Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple cell adhesion proteins are up-regulated in vascular endothelial cells in response to TNF alpha and other inflammatory cytokines. This increase in cell adhesion gene expression is thought to require the transcription factor NF-kappa B. Here, we show that peptide aldehyde inhibitors of the proteasome, a multicatalytic protease recently shown to be required for the activation of NF-kappa B, block TNF alpha induction of the leukocyte adhesion molecules E-selectin, VCAM-1, and ICAM-1. Striking functional consequences of this inhibition were observed in analyses of leukocyte-endothelial interactions under defined flow conditions. Lymphocyte attachment to TNF alpha-treated endothelial monolayers was totally blocked, while neutrophil attachment was partially reduced but transmigration was essentially prevented.
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PMID:The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. 753 41

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.
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PMID:Proteasome inhibitors block VCAM-1 and ICAM-1 gene expression in endothelial cells without affecting nuclear translocation of nuclear factor-kappa B. 862 76

Glomerular expression of intercellular adhesion molecule-1 (ICAM1) (CD54) and membrane cofactor protein (MCP; CD46) and positive infiltrating cells in leukocyte function associated antigen-1 (LFA1)alpha (CD11a) and C3bi receptors (CR3/CD11b, CR4/CD11c) were examined by the indirect immunoperoxidase method on 43 sets of repeated renal biopsy specimens from patients with immunoglobulin A nephropathy. Twenty-four-hour urine protein at the time of renal biopsy was also evaluated. Glomerular infiltration of LFA1alpha+ cells was significantly correlated with glomerular expression of ICAM1 (r = 0.494, P < 0.0001). Glomerular complement receptor type 4 (CR4)+ cells were significantly correlated with glomerular expression of MCP (r = 0.405, P < 0.0001). The glomerular expressions of ICAM1 and MCP were significantly correlated with each other (r = 0.700, P < 0.00001). The glomerular infiltrations of LFA1alpha+ and CR4+ cells were highly correlated with each other (r = 0.884, P < 0.00001), and both cell types were significantly correlated with urine protein (respectively, r = 0.426 and 0.478, P < 0.001 and 0.0001). When the change in these parameters between the time of the initial and follow-up biopsies was evaluated, there was a significant correlation between the change in glomerular expression of ICAM1 (DeltaICAM1) and MCP (DeltaMCP) as well as between the change in glomerular infiltration of LFA1alpha+ cells (DeltaLFA1alpha+) and CR4+ cells (DeltaCR4+). Both DeltaLFA1alpha+ and DeltaCR4+ were significantly correlated with the change in urine protein. These findings suggest that ICAM1/LFA1 interaction and MCP-mediated C3bi/C3biR interaction cooperate and participate in persistent glomerular infiltration of immune cells in immunoglobulin A nephropathy, and that these LFA1alpha+ and C3biR+ cells contribute to the induction of proteinuria.
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PMID:Intercellular adhesion molecule-1/leukocyte function associated antigen-1-mediated and complement receptor type 4-mediated infiltration and activation of glomerular immune cells in immunoglobulin A nephropathy. 871 20

It is becoming increasingly apparent that the chronic gut inflammation observed in the idiopathic inflammatory bowel diseases (e.g. ulcerative colitis, Crohn's disease) is associated with enhanced production of leukocyte-derived oxidants. Oxidants such as hydrogen peroxide are known to activate certain transcription factors such as nuclear transcription factor kappa beta. Nuclear transcription factor kB (NF-kappa B) is a ubiquitous transcription factor and pleiotropic regulator of numerous genes involved in the immune and inflammatory responses. This transcription factor is activated via the selective phosphorylation, ubiquination and degradation of its inhibitor protein I-kB thereby allowing translocation of NF-kappa B into the nucleus where it upregulates the transcription of a variety of adhesion molecules (e.g. ICAM-1, VCAM-1), cytokines (TNF, IL-1, IL-6) and enzymes (iNOS). The proteolytic degradation of the post-translationally modified I-kappa B is known to be mediated by the 26S proteasome complex. Based upon work from our laboratory, we propose that inhibition of NF-kappa B activation produces significant anti inflammatory activity which may be mediated by the inhibition of transcription of certain pro-inflammatory mediators and adhesion molecules.
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PMID:Oxidant-regulation of gene expression in the chronically inflamed intestine. 909 77

