Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eicosanoids, lymphokines, and free radicals are known to participate in the pathogenesis of inflammation. Tumour necrosis factor (TNF), interleukin-1 and 6 (IL-1 and IL-6) and colony stimulating factor -1 (CSF-1) are secreted mainly by activated macrophages, whereas T-cells secrete IL-2, IL-3, IL-4 and interferon-gamma (IFN-gamma). In addition, activated macrophages and lymphocytes can also produce eicosanoids and free radicals which have potent pro-inflammatory actions. Eicosanoids, lymphokines, and free radicals can modulate the immune response, cell proliferation, stimulate collagenase and proteases secretion and induce bone resorption; events which are known to be associated with various collagen vascular diseases. On the other hand transforming growth factor-beta (TGF-beta) produced by synovial tissue, platelets and lymphocytes can inhibit collagenase production, suppress T-cell and NK-cell proliferation and activation and block free radical generation and seems to be of benefit in rheumatoid arthritis. Drugs such as cyclosporine, 1,25,dihydroxycholecalciferol and pentoxyfylline can block lymphokine and TNF production and thus, may inhibit the inflammatory process. Essential fatty acids, the precursors of eicosanoids, are suppressors of T-cell proliferation, IL-1, IL-2 and TNF production and have been shown to be of benefit in rheumatoid arthritis, systemic lupus erythematosus and glomerulonephritis. Thus, the interactions between essential fatty acids, eicosanoids, lymphokines, TGF-beta and free radicals suggest that new therapeutic strategies can be devised to modify the course of collagen vascular diseases.
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PMID:Interaction(s) between essential fatty acids, eicosanoids, cytokines, growth factors and free radicals: relevance to new therapeutic strategies in rheumatoid arthritis and other collagen vascular diseases. 172 26

The effects of a broad array of cytokines, individually and in combination, were determined on separate functions (proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor [GM-CSF] production) and phenotype (expression of class II MHC antigens) of cultured fibroblast-like RA synoviocytes. The following recombinant cytokines were used: IL-1 beta, IL-2, IL-3, IL-4, IFN-gamma, tumor necrosis factor (TNF)-alpha, GM-CSF, and macrophage colony-stimulating factor (M-CSF). Only IFN-gamma induced HLA-DR (but not HLA-DQ) expression. TNF-alpha inhibited IFN-gamma-mediated HLA-DR expression (46.7 +/- 4.1% inhibition) and HLA-DR mRNA accumulation. This inhibitory effect was also observed in osteoarthritis synoviocytes. Only TNF-alpha and IL-1 increased synoviocyte proliferation (stimulation index 3.60 +/- 1.03 and 2.31 +/- 0.46, respectively). IFN-gamma (but none of the other cytokines) inhibited TNF-alpha-induced proliferation (70 +/- 14% inhibition) without affecting the activity of IL-1. Only IL-1 beta and TNF-alpha induced collagenase production (from less than 0.10 U/ml to 1.10 +/- 0.15 and 0.72 +/- 0.24, respectively). IFN-gamma decreased TNF-alpha-mediated collagenase production (69 +/- 19% inhibition) and GM-CSF production but had no effect on the action of IL-1. These data demonstrate mutual antagonism between IFN-gamma and TNF-alpha on fibroblast-like synoviocytes and suggest a novel homeostatic control mechanism that might be defective in RA where very little IFN-gamma is produced.
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PMID:Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes. 217 6

