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:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of recombinant human tumor necrosis factor alpha (TNF alpha) on collagen production and gene expression in cultured fibroblasts were studied. Cells were labeled with [3H]proline, and the radioactivity of collagenase-sensitive and -resistant proteins were used to calculate the rates of protein production. The net production of collagen relative to total proteins was inhibited by TNF alpha (0-1.2 nM) in a dose- and time-related manner. The specific activities of the free [3H]proline pool, which were similar in control and TNF alpha-treated cells, were used to calculate the absolute rates of protein production. The absolute rate of collagen production was decreased by 50% in the presence of 1.2 nM TNF alpha during 24-h incubations (851 +/- 104 versus 426 +/- 39 pmol/micrograms of DNA/h; p less than 0.01), whereas noncollagen protein production and the rate of procollagen secretion were unchanged. We found no evidence of cellular toxicity in cultured cells treated with TNF alpha. In addition, TNF alpha did not affect cell proliferation as determined by [6-3H]thymidine incorporation into DNA. Most of the collagen produced by the cultured fibroblasts was type I. Using hybridization with specific DNA probes there was an approximately 50% decrease in the quantity of procollagen alpha 1(I) mRNA, without changes in the quantity of alpha tubulin mRNA or the size of the transcripts, in cells incubated with TNF alpha. Interleukin-1 (2.5 ng/ml) also decreased the levels of procollagen alpha 1(I) mRNA by approximately 50%. Cycloheximide (0.1 mM), an inhibitor of protein synthesis, blocked the inhibitory effect of both TNF alpha and interleukin-1 on procollagen alpha 1(I) mRNA. Nuclear run-off assays demonstrated that TNF alpha decreased procollagen alpha 1(I) transcriptional activity by 50% and had no effects on alpha tubulin gene transcription. Thus, TNF alpha decreases collagen gene transcription, collagen mRNA levels, and collagen production in cultured fibroblasts.
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PMID:Tumor necrosis factor alpha inhibits collagen gene transcription and collagen synthesis in cultured human fibroblasts. 325 1

TNF stimulated transcription and secretion of the metalloproteinases collagenase and stromelysin in porcine articular chondrocytes. TNF induced metalloproteinase transcription could be inhibited with either protein kinase inhibitors (H7 or staurosporine) or by raising intracellular cAMP levels. HA1004, a protein kinase inhibitor structurally related to H7 but with a higher Ki for protein kinase C had no effect on TNF induced message levels. TNF treatment of chondrocytes did not induce membrane associated PKC or increase intracellular cAMP levels. Our results are consistent with the involvement of a staurosporine and H7 sensitive protein kinase distinct from PKC in TNF signal transduction in chondrocytes.
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PMID:Protein kinase regulation of tumor necrosis factor alpha stimulated collagenase and stromelysin message levels in chondrocytes. 750 65

Matrix metalloproteinases (MMPs) are a family of inducible enzymes that degrade extracellular matrix components, allowing cells to traverse connective tissue structures efficiently. Specific tissue inhibitors (TIMPs) function as physiologic inhibitors of MMP activity. Because neovascularization may require various proteinases, we characterized the profile of metalloenzyme production by microvascular endothelial cells (MEC) and the modulation of expression by phorbol esters (PMA) and by the physiologically relevant cytokines tumor necrosis factor-alpha (TNF-alpha), basic fibroblast growth factor, and interferon-gamma. MMP expression by MEC and large-vessel human umbilical vein endothelial cells (HUVEC) was determined by enzyme-linked immunosorbent assay, immunoprecipitation, Northern hybridization, and transfection assays. Constitutive expression of MMPs by endothelial cells was low. PMA stimulated the production of collagenase, stromelysin, 92-kDa gelatinase, and TIMP-1 in both endothelial cell types. TIMP-2 was constitutively expressed by MEC and HUVEC, but was down-regulated by PMA. TNF-alpha induced an endothelial-cell-specific up-regulation of collagenase with a concomitant inhibition of PMA-induced TIMP-1 up-regulation, a response that is distinct from that of fibroblasts. Interferon-gamma up-regulated TIMP-1 production by MEC and blocked PMA and TNF-induced up-regulation of collagenase. Northern hybridization assays showed pretranslational control of PMA-, basic fibroblast growth factor-, and TNF-alpha-induced MMP expression. Collagenase-promoter CAT constructs containing 2.28 kb of the 5' region of the collagenase gene demonstrated transcriptional regulation. The potential physiologic relevance of such regulation was shown in an in vitro migration assay. MEC were stimulated to migrate by wounding and exposure to TNF-alpha. Collagenase mRNA was prominently expressed by the migrating cells, as shown by in situ hybridization. In sum, MEC have a unique profile of MMP expression and regulation compared with other cell types, which may be important for wound healing and angiogenesis, particularly during the early phase of migration.
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PMID:Human dermal microvascular endothelial cells produce matrix metalloproteinases in response to angiogenic factors and migration. 754 47