The hepatic stellate cell (HSC), following a fibrogenic stimulus, is transformed from a quiescent to an activated cell. Cytokines induce NFkappaB activity in activated but not in quiescent HSCs with subsequent expression of NFkappaB-responsive genes, such as intercellular adhesion molecule (ICAM)-1 and interleukin (IL)-6. We investigated the effect of proteasome inhibitors and an IkappaB super-repressor on the cytokine mediated activation of NFkappaB, ICAM-1, and IL-6 in activated HSCs. Culture-activated HSCs were stimulated with IL-1beta or tumor necrosis factor alpha (TNFalpha) in the presence or absence of proteasome inhibitors, ALLN or MG-132, or after infection with an adenovirus expressing the IkappaB super-repressor (Ad5IkappaB) or beta-galactosidase (Ad5LacZ) as a control. NFkappaB activity was evaluated by immunofluorescence and by electrophoretic mobility shift assay. The steady state level of cytoplasmic IkappaB protein was measured by Western Blot. ICAM-1 and IL-6 expression was measured by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbant assay. Proteasome inhibitors, which block the degradation of IkappaB, and the Ad5IkappaB, which provides an exogenous nondegradable IkappaB, block the stimulation of NFkappaB activity by TNFalpha and IL-1beta in activated HSCs. These reagents block the subsequent nuclear translocation of p65 NFkappaB and induction of ICAM-1 and IL-6 by cytokines. The specificities of the proteasome inhibitors and the IkappaB super-repressor are demonstrated by their failure to block c-Jun N-terminal kinase induction by cytokines. Cytokine-induced stimulation of NFkappaB, ICAM-1, and IL-6 is blocked by proteasome inhibitors and Ad5IkappaB in activated HSCs. Inhibition of IkappaBalpha degradation is a potential target for anti-inflammatory therapy in the liver and might influence the activation process of HSCs following fibrotic stimuli.
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PMID:Inhibition of NFkappaB in activated rat hepatic stellate cells by proteasome inhibitors and an IkappaB super-repressor. 958 6

Fibroblasts from a variety of tissues interact with and influence the behavior of the cell types they are associated with by producing specific proteins that mediate these interactions. Thus, it is not surprising that fibroblasts have been shown to differ phenotypically and functionally depending on the tissue they are isolated from and its physiologic state. To study fibroblasts of hematopoietic tissues, cultures were established from human normal bone marrow (BM), and from non-myelometaplasic (NS) and myelometaplasic spleen (MMS) tissues and analyzed for phenotypic characteristics. The results are summarized as follows: (1) cytoskeletal elements: virtually all the MMS fibroblasts were stained positively for alpha-sm-actin while only a small fraction of BM and of NS fibroblasts were positive for this antigen; (2) extracellular matrix elements: MMS fibroblasts stained positively for ED-B fibronectin and tenascin while the other 2 fibroblast cell types did not; (3) cell surface molecules: NS and MMS fibroblasts expressed significantly higher levels of ICAM-1, VLA-4 and CD9 than BM fibroblasts. Moreover, MMS fibroblasts showed a higher expression of ICAM-1 and VLA-4 than NS fibroblasts; and (4) cytokines: IL-II, RANTES and MIP-1alpha were produced in higher amounts by BM than by NS fibroblasts. Conversely, production of GM-CSF, SCF, M-CSF and MCP-1alpha was elevated in NS compared with BM fibroblasts. The production of these cytokines was generally reduced in MMS cells. Overall, our results demonstrate that phenotypic characteristics can be identified to distinguish fibroblasts from normal and pathologic hematopoietic tissues. Such phenotypic characteristics suggest functional differences of each type of fibroblast in their influence on the blood cells with which they are associated.
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PMID:Phenotypic diversity in human fibroblasts from myelometaplasic and non-myelometaplasic hematopoietic tissues. 961 Jul 38

A growing body of experimental evidence indicates that leukocyte-endothelial cell interactions may play an important role in the pathogenesis of NSAID-induced gastropathy. Using a newly described, dual radiolabeled monoclonal antibody technique to quantify adhesion molecule surface expression in vivo, we have demonstrated increases in surface expression of ICAM-1 and P-selectin in the gastric mucosa after oral administration of indomethacin. We have also found that CD18-, ICAM-1-, or P-selectin-deficient mice are less sensitive to the ulcerogenic effects of orally administered indomethacin. Although there is virtually no information regarding the regulation of expression of endothelial cell adhesion molecules (ECAMs) in experimental NSAID-induced gastropathy, the nuclear transcription factor KB (NFKB) may represent a potential modulator of transcriptional activation of ECAM expression. We have demonstrated that two structurally distinct yet highly selective proteasome inhibitors (MG341, lactacystin) inhibit tumor necrosis factor (TNF)-induced NFKB activation as well as ECAM expression in human endothelial cells in vitro. In addition, we found that these proteasome inhibitors significantly reduced indomethacin-induced gastric mucosal injury as well as gastric mucosal ICAM-1 expression in the rat in vivo. We conclude from these studies that indomethacin activates NFKB (possibly via TNF synthesis) in gastric microvascular endothelial cells, thereby enhancing surface expression of ICAM-1 which binds the CD18 on polymorphonuclear leukocytes (PMNs). These adherent PMNs are then believed to mediate endothelial and/or epithelial cell injury either directly or indirectly.
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PMID:Molecular mechanisms involved in NSAID-induced gastropathy. 987 3