FK506, a neutral macrolide with immunosuppressive properties, was shown to selectively and rapidly inhibit the accumulation of IL-2 mRNA, as well as the mRNAs of other early (E) phase T cell activation genes such as IL-3, IL-4, GM-CSF, TNF alpha, IFN-gamma, and c-myc in activated human peripheral blood T cells. The activity of FK506, when compared to Cyclosporin A, another immunosuppressant, was 10 to 100x more potent in its ability to inhibit IL-2 mRNA synthesis. FK506 inhibited IL-2 mRNA accumulation in Con A, Con A plus PMA, Ionomycin plus PMA, anti-CD3, and anti-CD3 plus PMA activated T cells. Transcripts from other T cell gene classes such as the immediate early (IE) phase gene, c-fos, the late phase (L) genes, transferrin receptor, IL-2R alpha-chain, and TNF-beta, and the constitutive class genes glyceraldehyde-3-phosphate dehydrogenase and class I MHC HLA-B7 were not affected by FK506. The macrolide Rapamycin, which is structurally related to FK506, had no inhibitory effect on IE, E, L, or constitutive class mRNAs, but it appeared to increase the levels of the E-phase transcripts that were inhibited in FK506 treated T cells. The effect of FK506 on inducible genes in non-T and non-lymphoid human cells was studied in LPS-induced monocytes and PMA or IL-1 activated synovial fibroblasts. FK506 did not affect expression of the mRNAs for IL-1 alpha or IL-1 beta in human monocytes, or of stromelysin, collagenase, or TIMP in synovial fibroblasts. Nuclear run-off transcription studies indicate that FK506 inhibits transcription of the IL-2 gene. These studies suggest that Cyclosporin A and FK506 may effect a common early event in the T cell activation pathway.
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PMID:The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. 247 51

When mouse bone marrow-derived mast cells (BMMC) are cocultured with a confluent layer of mouse 3T3 fibroblasts in the presence of WEHI-3-conditioned medium, the mast cells undergo a phenotypic change toward that of a connective tissue mast cell, and the fibroblasts increase their synthesis of globopentaosylceramide. We now demonstrate that fibroblasts lose their contact inhibition and multiply such that by the 2nd and the 4th wk of coculture there are, respectively, approximately four-fold and six-fold more fibroblasts than in the cultures that are not exposed to BMMC. This in vitro increase in the number of fibroblasts is dependent on the number of mast cells (over the range of 6 x 10(4) to 1 x 10(6) BMMC/culture) initially seeded with the fibroblasts and on the concentration of WEHI-3-conditioned medium present during the coculture. That the fibroblasts also multiply in BMMC/fibroblast cocultures exposed to synthetic IL-3 or to purified IL-3 indicates that IL-3 is a component in WEHI-3-conditioned medium that induces mast cells to produce the fibroblast growth factor. The number of fibroblasts does not increase if fibroblasts are exposed to lysates of BMMC, or to BMMC-derived conditioned medium, or if the two cell types are separated from one another during the coculture with a 3-microns filter or a 0.4-microns filter. Thus, IL-3-activated BMMC must be in proximity to fibroblasts to induce them to multiply. Because of their increased numbers per culture dish, total fibroblasts that were cocultured with mast cells synthesized approximately two-fold more 35S-labeled proteoglycans, incorporated approximately 3-fold more [3H] proline into collagenase-sensitive proteins, and had substantially more alpha 2(I) collagen mRNA than fibroblasts that were maintained in the absence of mast cells. These is vitro studies reveal a sequence by which IL-3-activated mast cells may play a role in the induction of fibrosis.
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PMID:Regulation of the growth rate of mouse fibroblasts by IL-3-activated mouse bone marrow-derived mast cells. 278 27

Rats infected with the helminth Nippostrongylus brasiliensis were injected i.p. with 2 mCi of [35S] sulfate on days 13, 15, 17, and 19 after infection. The intestines were removed from animals on day 20 or 21 after infection, the intestinal cells were obtained by collagenase treatment and mechanical dispersion of the tissue, and the 35S-labeled mucosal mast cells (MMC) were enriched to 60 to 65% purity by Percoll centrifugation. The cell-associated 35S-labeled proteoglycans were extracted from the MMC-enriched cell preparation by the addition of detergent and 4 M guanidine HCl and were partially purified by density gradient centrifugation. The isolated proteoglycans were of approximately 150,000 m.w., were resistant to pronase degradation, and contained highly sulfated chondroitin sulfate side chains. Analysis by high-performance liquid chromatography of chondroitinase ABC-treated 35S-labeled proteoglycans from these rat MMC revealed that the chondroitin sulfate chains consisted predominantly of disaccharides with the disulfated di-B structure (IdUA-2SO4----GalNAc-4SO4) and disaccharides with the monosulfated A structure (G1cUA----GalNAc-4SO4). The ratio of disaccharides of the di-B to A structure ranged from 0.4 to 1.6 in three experiments. Small amounts of chondroitin sulfate E disaccharides (GlcUA----GalNAc-4,6-diSO4) were also detected in the chondroitinase ABC digests of the purified rat MMC proteoglycans, but no nitrous acid-susceptible heparin/heparan sulfate glycosaminoglycans were detected. The presence in normal mammalian cells of chondroitin sulfate proteoglycans that contain such a high percentage of the unusual disulfated di-B disaccharide has not been previously reported. The rat intestinal MMC proteoglycans are the first chondroitin sulfate proteoglycans that have been isolated from an enriched population of normal mast cells. They are homologous to the chondroitin sulfate-rich proteoglycans of the transformed rat basophilic leukemia-1 cell and the cultured interleukin 3-dependent mouse bone marrow-derived mast cell, in that these chondroitin sulfate proteoglycans as well as rat serosal mast cell heparin proteoglycans are all highly sulfated, protease-resistant proteoglycans.
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PMID:Intestinal mucosal mast cells from rats infected with Nippostrongylus brasiliensis contain protease-resistant chondroitin sulfate di-B proteoglycans. 308 52