An increase in gluconeogenesis contributes to the cachexia seen in severe injury, sepsis, and malignancy by converting amino acids from skeletal muscle to glucose. Since tumor necrosis factor alpha (TNF alpha) may mediate this cachexia, we examined the effect of this cytokine on gluconeogenesis. Twenty-eight male Fischer rats were injected intraperitoneally with TNF alpha (250 micrograms/kg) or saline, and after 4 hours, isolated hepatocytes were obtained by in situ collagenase liver perfusion. Hepatocytes were incubated with alanine (10 mM), and rates of gluconeogenesis were determined. Plasma lactate, glucose, insulin, glucagon, cortisol, and amino acids were measured. TNF alpha administration resulted in a 50% increase in gluconeogenesis from alanine (P < 0.05) and a three-fold increase in plasma glucagon (P = 0.01). Total and glucogenic plasma amino acids decreased with TNF alpha injection (P < 0.05). In vivo TNF alpha causes an increase in hepatic gluconeogenesis associated with increased plasma glucagon.
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PMID:Tumor necrosis factor alpha stimulates gluconeogenesis from alanine in vivo. 763 Jan 67

We investigated the nature of cytokines synthesized by human osteoarthritic (OA) synovium, particularly interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha). We examined the capacity of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) to block the synthesis of metalloproteases (collagenase and stromelysin), IL-1 beta, and IL-6 in osteoarthritis (OA) synovium. Human OA synovium were incubated in the presence or absence of lipopolysaccharide (LPS) or increasing concentrations of rhIL-1ra. The determinations of IL-1 alpha, IL-1 beta, TNF alpha, IL-6, and IL-1ra in culture medium were carried out using specific ELISA. Although both IL-1 isoforms and TNF alpha could be produced by OA synovium, IL-1 beta was the predominant cytokine synthesized either in the presence or absence of LPS. Treatment of the OA synovium with an increasing concentration of rhIL-1ra (0-10 micrograms/ml) showed a dose dependent reduction of both metalloproteases and IL-6. Maximal inhibition was 70% for collagenase, 80% for stromelysin, and 76% for IL-6. LPS treated synovium also showed a consistent suppression of metalloproteases and IL-6, although a higher IL-1ra concentration was required. Conversely, IL-1 beta production was not inhibited by IL-1ra, irrespective of the concentration used and whether the membranes were LPS stimulated. These data showed that IL-1 appears to be the major autocrine cytokine involved in the stimulation of metalloproteases and IL-6 synthesis in OA synovium.
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PMID:Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process. 775 12

5'-deoxy-5-fluorouridine (5'-FUdR) is a cytostatic that is biotransformed to 5-fluorouracil (5-FUra) by pyrimidine nucleoside phosphorylase (PyNPase), the expression of which is up-regulated by tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha) and interferon gamma (IFN gamma). In Lewis lung carcinoma (LLC) cell cultures, these inflammatory cytokines up-regulated the expression of type-IV collagenase, metastatic factor, as well as PyNPase and consequently enhanced the antiproliferative activity of 5'-FUdR. However, the activity of 5-FUra was not enhanced. It appears that 5'-FUdR selectively kills highly metastatic cells which are exposed to these intrinsic cytokines in tumor tissues, because of their high PyNPase activity. In fact, 5'-FUdR inhibited the spontaneous metastasis of LLC from the s.c. inoculation site to the lung. When 5'-FUdR was given during the process of metastasis it greatly reduced the number of tumor nodules in the lung even at doses 46 times lower than those inhibiting the primary tumor growth. In addition, 5'-FUdR, but not 5-FUra, lowered type-IV collagenase levels in the tumors at the low dose showing only anti-metastatic activity. On the other hand, 5-FUra showed anti-metastatic activity at doses similar to or only several times lower than those inhibiting the primary tumor growth.
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PMID:Selective inhibition of spontaneous pulmonary metastasis of Lewis lung carcinoma by 5'-deoxy-5-fluorouridine. 775 57

Tumor necrosis factor-alpha (TNF-alpha) is released from a cell membrane-anchored precursor by proteolytic cleavage. We have shown that broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs) prevent the processing of the TNF precursor but do not inhibit the release of other cytokines. Purified MMPs, stromelysin, matrilysin, collagenase, and the gelatinases can all cleave a recombinant pro-TNF substrate to yield mature TNF. MMP inhibitors prevent the rise in blood levels of TNF after endotoxin administration in rats and are effective in animal models of inflammatory disease such as adjuvant arthritis. Drugs that inhibit MMP action and TNF release show great promise for the treatment of autoimmune inflammatory diseases.
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PMID:Matrix metalloproteinases and processing of pro-TNF-alpha. 775 57

