Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Compound IX 207-887 is a novel antiarthritic agent which inhibits the release of interleukin-1 (IL-1) from human monocytes and mouse peritoneal macrophages in vitro at concentrations which are achieved therapeutically in human rheumatoid arthritis and in animal models of arthritis. In the present studies IL-1 activity in conditioned media, homogenates or lysates was monitored using four independent assay systems. Biologically active IL-1 was determined by, a) the induction of latent metalloproteinase-release from rabbit articular chondrocytes, which is relatively specific for IL-1 and b) by a sensitive thymocyte proliferation assay. Immunoreactive IL-1-beta was assayed by RIA and ELISA. In all test systems IX 207-887 significantly reduced both biologically active and immunoreactive IL-1 in culture media, whereas the levels of IL-1 in homogenates or lysates were either unaffected or only marginally reduced. The release of other monokines tested, such as interleukin-6 and tumour necrosis factor-alpha, and the secretion of lysozyme were only marginally influenced. IX 207-887 neither affected the adherence of human monocytes nor markedly inhibited IL-1 or IL-2-induced thymocyte proliferation. In the chondrocyte test no IL-1 antagonistic activity of IX 207-887 could be observed. All of these data indicate that IX 207-887 has the novel property of being an inhibitor of IL-1 release.
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PMID:Inhibition of interleukin-1 release by IX 207-887. 238 8

After hip prosthetic replacement, a progressive enlargement in the radiolucent area has often been observed around the implant, leading to loosening of the prosthesis. The purpose of this study was to investigate the mechanism of the radiolucent area formation. Radiolucent areas can be classified into either linear type or the erosive type, and these two types were compared histologically and biochemically. Interface membranes were obtained from patients at the time of surgery for revision of either cemented THA or cementless bipolar endprosthetic replacement. Histological specimens were stained by H.E., tartrate-resistant acid phosphate, and by the immunohistochemical reagents anti-macrophage antibody (CD 68), anti-T-lymphocyte (CD 3, CD 4, CD 8, CD 43), anti-interleukin-1 beta polyclonal antibody, anti-interleukin-6 polyclonal antibody, and anti-tumor necrosis factor-alpha polyclonal antibody. Biochemically, interleukin-1 beta, IL-6, IL-8, TNF-alpha were assayed by ELISA in the supernatant of homogenized samples and in organ culture media. Prostaglandin E2 was assayed by radioimmunoassay. The interfaces of the erosive type contained more debris (cement, high density polyethylene and metal), macrophages and multinucleated giant cells than the linear type. The interfaces of the linear type showed mainly fibrosis and necrosis. The levels of IL-6 and IL-8 in the homogenates and culture media from the erosive type were significantly higher than those from the linear type. We concluded that the bone resorption around the implant after hip prosthetic replacement occurred by two different pathways. One pathway involved the stimulation of macrophages by various debris and micromovement to form foreign body granulomas, which produced cytokines, prostaglandin E2 and metalloproteinase to resorb bone. The erosive type would arise from this pathway. The other possible mechanism involved a biomechanically unstable implant which caused bone necrosis probably by mechanical stress. The linear type may arise from this pathway.
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PMID:[Mechanism of the radiolucence around the implant after hip prosthetic replacement]. 855 Oct 95

Certain membrane-anchored proteins, including several cytokines and cytokine receptors, can be released into cell supernatants through the action of endogenous membrane-bound metalloproteinases. The shed molecules are then able to fulfill various biological functions; for example, soluble interleukin-6 receptor (sIL-6R) can bind to bystander cells, rendering these cells sensitive to the action of IL-6. Using IL-6R as a model substrate, we report that the metalloproteinase from Serratia marcescens mimics the action of the endogenous shedding proteinase. Treatment of human monocytes with the bacterial protease led to a rapid release of sIL-6R into the supernatant. This effect was inhibitable with TAPI [N-(D,L-[2-(hydroxyaminocarbonyl)methyl]-4-methylpentanoyl) L-3-(2' naphthyl)-alanyl-L-alanine, 2-aminoethyl amide], a specific inhibitor of the membrane-bound intrinsic metalloproteinase, but not with other conventional proteinase inhibitors. sIL-6R-liberating activity was also detected in culture supernatants of Staphylococcus aureus, Pseudomonas aeruginosa, and Listeria monocytogenes, organisms that are known to produce metalloproteinases. sIL-6R released through the action of S. marcescens metalloproteinase retained biological activity and rendered IL-6-unresponsive human hepatoma cells sensitive to stimulation with IL-6. This was shown by Northern (RNA) blot detection of haptoglobin mRNA and by quantitative measurements of de novo-synthesized haptoglobin in cell supernatants. Analysis of immunoprecipitated, radiolabeled sIL-6R revealed that the bacterial protease cleaved IL-6R at a site distinct from that utilized by the endogenous protease. These studies show that membrane-anchored proteins can be released in active form through cleavage at multiple sites, and they uncover a novel mechanism via which microbial proteases possibly provoke long-range biological effects in the host organism.
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PMID:Novel pathogenic mechanism of microbial metalloproteinases: liberation of membrane-anchored molecules in biologically active form exemplified by studies with the human interleukin-6 receptor. 875 12