We previously demonstrated that fluctuations in circulating metachromatic cell progenitors were inversely related to nasal metachromatic cell (NMC) counts and nasal symptoms in allergic rhinitis. Now, we have quantitated NMC progenitors and lineage-specific growth factors using a hemopoietic colony assay. Cell suspensions from excised collagenase-treated nasal polyps (n = 7) contained 3.8 +/- 1.1 granulocyte colony-forming cells per 10(6) cells plated, compared to less than or equal to 0.5 in human tonsil suspensions, less than or equal to 0.5 in nasal mucosal epithelial scrapings, and 33 +/- 8 in peripheral blood of patients with ragweed allergic rhinitis (p less than 0.01). The percentage of metachromatic cells in nasal-polyp-derived colonies was 47 +/- 10 compared with 3.0 +/- 0.7 in peripheral blood colonies (p less than 0.005). Highly potent metachromatic cell colony-stimulating activity (CSA) was detected in supernatants from cultured human nasal epithelial scrapings from both polyps and atopic nasal mucosa, but not from nonatopic nasal mucosa. Supernatants from polyp mononuclear cells stimulated with phytohemagglutinin also contained metachromatic cell-CSA, which had an approximate molecular size of 25 to 70,000 daltons on column chromatography. An IL-3-like activity was also detected in these supernatants. These observations provide further evidence for in situ hemopoietic mechanisms in human nasal mucosa, involving epithelium-derived stimulation of local metachromatic cell progenitor growth and differentiation in allergic rhinitis.
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PMID:Metachromatic cell progenitors and specific growth and differentiation factors in human nasal mucosa and polyps. 349 16

Chondroitin sulfate E proteoglycan was extracted in the presence of protease inhibitors from 6 X 10(9) mouse bone marrow-derived, interleukin 3-dependent mast cells, of which 3 X 10(7) had been biosynthetically labeled with [35S]sulfate or [3H]glycine. Chondroitin sulfate E proteoglycan was purified to apparent homogeneity by density-gradient centrifugation, differential molecular weight dialysis, DEAE-52 ion exchange chromatography, and Sepharose CL-4B gel filtration chromatography. Chondroitin sulfate E proteoglycan, radiolabeled with [3H]glycine or [35S]sulfate, filtered as a single peak of radioactivity on Sepharose CL-4B with a Kav of 0.41. When purified [3H]glycine-labeled proteoglycan was digested with chondroitinase ABC and subjected to gel filtration, all of the radioactivity was shifted to a lower molecular weight. As assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis the Mr of the peptide core obtained by chondroitinase ABC treatment was approximately 10,000. The purified proteoglycan was resistant to degradation by collagenase, clostripain, trypsin, chymotrypsin, elastase, chymopapain, V8 protease, proteinase K, and Pronase, as assessed by gel filtration chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Analysis of the core peptide of the intact proteoglycan revealed that glycine, serine, and glutamic acid/glutamine accounted for 70% of the total amino acids and were present in a molar ratio of 4.3/1.6/1.0. When analyzed for neutral hexose content by gas-liquid chromatography, the proteoglycan contained approximately 2% of its weight as mannose, fucose, galactose, and other sugars, indicating that oligosaccharides were linked to the peptide core. The mouse bone marrow-derived mast cell chondroitin sulfate E proteoglycan, like the rat serosal mast cell heparin proteoglycan, is markedly protease resistant, has highly sulfated glycosaminoglycans, and contains a peptide core that is rich in serine and glycine. These characteristics of the mast cell class of intracellular proteoglycans may contribute to their function in stimulus-induced granule secretion as well as in mediator storage, including retention of cationic neutral proteases.
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PMID:Purification and analysis of the core protein of the protease-resistant intracellular chondroitin sulfate E proteoglycan from the interleukin 3-dependent mouse mast cell. 393 50

