Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to investigate the capacity of human vascular smooth muscle cells (SMCs) to produce a cytokine chemotactic for monocytes (monocyte chemotactic protein [MCP]) and by way of comparison, a related polypeptide activator of neutrophils (known as interleukin-8 [IL-8] or neutrophil activating protein-1 [NAP-1]. On exposure to IL-1, SMCs released high levels of chemotactic activity for monocytes, which could be removed by absorption with anti-MCP antibodies. MCP production by activated SMCs was comparable to that of IL-1-stimulated umbilical vein endothelial cells. Activated SMCs released appreciable levels of IL-8, as determined by a specific enzyme-linked immunosorbent assay, but little chemotactic activity for neutrophils. IL-1-treated SMCs expressed high levels of both MCP and IL-8 mRNA transcripts, as assessed by Northern blot analysis. Tumor necrosis factor and bacterial lipopolysaccharide but not IL-6 also induced MCP and IL-8 gene expression in SMCs. Nuclear runoff analysis revealed that IL-1 augmented transcription of the MCP and IL-8 genes. The capacity of SMCs to produce a cytokine (MCP) that recruits and activates circulating mononuclear phagocytes may be of considerable importance in the pathogenesis of vascular diseases (e.g., vasculitis and atherosclerosis) that are characterized by monocyte infiltration of the vessel wall.
 ...
PMID:Expression of monocyte chemotactic protein and interleukin-8 by cytokine-activated human vascular smooth muscle cells. 191 3

We studied cytokine-related functional properties of four mouse endotheliomas from different anatomical sites obtained by transformation with middle T oncogene. We examined mRNA expression of IL-6, IL-1 alpha, macrophage-CSF, granulocyte/macrophage-CSF, and two members of an emerging super-family of chemotactic cytokines (JE/monocyte chemoattractant protein-1 (MCP-1) and KC). Exposure to IL-1 augmented or induced cytokine gene transcripts in three endothelioma lines (eEnd.1, sEnd.1, and tEnd) with maximal expression in tEnd.1 cells. Endothelioma cells also responded to TNF-alpha and LPS. Levels of IL-6 and monocyte chemotactic activity (a JE/MCP activity) correlated with mRNA expression. IL-1 also induced production of procoagulant activity and platelet-activating factor in endothelioma cells, with heterogeneity in the levels of response among individuals lines. Murine melanoma B16-F1, human colon carcinoma HT29 cells, CB33MT lymphoblastoid cells, and monocytes adhered to endothelioma monolayers and the adhesive properties of these cell lines were modulated by IL-1 beta, with marked differences among themselves. Murine EC derived from brain capillaries, used as control, shared several properties with bEnd.4 line. Endothelioma lines cause tumors by recruiting host cells. The capacity to produce cytokines that directly or indirectly attract host vascular cells, may play an important role in hemangioma induction in vivo. Murine endothelioma lines, generated by transformation with the polyoma middle T oncogene, retain functional properties of normal endothelium, and may represent an invaluable tool for analysis of the immunobiology and heterogeneity of EC in different tissues.
 ...
PMID:Murine endothelioma cell lines transformed by polyoma middle T oncogene as target for and producers of cytokines. 191 46

Endothelial cells are critical elements in the evolution of all types of cutaneous inflammation. They participate through the synthesis and secretion of pro-inflammatory cytokines, including interleukin 1 (IL-1), IL-6, and IL-8, as well as M-CSF, G-CSF, GM-CSF, gro alpha, and MCP. They also express a series of cell-surface proteins and glycoproteins known as cell adhesion molecules that allow circulating leukocytes to bind to endothelial cells and allow endothelial cells to bind to matrix proteins. The regulated expression of these molecules, including those in the integrin, immunoglobulin gene, and selection families, allows for the precise trafficking of circulating leukocytes to sites of inflammation, injury, or immunologic stimulation in the skin. Furthermore, emerging evidence clearly indicates that selected differences exist between endothelial cells of the microvasculature and those that line large blood vessels. These include differences in secreted products, differences in the expression of cell adhesion molecules, and differences in cytokine-induced regulation of commonly expressed cell adhesion molecules, among others. Thus, a precise delineation of the biology of cutaneous microvascular endothelial cells is important to our understanding of cutaneous inflammation.
 ...
PMID:Role of microvascular endothelial cells in inflammation. 842 79