Tumor necrosis factor alpha (TNF alpha) has multiple biological functions including the prolonged activation of the collagenase and c-jun genes, which are regulated via their AP-1 binding sites. We show that incubating human fibroblasts with TNF alpha induces prolonged activation of JNK, the c-Jun kinase, which phosphorylates the transactivation domain of c-Jun. Furthermore, an immune complex kinase assay specifically demonstrates that TNF alpha stimulates the activity of JNK1, the recently described predominant form of JNK. TNF alpha also produces a small and transient increase in extracellular signal-regulated kinase (ERK) activity and no measured increase in Raf-1 kinase activity. On the other hand, epidermal growth factor causes a prolonged activation of Raf-1 kinase and ERK activity and a smaller, more transient activation of JNK, whereas the phorbol ester phorbol 12-myristate 13-acetate causes a small stimulation of Raf-1 kinase and a pronounced stimulation of ERK activity. The activation of JNK by TNF alpha does not correlate with Raf-1 or ERK activity. The kinetics of Raf-1, ERK, and JNK induction by epidermal growth factor, phorbol 12-myristate 13-acetate, or TNF alpha indicate distinct mechanisms of activation in human fibroblasts.
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PMID:Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase. 792 60

Cyclosporin A is successfully used in the treatment of scleroderma, a condition with excessive deposition of collagen in the dermis. Cultured human dermal fibroblasts were used as a model to study the effects of cyclosporin A on metalloproteinase expression and activity. Fibroblasts were treated with collagenase inducing agents, phorbol 12-myristate 13-acetate (PMA), cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), and the calcium ionophore A23187 in the presence of cyclosporin A under serum-free conditions, and alterations in metalloproteinase expression were studied by Northern hybridization and immunoblotting analyses, and assays for collagenolytic activity. Induction of collagenase expression by PMA and cytokines was enhanced severalfold by 1-10 microM cyclosporin A. Treatment of cells with cyclosporin A alone caused only a minor increase in collagenase mRNA levels. The secretion of immunoreactive collagenase protein and the level of p-aminophenylmercuric acetate activatable collagenase activity were increased by PMA and further enhanced by cyclosporin A. The expression of the other metalloproteinases stromelysin-1, 92-kD gelatinase, and 72-kD gelatinase or metalloproteinase inhibitor TIMP-1 were not affected by cyclosporin A. Time dependence analysis of the expression of the mRNAs for c-jun and junB indicated that the induction of these genes persisted significantly longer in cells treated with both PMA and cyclosporin A than in cells treated with PMA alone. Enhanced induction of collagenase mRNA may thus result from prolonged AP-1 activity. The results indicate that cyclosporin A potently enhances the expression of collagenase in dermal fibroblasts.
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PMID:Cyclosporin A enhances cytokine and phorbol ester-induced fibroblast collagenase expression. 800 58

Biochemical, histologic, and immunohistochemical analyses were performed on 34 interface membranes obtained from 33 patients during revision total knee arthroplasty. The membranes had surrounded components of cementless (n = 11) and cemented (n = 23) knee prostheses that were aseptically loose. None of these implant failures was caused by catastrophic polyethylene erosion leading to metal-to-metal contact. The histologic findings were similar in the membranes from cemented and cementless knee components: small polyethylene debris within macrophages and large birefringent polyethylene debris within foreign-body giant cells. Metallic debris was seen in membranes from both groups, but cemented membranes had more polymethylmethacrylate particles and more hyalinization. Intracytoplasmic asteroid bodies were observed in several foreign-body giant cells in both types of membranes. No significant differences were found between the two groups in levels of collagenase, prostaglandin E2 (PGE2), interleukin-1 (IL-1), interleukin-6 (IL-6), or tumor necrosis factor-alpha (TNF-alpha), nor in the population of inflammatory cells stained with IL-1, IL-6, and TNF-alpha antibodies. Membranes that had surrounded components with radiographic evidence of diffuse or localized periprosthetic bone loss released significantly more collagenase, IL-1, IL-6, and TNF than did membranes from components without bone loss. These two groups, however, did not have significantly different PGE2 levels. These findings suggest that polyethylene and metal debris may play a role in macrophage activation and the release of mediators of bone resorption in the membranes surrounding failed cemented and cementless total knee implants.
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PMID:A biochemical, histologic, and immunohistologic analysis of membranes obtained from failed cemented and cementless total knee arthroplasty. 799 73


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