Migration of CD4 cells into the pancreas represents a hallmark event in the development of insulin-dependent diabetes mellitus. Th1, but not Th2, cells are associated with pathogenesis leading to destruction of islet beta-cells and disease onset. Lymphocyte extravasation from blood into tissue is regulated by multiple adhesion receptor/counter-receptor pairs and chemokines. To identify events that regulate entry of CD4 cells into the pancreas, we transferred Th1 or Th2 cells induced in vitro from islet-specific TCR transgenic CD4 cells into immunodeficient (NOD.scid) recipients. Although both subsets infiltrated the pancreas and elicited multiple adhesion receptors (peripheral lymph node addressin, mucosal addressin cell adhesion molecule-1, LFA-1, ICAM-1, and VCAM-1) on vascular endothelium, entry/accumulation of Th1 cells was more rapid than that of Th2 cells, and only Th1 cells induced diabetes. In vitro, Th1 cells were also distinguished from Th2 cells by the capacity to synthesize several chemokines that included lymphotactin, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1alpha, whereas both subsets produced macrophage inflammatory protein-1beta. Some of these chemokines as well as RANTES, MCP-3, MCP-5, and cytokine-response gene-2 (CRG-2)/IFN-inducible protein-10 (IP-10) were associated with Th1, but not Th2, pancreatic infiltrates. The data demonstrate polarization of chemokine expression by Th1 vs Th2 cells, which, within the microenvironment of the pancreas, accounts for distinctive inflammatory infiltrates that determine whether insulin-producing beta-cells are protected or destroyed.
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PMID:Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes. 1007 90

The objective of this study was to assess the effects of two structurally distinct yet selective proteasome inhibitors (PS-341 and lactacystin) on leukocyte adhesion, endothelial cell adhesion molecule (ECAM) expression, and nuclear factor-kappaB (NF-kappaB) activation in tumor necrosis factor (TNF)-alpha-stimulated human umbilical vein endothelial cells (HUVEC) and the transformed, HUVEC-derived, ECV cell line. We found that TNF (10 ng/ml) significantly enhanced U-937 and polymorphonuclear neutrophil (PMN) adhesion to HUVEC but not to ECV; TNF also significantly enhanced surface expression of vascular cell adhesion molecule 1 and E-selectin (in HUVEC only), as well as intercellular adhesion molecule 1 (ICAM-1; in HUVEC and ECV). Pretreatment of HUVEC with lactacystin completely blocked TNF-stimulated PMN adhesion, partially blocked U-937 adhesion, and completely blocked TNF-stimulated ECAM expression. Lactacystin attenuated TNF-stimulated ICAM-1 expression in ECV. Pretreatment of HUVEC with PS-341 partially blocked TNF-stimulated leukocyte adhesion and ECAM expression. These effects of lactacystin and PS-341 were associated with inhibitory effects on TNF-stimulated NF-kappaB activation in both HUVEC and ECV. Our results demonstrate the importance of the 26S proteasome in TNF-induced activation of NF-kappaB, ECAM expression, and leukocyte-endothelial adhesive interactions in vitro.
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PMID:Effect of selective proteasome inhibitors on TNF-induced activation of primary and transformed endothelial cells. 1019 16

Membrane-permeable proteasome inhibitors, lactacystin (LC) and N-acetyl-Leu-Leu-norleucinal (ALLN), but not calpain inhibitor Z-Leu-leucinal (ZLL), prevented LFA-1/ICAM-1-dependent cellular adhesion of TPA-stimulated HL-60 cells. These proteasome inhibitors affected neither the induction of monocytic differentiation nor the accompanying protein-tyrosine phosphorylation. They suppressed the increase in the avidity of LFA-1 to ICAM-1 without changing the expression of these molecules. Immunoblotting using monoclonal antibody FK-1, which reacts specifically with polyubiquitinated proteins, demonstrated that the proteasome inhibitors caused the drastic accumulation of the polyubiquitinated proteins in the membrane fraction of TPA-treated HL-60 cells. This indicates that accompanying activation of LFA-1, TPA induces the polyubiquitination of the membrane proteins, which are rapidly degraded by proteasomes. These data taken together show that proteolysis mediated by the ubiquitin-proteasome system is a prerequisite for the induction of LFA-1-dependent adhesion of HL-60 cells.
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PMID:Ubiquitin-proteasome system is involved in induction of LFA-1/ICAM-1-dependent adhesion of HL-60 cells. 1038 Aug 99


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