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)

Oncostatin M (OSM), a member of the IL-6 superfamily of cytokines, is elevated in patients with rheumatoid arthritis and, in synergy with IL-1, promotes cartilage degeneration by matrix metalloproteinases (MMPs). We have previously shown that OSM induces MMP and tissue inhibitor of metalloproteinase-3 (TIMP-3) gene expression in chondrocytes by protein tyrosine kinase-dependent mechanisms. In the present study, we investigated signaling pathways regulating the induction of MMP and TIMP-3 genes by OSM. We demonstrate that OSM rapidly stimulated phosphorylation of Janus kinase (JAK) 1, JAK2, JAK3, and STAT1 as well as extracellular signal-regulated kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase 1/2 mitogen-activated protein kinases in primary bovine and human chondrocytes. A JAK3-specific inhibitor blocked OSM-stimulated STAT1 tyrosine phosphorylation, DNA-binding activity of STAT1 as well as collagenase-1 (MMP-1), stromelysin-1 (MMP-3), collagenase-3 (MMP-13), and TIMP-3 RNA expression. In contrast, a JAK2-specific inhibitor, AG490, had no impact on these events. OSM-induced ERK1/2 activation was also not affected by these inhibitors. Similarly, curcumin (diferuloylmethane), an anti-inflammatory agent, suppressed OSM-stimulated STAT1 phosphorylation, DNA-binding activity of STAT1, and c-Jun N-terminal kinase activation without affecting JAK1, JAK2, JAK3, ERK1/2, and p38 phosphorylation. Curcumin also inhibited OSM-induced MMP-1, MMP-3, MMP-13, and TIMP-3 gene expression. Thus, OSM induces MMP and TIMP-3 genes in chondrocytes by activating JAK/STAT and mitogen-activated protein kinase signaling cascades, and interference with these pathways may be a useful approach to block the catabolic actions of OSM.
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PMID:Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway. 1120 8

In experimental arthritis, blocking of the receptor activator of nuclear factor kappaB ligand (RANKL) by osteoprotegerin (OPG) treatment prevents bone loss but not inflammation, suggesting that there are inflammation-related factors that regulate RANKL and OPG. However, it is not known which factors regulate RANKL and OPG in human inflammation-induced bone loss. To clarify the inflammation-related factors that play a role in periarticular osteoporosis in patients with rheumatoid arthritis (RA), the synovial fluid and synovium of the knee joint, and the periarticular cancellous bone of the femoral condyle were collected at surgery from postmenopausal women with RA or osteoarthritis (OA). All patients with RA had radiologic bone loss on the femoral condyles, while such a loss was not observed in patients with OA. The present study examined: (i) tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1beta and IL-6 levels in synovial fluid: (ii) TNFalpha, IL-1beta and IL-6 messenger RNA (mRNA) expression in the synovium and the cancellous bone that contained bone marrow; and (iii) IL-6 and prostaglandin E2 (PGE2) production in cultured osteoblast-lineage cells derived from collagenase-treated cancellous bone fragments. Inflammation of the knee joints in patients with RA was confirmed by significantly higher proinflammatory cytokine levels in the synovial fluid and the synovium than those seen in patients with OA. In patients with RA, mRNA expression of IL-6, but not TNFalpha and IL-1beta, in the cancellous bone and IL-6 and PGE2 production in the osteoblast-lineage cells were significantly higher than in patients with OA. These findings suggest, for the first time, that IL-6 is involved in periarticular osteoporosis in postmenopausal women with RA. IL-6 and PGE2 released from osteoblast-lineage cells could be, at least in part, responsible for human inflammation-induced bone loss.
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PMID:Involvement of interleukin-6 and prostaglandin E2 in periarticular osteoporosis of postmenopausal women with rheumatoid arthritis. 1128 Nov 65