Tumor necrosis factor (TNF)-alpha is initially synthesized as an extracellular membrane-associated 26-kDa protein that is further cleaved at Ala76-Val77 to yield the soluble 17-kDa form. Recently, peptide-hydroxamate metalloproteinase inhibitors have been reported to block the proteolytic processing of TNF-alpha, thus suggesting that the putative TNF-alpha converting enzyme (TACE) is a zinc-dependent metalloendopeptidase. In this report, we characterize a TNF-alpha converting activity (TACA) that cleaves in vitro the human 26-kDa TNF-alpha at the physiological processing site. The chromatography steps followed for purification and the use of a panel of proteinase inhibitors indicate that the enzyme responsible for TACA is a membrane glycosylated metalloendopeptidase which is most likely different from the matrix-degrading metalloproteinases. The failure of TACA to process a Val77-->Gly77 precursor mutant emphasizes the importance of hydrophobic residue at P1' position. In addition, TACA is not able to cleave the mouse pro-TNF-alpha and does not catalyze in vitro the processing of other transmembrane proteins susceptible to metalloproteinase-mediated shedding, such as interleukin-6 or TNF receptors. These studies suggest the existence of an enzyme specific for TNF-alpha within the metalloproteinases involved in the processing/shedding of a number of cytokines and cytokine receptors.
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PMID:Partial purification and characterization of a tumor necrosis factor-alpha converting activity. 917 21

We studied the pathways of macrophage response to lipopolysaccharide (LPS). When mouse macrophages pre-exposed to LPS were restimulated with this agent, reduced tumour necrosis factor-alpha (TNF-alpha) responses (desensitization/endotoxin tolerance) were accompanied by increased (priming) nitric oxide (NO) responses. Priming was also inducible with recombinant interferon-beta (IFN-beta). The requirement of TNF-alpha biosynthesis in the LPS-induced priming was also suggested by the observation that both anti-TNF-alpha serum and pentoxifylline inhibited this effect. However, addition of mouse recombinant TNF-alpha (mrTNF-alpha) did not enhance the priming induced by LPS or IFN-beta, and preincubation with mrTNF-alpha alone, or in association with other cytokines produced by macrophages (interleukin-1 beta, interleukin-6, or leukaemia inhibitory factor), did not induce a priming effect. We found however, that pentoxifylline, which blocked the priming, also decreased the level of membrane-bound TNF-alpha. Furthermore, exposure to compound BB-3103 (a metalloproteinase inhibitor that blocks the processing of membrane-bound TNF-alpha yielding to the secreted cytokine) enhanced the priming effect, the expression of membrane TNF-alpha and the specific binding of LPS. These observations suggest that the membrane form of TNF-alpha is involved in the interaction of LPS with a receptor required for LPS-induced priming.
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PMID:Involvement of the membrane form of tumour necrosis factor-alpha in lipopolysaccharide-induced priming of mouse peritoneal macrophages for enhanced nitric oxide response to lipopolysaccharide. 941 35

The in-vitro effects of avocado and soybean unsaponifiable residues on neutral metalloproteinase activity, cytokines and prostaglandin E2 (PGE2) production by human articular chondrocytes were investigated. Avocado and soybean unsaponifiable residues were mixed in three ratios: 1:2 (A1S2), 2:1 (A2S1) or 1:1 (A2S2). Freshly isolated human chondrocytes were cultured for 72 h in the absence or presence of interleukin-1beta, (IL-1beta) (17 ng/ml), with or without unsaponifiable residue mixtures at a concentration of 10 microg/ml. A/S unsaponifiable residues were also tested separately at concentrations of 3.3, 6.6 and 10 microg/ml. All A/S unsaponifiable mixtures reduced the spontaneous production of stromelysin, interleukin-6 (IL-6), interleukin-8 (IL-8) and prostaglandin E2 (PGE2) by chrondrocytes. At concentrations of 3.3 and 6.6 microg/ml, A/S residues, tested separately, were potent inhibitors of the production of IL-8 and PGE2. Nevertheless, only avocado residue inhibited IL-6 production at these concentrations. A/S unsaponifiable mixtures had a more pronounced inhibitory effect on cytokine production than avocado or soybean residues added alone. As anticipated, IL-1beta induced a marked release of collagenase, stromelysin, IL-6, IL-8 and PGE2. A/S unsaponifiable mixtures partially reversed the IL-1 effects on chrondrocytes. These findings suggest a potential role for A/S unsaponifiable extracts in mitigating the deleterious effects of IL-1beta: on cartilage.
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PMID:Effects of three avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and prostaglandin E2 production by human articular chondrocytes. 958 76

