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)

In an effort to elucidate the activation status of neutrophils (PMN) in inflammatory joint disease the expression of relevant cell surface proteins was examined using immunofluorescence and flow cytometry. Paired samples of SF and peripheral blood were obtained from 18 patients with RA and PMN purified using methods designed to minimize activation in vitro. We then used flow cytometry to measure expression of the four membrane complement regulatory molecules, decay accelerating factor (DAF; CD55), complement receptor 1 (CR1; CD35), membrane cofactor protein (MCP; CD46) and CD59; two adhesion molecules of the integrin family LFA1 (alpha chain, CD11a), complement receptor 3 (CR3; alpha chain, CD11b), and their common beta chain (CD18); the major receptor for immune complexes Fc gamma RIII (CD16), and the leucocyte common antigen tyrosine phosphatase (L-CA; CD45). Expression of these molecules was also measured on peripheral blood PMN from 18 age- and sex-matched normal controls. In RA, SF PMN expressed significantly higher levels of the complement regulators CD55 and CD35, the adhesion molecule CR3 (CD11b/CD18) and of CD45 but significantly lower levels of CD46 and CD11a in comparison with blood PMN from the same patient. Expression of CD59 and CD16 did not differ between the two groups. These changes may increase adhesiveness and complement resistance of PMN in SF compared with blood. PMN from RA expressed significantly less of all the complement C3 convertase regulators (CD55, CD46, CD35), all the adhesion molecules (CD11a, CD11b, CD18) and the phosphatase CD45 than did blood PMN from age and sex-matched control individuals.
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PMID:Expression of complement regulatory molecules and other surface markers on neutrophils from synovial fluid and blood of patients with rheumatoid arthritis. 805 95

The objectives of this study were to (1) assess the role of the 26S proteasome complex in regulating the expression of the inducible isoform of nitric oxide synthase (iNOS) and vascular cell adhesion molecule-1 (VCAM-1) in a model of chronic granulomatous colitis in vivo and (2) determine the role of the proteasome in regulating the inflammatory response observed in this model of chronic gut inflammation. The selective proteasome inhibitor MG-341 (0.3 mg/kg) was administered by gavage beginning immediately before the induction of colitis and continuing daily thereafter for the entire 14-day experimental period. We found that chronic proteasome inhibition using MG-341 significantly attenuated the peptidoglycan/polysaccharide (PG/PS)-induced up-regulation of iNOS in the colon and spleen and the consequent increase in plasma levels of nitrate and nitrite. Furthermore, we found that the proteasome inhibitor suppressed the up-regulation of the adhesion molecule VCAM-1 in the colon. We also found that MG-341 attenuated PG/PS-induced increases in macroscopic colonic inflammation, bowel wall thickness, colonic dry weight and colonic MPO activity. Treatment with MG-341 also significantly reduced PG/PS-induced increases in macroscopic spleen inflammation, spleen weight and spleen MPO activity. We conclude that the 26S proteasome complex plays an important role in regulating the PG/PS-induced up-regulation of iNOS and VCAM-1 in vivo and appears to be important in regulating colonic and splenic inflammation.
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PMID:Proteasome inhibition attenuates nitric oxide synthase expression, VCAM-1 transcription and the development of chronic colitis. 931 79

Activation of the transcription factor NF-kappa B is a paradigm for signal transduction through the ubiquitin-proteasome pathway: ubiquitin-dependent degradation of the transcriptional inhibitor I kappa B in response to cell stimulation. A major issue in this context is the nature of the recognition signal and the targeting enzyme involved in the proteolytic process. Here we show that following a stimulus-dependent phosphorylation, and while associated with NF-kappa B, I kappa B is targeted by a specific ubiquitin-ligase via direct recognition of the signal-dependent phosphorylation site; phosphopeptides corresponding to this site specifically inhibit ubiquitin conjugation of I kappa B and its subsequent degradation. The ligase recognition signal is functionally conserved between I kappa B alpha and I kappa B beta, and does not involve the nearby ubiquitination site. Microinjection of the inhibitory peptides into stimulated cells abolished NF-kappa B activation in response to TNF alpha and the consequent expression of E-selectin, an NF-kappa B-dependent cell-adhesion molecule. Inhibition of NF-kappa B function by specific blocking of ubiquitin ligase activity provides a novel approach for intervening in cellular processes via regulation of unique proteolytic events.
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PMID:Inhibition of NF-kappa-B cellular function via specific targeting of the I-kappa-B-ubiquitin ligase. 935 30

