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)

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

We have studied synthesis of the complement components and regulatory proteins of the alternative pathway and the membrane attack complex in synovial membrane. RNA was extracted from synovial tissue of patients with rheumatoid arthritis (RA) or osteoarthritis (OA) as well as from normal synovial membrane. Dot blot analysis showed the presence of mRNAs for all the complement components and regulatory proteins (C3, factor B, factor D, C5, C6, C7, C9, factor H, factor I, S-protein, SP-40, 40, DAF, MCP, CR1, CD59), except for properdin, C8 alpha, C8 beta and C8 gamma in all three types of synovial membrane studied. In an attempt to determine which components were synthesised by each cell type, monocytes (mononuclear phagocytes), human umbilical vein endothelial cells (HUVEC), synovial membrane fibroblasts (from normal, OA and RA synovial membrane) and peripheral blood lymphocytes were cultured in vitro and secretion rates of individual components were measured and total cellular RNA analysed by northern blotting. Monocytes secreted properdin, C3, and factor H but not factor B, factor I, C5, C6, C7, C8 or C9. Fibroblasts and endothelial cells secreted factor B, factor H and factor I, but not properdin, C5, C6, C7, C8 or C9. Lymphocytes did not secrete any of these components. mRNAs encoding C3, factor B, factor H, S-protein, SP-40, 40, MCP and DAF were detected in all three other cell types (monocytes, fibroblasts and HU-VEC), but factor I and CD59 mRNAs were not detected in monocytes. C5, C6, C7, C8 alpha, C8 beta, CD8 gamma and C9 mRNAs were not detected in any of the cell types studied.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of the components and regulatory proteins of the alternative complement pathway and the membrane attack complex in normal and diseased synovium. 831 Feb 5

The human cell surface complement regulatory proteins CD46 (MCP), CD55 (DAF) and CD35 (CR1) protect autologous cells from complement-mediated damage by inhibiting C3 and C5 convertases. This regulatory potential has previously been exploited in the treatment of some models of inflammatory injury by the generation of recombinant soluble (rs) proteins, such as rsCD55 and rsCD35 . More recently, we have shown that rsCD46 inhibits complement activation in the fluid phase. In this report, the ability of rsCD46, rsD55 and rsCD35 to regulate human complement activation mediated by the classical pathway in vitro was clearly demonstrated by all three soluble proteins; however, rsCD35 was a more effective inhibitor than either rsCD46 or rsCD55. A combination of rsCD46+ rsCD55 was more potent than either of these proteins alone. Cell lysis via alternative pathway activation in vitro was efficiently regulated by rsCD46 and rsCD35 to a similar extent, whereas rsCD55 was not effective. Assays of rsCD46 in vivo have previously not been possible due to difficulties in expressing sufficient quantities of protein. This limitation has been overcome and now we report the ability of rsCD46 to inhibit immune complex-mediated inflammation in a rat using the reverse passive Arthus reaction model. Administration of rsCD46 significantly reduced the size of lesion, and histological examination showed a reduction in inflammatory infiltrate and edema. These data suggest that rsCD46, in addition to rsCd55 and rsCD35, may be useful a therapeutic agent.
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PMID:A functional analysis of recombinant soluble CD46 in vivo and a comparison with recombinant soluble forms of CD55 and CD35 in vitro. 860 24

Complement in the postmortem brains of 15 cases of Pick's disease has been widely analyzed immunohistochemically and, in 2 cases, by immunoelectron microscopy. Astrocytes and the Pick bodies and cytoplasm of ballooned neurons were immunoreactive with antibodies to classical pathway components C1, C1q, C4, C2 and C3 and the terminal complex components C5, C6 and C8. In almost all cases, no immunostaining was obtained with antibodies against C9 and neoepitopes in the membrane attack complex (MAC), the complement complex responsible for cytotoxicity. However, unequivocal staining with antibodies to two soluble complement regulatory proteins, S-protein and clusterin, and to the membrane complement inhibitor CD59 was found, although three other membrane inhibitors, CR1(CD35), DAF (CD55), and MCP (CD46), were not detected. The complement immunoreactivity of astrocytes and neurons could be the result of complement biosynthesis or attack. Complement attack will be restricted by the expressed regulatory proteins. However, neurons may be the victims of attack since they show pathological change. The internalization of complement-attacked membrane, perhaps involving the genesis of Pick bodies and ballooning, may explain the intracellular immunolocalization of complement in damaged neurons. Immunoglobulins, as a possible source of complement activation, were observed in only two cases, leaving unresolved the trigger for complement activation in the other cases.
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PMID:Role of complement in the aetiology of Pick's disease? 862 48

Previous studies have suggested that the residues 727-768 of human (Hu) C3 contain the binding sites for CR1, factor H, and factor B. Here, we have (1) characterized further some of the C3 structural requirements for its binding to CR1, H, and B, (2) investigated the functions associated with these C3-ligand interactions, and (3) studied the relationship of MCP-binding sites in C3 with those for CR1, H, and B. Hu C3 molecules in which residues 727-768 were deleted (designated C3delta727-768) or substituted with the corresponding segment of cobra venom factor, Xenopus, or trout C3 (chimeric C3s) were expressed in the baculovirus system and analyzed for their reactivity with C3-binding proteins. In contrast to wild-type iC3 which, in the presence of CR1, is cleaved by factor I to iC3b-a and C3c-a and C3dg, all chimeric C3s were cleaved only to iC3b-a. In addition, the cleavage of deleted (C3delta727-768) iC3 to iC3b-a by factor I in the presence of CR1 was significantly reduced, whereas it remained unaltered in the presence of MCP. Cleavage of iC3 to iC3b-a by factor I and H was similar in all expressed C3s except C3delta727-768, whose cleavage was significantly reduced. All of the expressed molecules except C3delta727-768 were capable of forming the fluid-phase alternative pathway C3 convertase, and all reacted with properdin. These results suggest that during cleavage of iC3 by factor I and CR1, or H, CR1 and H bind to at least two sites on C3 and that the MCP binding site(s) on C3b are different from those for CR1. They also indicate that some or all of the C3 residues that are directly involved in, or contribute to, the structure of one of the CR1 and H binding sites are located within residues 727-768. These studies also demonstrate that, although this segment of C3 may be involved in C3-factor B interaction, other residues in addition to 736EE (previously implicated in B binding) must also contribute significantly to this interaction.
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PMID:Dissection of CR1, factor H, membrane cofactor protein, and factor B binding and functional sites in the third complement component. 864 30