The effects of N-acetyl-leucinyl-leucinyl-norleucinal (ALLN), a potent inhibitor of proteolysis catalyzed by proteasomes, on the activation of NF-kappaB in vitro and in vivo have been examined. Confirming earlier observations, ALLN inhibits the activation of NF-kappaB in macrophage cultures stimulated with LPS, resulting in the intracellular accumulation of IkappaB and p105. The synthesis of TNF, a reaction dependent upon NF-kappaB activation, is blocked by ALLN. Treatment of mice with LPS results in the induction of TNF and IL-6 within 90 min followed by lethal shock at 24 hr. In mice pretreated with ALLN, serum TNF and IL-6 levels were significantly lower than those in untreated animals. These studies suggest that the proteasome is a novel target for the identification of agents that may be useful in the treatment of those diseases whose etiology is dependent on the activation of NF-kappaB.
 ...
PMID:N-acetyl-leucinyl-leucinyl-norleucinal inhibits lipopolysaccharide-induced NF-kappaB activation and prevents TNF and IL-6 synthesis in vivo. 902 26

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.
 ...
PMID:Oxidant-regulation of gene expression in the chronically inflamed intestine. 909 77

The Rel/NF kappa B family of eukaryotic transcription factors are critical in immune and inflammatory processes regulating the expression of a wide variety of cytokines including IL-1, IL-2, IL-6, TNF-alpha and GM-CSF. Its ubiquitous distribution, rapid induction and regulation, the complexity of its subunits and its apparent involvement in several diseases has made this transcription factor a subject of intense study in normal cellular growth and cancer. Emerging studies have implicated a role for this transcription factor in the normal processes of aging. As significant declines in immune function is a natural concomitant to advancing age, the regulation of transcription factor NF kappa B appears to play a pivotal role in immune dysregulation during senescence, contributing to down regulation of both IL-2 and IL-2 receptor-alpha expression. Our studies have contributed to understanding the regulation of lowered NF kappa B induction in T cells during aging in humans and mice. Since we have shown that the lowered induction of NF kappa B in activated T cells from the elderly can be attributed to impaired degradation of the inhibitor I kappa B-alpha due to lowered proteasomal activity, we suspect that a similar alteration in proteasomal activity may be operative in age-dependent failure of immune function including the inability to initiate DNA synthesis following activation, skewing of T cell repertoire, lowered cytolytic activity and accumulation of aberrant proteins. Understanding the regulation of the proteasome pathway during immune senescence may provide new avenues for therapeutic intervention for immune based geriatric diseases.
 ...
PMID:Regulation of transcription factor NF kappa B in immune senescence. 944 66

Recombinant mouse mast cell protease 6 (mMCP-6) was generated to study the role of this tryptase in inflammatory reactions. Seven to forty-eight hours after the i.p. injection of recombinant mMCP-6 into BALB/c, mast cell-deficient WCB6F1-Sl/Sl(d), C5-deficient, or mMCP-5-null mice, the number of neutrophils in the peritoneal cavity of each animal increased significantly by >50-fold. The failure of the closely related recombinant tryptase mMCP-7 to induce a comparable peritonitis indicates that the substrate specificities of the two tryptases are very different. Unlike most forms of acute inflammation, the mMCP-6-mediated peritonitis was relatively long lasting and neutrophil specific. Mouse MCP-6 did not induce neutrophil chemotaxis directly in an in vitro assay, but did promote chemotaxis of the leukocyte in the presence of endothelial cells. Mouse MCP-6 did not induce cultured human endothelial cells to express TNF-alpha, RANTES, IL-1alpha, or IL-6. However, the tryptase induced endothelial cells to express large amounts of IL-8 continually over a 40-h period. Neither enzymatically active mMCP-7 nor enzymatically inactive pro-mMCP-6 was able to induce endothelial cells to increase their expression of IL-8. Although the mechanism by which mMCP-6 induces neutrophil accumulation in tissues remains to be determined, the finding that mMCP-6 induces cultured human endothelial cells to selectively release large amounts of IL-8 raises the possibility that this tryptase regulates the steady state levels of neutrophil-specific chemokines in vivo during mast cell-mediated inflammatory events.
 ...
PMID:Induction of a selective and persistent extravasation of neutrophils into the peritoneal cavity by tryptase mouse mast cell protease 6. 946 53