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

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

In xenotransplantation the use of donors transgenic for recipient-type complement regulatory protein decay-accelerating factor (DAF/CD55) or membrane co-factor protein (MCP/CD46) protects grafts against hyperacute rejection (HAR), which is primarily mediated by xenoreactive natural antibodies and complement. In the Langendorff model, we previously demonstrated that rat hearts transgenic for human CD55 (hCD55), perfused with human serum, were protected against HAR. However, ex vivo, these hearts were found to be destroyed by a process occurring after the period of HAR. The question arose as to whether hearts transgenic for hCD55 are also protected against adhesion and infiltration by cells implicated in the early phases of xenograft rejection. The aim of the present study was to analyze this process in the ex vivo heart perfusion model. hCD55-transgenic rat hearts and their controls were perfused with either heat-inactivated or normal human blood solutions for 60 min. Although most of the hearts had stopped beating within the 60-min perfusion period, the perfusion was not stopped to enable adhesion of cells during a fixed period identical for all groups. Independent of the presence of complement, H&E-stained tissues of hCD55-transgenic hearts revealed fewer PMN leukocytes adhering to the endothelium than the controls (mean: 31% vs 60%). Standard histology and immunohistochemistry showed that hCD55-transgenic hearts exhibited less interstitial edema, hemorrhage, microthrombosis, fibrin deposition, and leukocyte infiltration than did the controls. All hearts showed mild to moderate levels of P-selectin and similar levels of ICAM-1, C3c, C9, IgA, IgG, and IgM deposition. hCD55 expressed on rat hearts not only inhibits complement activation, but also human leukocyte adhesion and apparently functions as an anti-adhesion molecule. hCD55 is an efficient factor in protecting grafts against HAR and protects the graft against adhesion of leukocytes as well.
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PMID:Human decay-accelerating factor expressed on rat hearts inhibits leukocyte adhesion. 1266 11

Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), an adhesion molecule expressed on hematopoietic and endothelial cells, mediates apoptosis, cell proliferation, and migration and maintains endothelial integrity in addition to its roles as a modulator of lymphocyte and platelet signaling and facilitator of neutrophil transmigration. Recent data suggest that CD31 functions as a scaffolding protein to regulate phosphorylation of the signal transducers and activators of transcription (STAT) family of signaling molecules, particularly STAT3 and STAT5. STAT3 regulates the acute phase response to innate immune stimuli such as lipopolysaccharide (LPS) and promotes recovery from LPS-induced septic shock. Here we demonstrate that CD31-deficient mice have reduced survival during endotoxic LPS-induced shock. As compared to wild-type controls, CD31-deficient mice showed enhanced vascular permeability; increased apoptotic cell death in liver, kidney, and spleen; and elevated levels of serum tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFNgamma), MCP-1, MCP-5, sTNRF, and IL-6. In response to LPS in vivo and in vitro, splenocytes and endothelial cells from knockout mice had reduced levels of phosphorylated STAT3. These results suggest that CD31 is necessary for maintenance of endothelial integrity and prevention of apoptosis during septic shock and for STAT3-mediated acute phase responses that promote survival during septic shock.
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PMID:Enhanced susceptibility to endotoxic shock and impaired STAT3 signaling in CD31-deficient mice. 1563 11

