 expression, caspase-3 activity, and the frequency of apoptotic cells, as compared with controls. Unlike in controls, Ad-HO-1-transfected macrophages markedly increased hepatic expression of antiapoptotic Bcl-2/Bcl-xl and depressed caspase-3 activity. These results establish the precedent for a novel investigative tool and provide the rationale for a clinically attractive new strategy in which native macrophages can be transfected ex vivo with cytoprotective HO-1 and then infused, if needed, to prospective recipients exposed to hepatic IR-mediated local inflammation, such as during liver transplantation, resection, or trauma.
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PMID:Adoptive transfer of ex vivo HO-1 modified bone marrow-derived macrophages prevents liver ischemia and reperfusion injury. 2002 97

Skin inflammation plays an important role during the healing of American tegumentary leishmaniasis (ATL), the distribution of cells in active lesions may vary according to disease outcome and parasite antigens in ATL scars have already been shown. We evaluated by immunohistochemistry, 18 patients with 1- or 3-year-old scars and the corresponding active lesions and compared them with healthy skin. Small cell clusters in scars organized as in the active lesions spreaded over the fibrotic tissue were detected, as well as close to vessels and cutaneous glands, despite a reduction in the inflammatory process. Analysis of 1-year-old scar tissue showed reduction of NOS2, E-selectin, Ki67, Bcl-2 and Fas expression. However, similar percentages of lymphocytes and macrophages were detected when compared to active lesions. Only 3-year-old scars showed reduction of CD3(+), CD4(+) and CD8(+)T cells, in addition to reduced expression of NOS2, E-selectin, Ki67 and BCl-2. These results suggest that the pattern of cellularity of the inflammatory reaction observed in active lesions changes slowly even after clinical healing. Analysis of 3-year-old scars showed reduction of the inflammatory reaction as demonstrated by decrease in inflammatory cells and in the expression of cell-activity markers, suggesting that the host-parasite balance was only established after that period.
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PMID:Signs of an in situ inflammatory reaction in scars of human American tegumentary leishmaniasis. 2039 29


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