Rat oligodendrocytes spontaneously activate complement (C) and lack the C inhibitor CD59. As a consequence, rat oligodendrocytes are susceptible to lysis by autologous C in vitro. Expression of C inhibitors on human oligodendrocytes in vitro and other human glia has yet to be well characterized. We have previously shown expression at the mRNA level of the membrane inhibitors CD59, decay-accelerating factor (DAF; CD55) and membrane cofactor protein (MCP; CD46) in human astrocytes. We here examine the expression of membrane and secreted C inhibitors by the oligodendrocyte cell line, HOG. HOG cells abundantly expressed CD59, assessed at protein and mRNA level, and expressed DAF and MCP, albeit at a lower level. Expression of all three inhibitors was enhanced by incubation with interferon-gamma or with phorbol ester (PMA). Complement receptor type 1 (CR1; CD35) was neither expressed constitutively nor induced by cytokines. HOG also constitutively secreted C1-inhibitor, S-protein and clusterin. Factor H was secreted only after stimulation with cytokines. C4b binding protein was expressed at a very low level and was detected only at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR). For comparison, astrocyte expression of CD59, DAF, MCP and CR1 was confirmed at the mRNA and protein levels. HOG did not activate C spontaneously, as judged by the lack of deposition of C fragments, and were not lysed by C even after inhibition of CD59 and DAF using specific monoclonal antibodies.
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PMID:Complement regulatory protein expression by a human oligodendrocyte cell line: cytokine regulation and comparison with astrocytes. 895 45

Two human neuroblastoma cell lines activated the classical pathway of complement in serum. Activation caused the opsonisation of these cells with complement fragments but with moderate cell killing. Neuroblastoma expressed regulators MCP and CD59 but did not express DAF or CR1. Neutralisation of CD59 rendered the cells susceptible to killing. Neuroblastoma also expressed C1-inhibitor, factor H, clusterin and S-protein. Expression of several regulators was enhanced by incubation with cytokines. Complement inhibition using soluble CRI markedly reduced opsonisation and killing of neuroblastoma. Our results suggest that complement might play a role in neuronal loss and that treatment with complement inhibitors might be of therapeutic value.
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PMID:Complement activation on human neuroblastoma cell lines in vitro: route of activation and expression of functional complement regulatory proteins. 896 11

The effect of M-CSF and C5a on the expression of complement-related membrane proteins on the peripheral white blood cells was investigated. M-CSF or C5a was added into the suspension of the peripheral white blood cells. The expression of the complement receptors, CD35 (CR1) and CD11b/18 (CR3), and inhibitory membrane proteins, DAF and MCP, was measured by flow cytometry. M-CSF increased CR3 on polymorphonuclear cells (PMNs) and CR1, CR3, MCP and DAF on monocytes. C5a increased CR1, CR3 and DAF on PMNs, but did not affect the expression of those on monocytes. It is concluded that M-CSF possessed the activity of increase expression of both complement regulatory proteins and complement receptors of monocytes and C5a selectively affected the expression of those on PMNs.
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PMID:[Effect of macrophage colony-stimulating factor on complement receptors and complement regulatory proteins on human peripheral white blood cells]. 913 36

The data on structure, biochemical properties and functions of membrane proteins, performing cell defence against complement lysis, are summarized. Proteins DAE (decay accelerating factor) and CR1 (complement receptor of type 1) reduce the stability of complement convertases and cause their dissociation. MCP (membrane cofactor protein) and CR1 act as cofactors. In factor I mediated proteolysis of the convertase fragments C3b and C4b. The proteins C8bp-(C8-binding protein) and protectin affect membrane attack complex assembly. In contrast to MCP and CR1, which are integrative proteins, DAF, C8bp and protectin are bound to membranes with their glycophospholypid anchors. Tissue distribution of the proteins and the ways of their solubilization into biological fluids are reviewed.
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PMID:[Membrane proteins as regulators of the complement system]. 927 23

In multiple sclerosis, infiltrating T lymphocytes and perivascular microglia may initiate demyelinating lesions, but a role for antibody and complement in the ensuing inflammatory damage to myelin and oligodendrocytes is likely. In most tissues, ubiquitously expressed complement regulatory proteins prevent autologous destruction, protecting host cells from the powerful cytolytic activity of activated complement. We have studied the surface expression of a comprehensive range of complement regulatory proteins by live adult human oligodendrocytes in vitro. Only DAF of the activation pathway regulators was expressed, not CR1 or MCP. Of the membrane attack pathway regulatory proteins, HRF was not expressed, while substantial heterogeneity of CD59 expression by oligodendrocytes was found. Clusterin expression was not found. A relative deficiency of protective complement regulatory proteins on human oligodendrocytes may contribute to their selective damage in multiple sclerosis.
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PMID:The expression of complement regulatory proteins by adult human oligodendrocytes. 960 Jul 10


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