The ubiquitin proteasome system (UPS) is a major cellular protein degradation pathway that involves the modulation of key proteins controlling inflammation, cell cycle regulation and gene expression. Modulation of the UPS with proteasome inhibitors has indicated efficacy in the treatment of several disease states including cancer and neuro-inflammatory disorders. In particular, a series of recent reports have evaluated the pre-clinical efficacy of the proteasome inhibitor MLN519 for the treatment of focal ischemic/reperfusion brain injury in rats. Evidence from these studies indicate that the neuroprotection provided by MLN519 is related to an anti-inflammatory effect linked to the modulation of nuclear factor kappaB (NF-kappaB) activity, attenuation of cytokine (TNF-alpha, IL-1beta, and IL-6) and cellular adhesion molecule (ICAM-1 and E-selectin) expression, and reduction of neutrophil and macrophage infiltration into the injured rat brain. It is the aim of this paper to review the experimental neuroprotection data reported using MLN519 with a focus on the molecular and cellular mechanisms of anti-inflammatory action.
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PMID:Neuroprotection with the proteasome inhibitor MLN519 in focal ischemic brain injury: relation to nuclear factor kappaB (NF-kappaB), inflammatory gene expression, and leukocyte infiltration. 1675 50

The aim of this study is to investigate the role of proteasome in the pathogenesis of lung injury induced by intestinal ischemia/reperfusion (I/R) by examining the effect of the proteasome inhibitor lactacystin on neutrophil infiltration, intracellular adhesion molecule-1 (ICAM-1) expression and nuclear factor kappa B (NF-kappaB) activation. Thirty-two Wistar rats were divided into (1) control, (2) intestinal I/R, (3) 0.2 mg/kg lactacystin pretreated, and (4) 0.6 mg/kg lactacystin pretreated groups (n=8). Injuries in lung and intestine were induced by intestinal I/R, and were characterized by histological edema, hemorrhage and infiltration of inflammatory cells. The results showed a significant increase in serum creatine kinase B (CK-B) and lung water content in intestine and lung injuries. As compared with the control group, the myeloperoxidase (MPO) activity in intestine and lung as well as the serum TNF-alpha level increased significantly in intestinal I/R group. Simultaneously, expression of ICAM-1 and NF-kappaB p65 was also observed in the I/R group. Pre-treatment with lactacystin markedly reduced 20S proteasome activity in circulating white blood cells and ameliorated intestine and lung injuries. These results demonstrated that the proteasome participates in the pathogenesis of lung injury induced by intestinal I/R. Lactacystin as a proteasome inhibitor can prevent this kind of injury by decreasing ICAM-1 and TNF-alpha production via the inhibition of NF-kappaB activation.
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PMID:Proteasome inhibition attenuates lung injury induced by intestinal ischemia reperfusion in rats. 1687 3

Acoustic trauma induces cochlear inflammation. We hypothesized that chemokines are involved in the recruitment of leukocytes as part of a wound healing response. The cochleas of NIH-Swiss mice, exposed to octave-band noise (8-16 kHz, at 118 dB) for 2h, were examined after the termination of exposure. Leukocytes were identified immunohistochemically with antibodies to CD45 and F4/80. Gene array analysis followed by RT-PCR was performed on cochlear tissue to identify up-regulation of chemokine and adhesion molecule mRNA. The expression of the adhesion molecule ICAM-1 was also investigated immunohistochemically. Few CD45- or F4/80-positive leukocytes were observed in the non-exposed cochlea. Following acoustic trauma however, the number of CD45-positive cells was dramatically increased especially after 2 and 4 days, after which time the numbers decreased. F4/80-positive cells also increased in number over the course of a week. Gene array analysis indicated increased expression of monocyte chemoattractant protein 5 (MCP-5), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein-1beta (MIP-1beta) and ICAM-1. RT-PCR, performed using primers for the individual mRNA sequences, confirmed the increased expression of MCP-1, MCP-5, MIP-1beta, and ICAM-1 relative to non-exposed mice. In the normal cochlea, ICAM-1 immunohistochemical expression was observed in venules, spiral ligament fibrocytes and in endosteal cells of the scala tympani. Expression increased to include more of the spiral ligament and endosteal cells after acoustic trauma. A cochlear inflammatory response is initiated in response to acoustic trauma and involves the recruitment of circulating leukocytes to the inner ear.
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PMID:Immune cell recruitment following acoustic trauma. 1708 14


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