Kupffer cells were isolated from C57BL/6 mice by collagenase perfusion and assessed for response to colony-stimulating factors (CSFs) in terms of their phenotypic change and proliferation. Kupffer cells expressed F4/80, but not Mac-1, CD71, or asialo-GM1 initially. This phenotype pattern was different from that of alveolar and peritoneal macrophages. After stimulation with recombinant human macrophage CSF (M-CSF) or mouse granulocyte-macrophage CSF (GM-CSF), Kupffer cells expressed Mac-1 and a low level of CD71 in addition to F4/80 and increased in phagocytotic activity in association with the expression of CR3. Both M-CSF and GM-CSF, but not human IL-3, induced the proliferation of Kupffer cells in a dose-dependent manner, and after 7 days, the number of the cells increased to about four to six times the initial number. The relatively high dose of GM-CSF downmodulated the M-CSF receptor on Kupffer cells and inhibited the cell proliferation induced by the optimal dose of M-CSF. These data indicated that murine Kupffer cells have a different phenotype from other macrophages and that they respond to M-CSF and GM-CSF, leading to functional maturation and proliferation.
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PMID:Phenotypic change and proliferation of murine Kupffer cells by colony-stimulating factors. 869 46

Even today prematurity is the major cause of perinatal mortality. Prematurity has multiple causes. There is a growing body of evidence supporting the association between silent intrauterine infection and preterm birth. Bacterial products may activate macrophages ubiquitous present in the decidua, placenta and fetal membranes. These cells after activation secrete a large variety of mediators including tumour necrosis factor alpha (TNFalpha) and interleukin (IL)-1. Besides these cytokines IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, epidermal growth factor, granulocyte-colony stimulating factor and transforming growth factor beta have been identified in intrauterine tissues and in the amniotic fluid. The majority of these substances (TNFalpha, IL-1, IL-2, IL-3, IL-6) can stimulate the prostaglandin-biosynthesis by intrauterine tissues (amnion, chorion, decidua), some of them have antiinflammatory effects (IL-10, transforming growth factor alpha). These effects are mediated by receptors on the target cells; specific receptor antagonists (for example for IL-1) were found in high concentrations in amniotic fluid during normal pregnancy. This cytokine network is in a sensitive balance and probably associated with an uncomplicated course of pregnancy. Systemic or localized infections as well as tissue injury initiate the induction of the prostaglandin synthesis cascade thus leading to pregnancy loss via augmented cytokine secretion. Furthermore, cytokines may be involved in the regulation of preterm and term cervical ripening. The changes in mechanical properties of the cervix are associated with a reduction of collagen content and alterations in the glycosaminoglycan pattern within the cervical extracellular matrix. IL-1 can stimulate the synthesis of collagenases, and IL-8 may play an important role in the regulation of the invasion of neutrophilic granulocytes into the cervical stroma with subsequent degranulation and release of proteases. The cytokine-stimulated collagenase production in the fetal membranes is responsible for the reduction of their tensile strength and may be associated with rupture of the membranes. The cytokine network seems to be a sensitive regulation system. Disturbances of its balance by environmental (e.g. infection) or intrauterine influences (e. g. extension by the fetus) may lead to termination of pregnancy.
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PMID:[The role of cytokines in the induction of labor, cervical ripening and rupture of the fetal membranes]. 1676 18