Interleukin-6 (IL-6) is the major growth factor for human myeloma cells, exerting its effect through the IL-6 receptor (IL-6R). A soluble form of IL-6R (sIL-6R) has been identified, which increases the sensitivity of myeloma cells to IL-6. In patients with multiple myeloma (MM), serum concentrations of sIL-6R are elevated and associated with poor prognosis. The present study was undertaken to determine whether proteolytic cleavage of IL-6R could contribute to sIL-6R release from human myeloma cells, and also to identify the class of proteinase responsible for this event. Human myeloma cell lines were shown to express IL-6R upon their surface and also to release sIL-6R into culture supernatants. In addition, phorbol 12-myristate 13-acetate (PMA) stimulated a loss of IL-6R from the cell surface, with a corresponding increase in the concentration of sIL-6R in the supernatant. Inhibitors of serine and cysteine proteinases, and tissue inhibitor of metalloproteinase (TIMP) -1 and TIMP-2, were shown to have no effect on the magnitude of sIL-6R release. In contrast, TIMP-3 and a hydroxamate-based metalloproteinase inhibitor (BB-94), inhibited both constitutive and PMA-induced release of sIL-6R. Myeloma cells freshly isolated from the bone marrow of a patient with MM were also shown to express IL-6R upon their surface, and to shed this receptor in response to PMA. These data demonstrate that increased proteolytic cleavage of IL-6R, mediated by a non-matrix-type metalloproteinase, is likely to contribute to the elevated concentrations of sIL-6R found in the serum of patients with MM. Inhibition of sIL-6R release by hydroxamate-based metalloproteinase inhibitors may represent a novel therapeutic approach to the treatment of MM.
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PMID:Human myeloma cells shed the interleukin-6 receptor: inhibition by tissue inhibitor of metalloproteinase-3 and a hydroxamate-based metalloproteinase inhibitor. 967 43

Cytokines constitute a major class of mediators responsible for "activation" of hepatic stellate cells (HSCs) in vitro and in vivo. They are largely divided into mitogenic (transforming growth factor-alpha, platelet-derived growth factor, interleukin-1, tumor necrosis factor-alpha, and insulin-like growth factor) and fibrogenic (transforming growth factor-beta and interleukin-6) cytokines. In addition to their mitogenic (stimulation of cell proliferation) and fibrogenic (induction of matrix proteins) properties, they are also shown to confer in vitro unique cellular changes known to be the key features of HSC "activation," including loss of vitamin A, stimulation of migration, enhanced cellular contractility, and matrix metalloproteinase and tissue inhibitor of metalloproteinase induction. Potential cellular sources of the cytokines consist of hepatic macrophages, endothelial cells, biliary epithelial cells, lymphocytes, platelets, hepatocytes, and activated HSCs. To better understand the mode of actions and the pathogenetic significance of cytokines/chemokines involved in "activation" of HSCs, the following four questions need to be addressed: (1) What other cytokines are expressed by HSCs to establish critical autocrine stimulation? (2) What are endogenous or exogenous priming factors for HSC stimulation? (3) What is the mechanism of activation for transforming growth factor-beta, the pivotal fibrogenic cytokine? (4) How important are HSC-derived proinflammatory mediators in liver fibrosis? This review will discuss these questions, along with the current understanding of the role of cytokines in HSC activation.
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PMID:Cytokine regulation of hepatic stellate cells in liver fibrosis. 1037 13

Airway remodeling is a well-recognized feature in patients with chronic asthma. The accumulation in the submucosa of fibrous proteins that are substrates of matrix metalloproteinases (MMP), and the demonstration of increased levels of MMP-9 in bronchoalveolar lavage fluid, prompted us to determine whether there was an imbalance between MMPs and tissue inhibitors of metalloproteinase (TIMP) in such patients. We investigated the presence of TIMPs and other MMPs. TIMP levels were compared with those of all MMPs and inflammatory cytokines. Adults with stable asthma, either untreated or treated with glucocorticoids (GCs), were enrolled. Healthy nonsmokers served as a control population. MMPs and TIMPs were identified through zymography or immunoblotting. TIMPs, MMPs, and cytokines were measured with enzyme immunoassays. TIMP-1 levels were significantly higher in untreated asthmatic subjects than in GC-treated subjects or controls (p < 0.0001), and were far greater than those of MMP-1, MMP-2, MMP-3, and MMP-9 combined. TIMP-2 was undetectable. TIMP-1 levels were correlated with levels of interleukin-6 (p < 0.012) and the number of alveolar macrophages recovered (p < 0.005). This observation has important implications, since an excess of TIMP-1 could lead to airway fibrosis, a hallmark of airway remodelling in patients with chronic asthma.
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PMID:Tissue inhibitor of metalloproteinase-1 levels in bronchoalveolar lavage fluid from asthmatic subjects. 1039 Apr 19

In vitro treatment with clarithromycin inhibited the expression of the matrix metalloproteinase-9, transforming growth factor beta, and tumor necrosis factor alpha genes in 13762NF rat mammary adenocarcinoma cells. Transient enhancement, rather than inhibition, was observed for the interleukin-6 gene, and no significant change was observed for the tissue inhibitor of metalloproteinase-2 gene. Such an effect was not observed for cefotiam or gentamicin.
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PMID:Differential modulatory effects of clarithromycin on the production of cytokines by a tumor. 1054 65


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