We recently described a novel population of blood-borne cells, termed fibrocytes, that display a distinct cell surface phenotype (collagen+/CD13+/CD34+/CD45+), rapidly enter sites of tissue injury, and contribute to scar formation. To further characterize the role of these cells in vivo, we examined the expression of type I collagen and cytokine mRNAs by cells isolated from wound chambers implanted into mice. Five days after chamber implantation, CD34+ fibrocytes but not CD14+ monocytes or CD90+ T cells expressed mRNA for type I collagen. Fibrocytes purified from wound chambers also were found to express mRNA for IL-1beta, IL-10, TNF-alpha, JE/MCP, MIP-1alpha, MIP-1beta, MIP-2, PDGF-A, TGF-beta1, and M-CSF. The addition of IL-1beta (1-100 ng/ml), a critical mediator in wound healing, to fibrocytes isolated from human peripheral blood induced the secretion of chemokines (MIP-1alpha, MIP-1beta, MCP-1, IL-8, and GRO alpha), hemopoietic growth factors (IL-6, IL-10, and macrophage-CSF), and the fibrogenic cytokine TNF-alpha. By contrast, IL-1beta decreased the constitutive secretion of type I collagen as measured by ELISA. Additional evidence for a role for fibrocytes in collagen production in vivo was obtained in studies of livers obtained from Schistosoma japonicum-infected mice. Mouse fibrocytes localized to areas of granuloma formation and connective matrix deposition. We conclude that fibrocytes are an important source of cytokines and type I collagen during both the inflammatory and the repair phase of the wound healing response. Furthermore, IL-1beta may act on fibrocytes to effect a phenotypic transition between a repair/remodeling and a proinflammatory mode.
 ...
PMID:Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. 955 99

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.
 ...
PMID:Inhibition of NFkappaB in activated rat hepatic stellate cells by proteasome inhibitors and an IkappaB super-repressor. 958 6

The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1. These so-called IL-6-type cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation. The current knowledge on the signal-transduction mechanisms of these cytokines from the plasma membrane to the nucleus is reviewed. In particular, we focus on the assembly of receptor complexes after ligand binding, the activation of receptor-associated kinases of the Janus family, and the recruitment and phosphorylation of transcription factors of the STAT family, which dimerize, translocate to the nucleus, and bind to enhancer elements of respective target genes leading to transcriptional activation. The important players in the signalling pathway, namely the cytokines and the receptor components, the Janus kinases Jak1, Jak2 and Tyk2, the signal transducers and activators of transcription STAT1 and STAT3 and the tyrosine phosphatase SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase] are introduced and their structural/functional properties are discussed. Furthermore, we review various mechanisms involved in the termination of the IL-6-type cytokine signalling, namely the action of tyrosine phosphatases, proteasome, Jak kinase inhibitors SOCS (suppressor of cytokine signalling), protein inhibitors of activated STATs (PIAS), and internalization of the cytokine receptors via gp130. Although all IL-6-type cytokines signal through the gp130/Jak/STAT pathway, the comparison of their physiological properties shows that they elicit not only similar, but also distinct, biological responses. This is reflected in the different phenotypes of IL-6-type-cytokine knock-out animals.
 ...
PMID:Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. 971 87


1 2 3 4 5 6 7 8 9 10 Next >>