A major function of alpha-1-antitrypsin (AAT) is the inhibition of overexpressed serine proteinases during inflammation. However, it is also known that the biological activity of AAT is affected by chemical modifications, including oxidation of the reactive-site methionine, polymerization, and cleavage by unspecific proteases, all of which will result in AAT inactivation and/or degradation. All inactive forms of AAT can be detected in tissues and fluids recovered from inflammatory sites. To test for a possible link between the inflammation-generated, noninhibitory, cleaved form of AAT and cellular processes associated with inflammation, we studied the effects of this form at varying concentrations on human monocytes in culture. We found that cleaved AAT at concentrations ranging between 1 and 10 microM in monocyte cultures over 24 h induces elevation in monocyte chemoattractant protein-1 (MCP-1) and pro-inflammatory cytokines such as TNFalpha and IL-6 and also increases production of interstitial collagenase (MMP-1) and gelatinase B (MMP-9), members of two different classes of matrix metalloproteinase. Moreover, monocytes stimulated with higher doses of cleaved AAT show an increase in cellular oxygen consumption by about 30%, while native AAT under the same experimental conditions inhibits oxygen consumption by about 50%. These results indicate that the cleaved form of AAT may play a role in monocyte recruitment and pro-inflammatory activation during inflammatory processes, and also suggest that changes in structure occurring upon AAT cleavage could alter its functional properties with potential pathological consequences.
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PMID:Effects of noninhibitory alpha-1-antitrypsin on primary human monocyte activation in vitro. 1136 45

Molecular biology techniques help to study details of testicular cell interactions, which play an important role in the control of spermatogenesis and secretory function of the male gonad. This paper presents an example of application of such techniques, with evaluation of their usability, in the study on expression of some cytokines involved in cellular interactions in the rat testis. Testicular cells were isolated by digestion with collagenase followed by percoll gradient centrifugation or by the adherence technique (macrophages). Then RNA was isolated from cells using Chomczynski-Sacchi method and analysed by electrophoresis and spectrophotometry. RNA was reversely transcribed using oligo-dT15 primer and AMV (Avian Myeloblastosis Virus) transcriptase. cDNA was amplified by PCR with primers for rat IL-1alpha, IL-1beta, IL-6 and Tbr (Thermus brockianus) polymerase. RT-PCR products were analysed by electrophoresis. Chomczynski-Sacchi method proved to be effective for isolation of good quality RNA even from small number of cells. RT-PCR revealed the presence of mRNA for studied cytokines in isolated cell. The results indicate that the applied techniques are useful in studies on the function of male gonad and indicate the need for use of semi-quantitative methods for evaluation of cytokine expression.
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PMID:An example of application of molecular techniques to the study on the local regulatory system controlling the function of the rat male gonad. 1137 83

The increasing availability of mice with gene supplementation (transgenic), site-specific inactivation mutations (gene "knock-outs"), or site-specific genetic modification mutations (gene "knock-ins") has spurred interest in the development of murine trauma models. In this study, C57 BL/6 mice (28 g) were given a cutaneous burn over 40% total body surface area by applying brass probes (1 x 2 x 0.003 cm) heated to 100 degrees C in boiling water to the animals side and back for 5 s. Shams received anesthesia alone and not burn. Mice were killed 24 h post-burn to determine presence of partial-thickness or full-thickness burn injury, cardiac contractile function (Langendorff perfusion, n = 7 or 8 mice/group) or to examine cardiac myocyte cytokine secretion in isolated cardiomyocytes (collagenase perfusion, n = 4 or 5 mice/group). All mice were killed 24 h post-burn for subsequent cardiac or cardiomyocyte studies. Our studies confirm that this murine model of burn trauma produced mixed partial- or full-thickness burn injury, whereas there was no necrosis or inflammation in sham burn mice. Baseline hematocrits were similar in all mice (44+/-1) but decreased after burn trauma (37+/-1), likely because of the volume of fluid resuscitation and hemodilution. Burn trauma impaired cardiac contraction and relaxation as indicated by the lower left ventricular pressure (LVP) measured in burn (56+/-4) compared to that measured in shams (84+/-1 mmHg, P < 0.001), a lower rate of LVP rise (+dP/dt max, 1393+/-10 vs. 2000+/-41 mmHg/s, P < 0.002), and reduced LVP fall (-dP/dt max, 1023 - 40 vs. 1550+/-50, P < 0.001). These differences occurred despite similar coronary perfusion pressures and heart rates in both sham and burn mice. Ventricular function curves were shifted downward in the burn mice in the direction of contractile failure; in addition, hearts from burn mice had reduced LVP and +dP/dt responses to increases in coronary flow rate, increases in perfusate Ca2+, and to isoproterenol challenge (P < 0.05). Burn trauma promoted cardiac myocyte secretion of tumor necrosis factor (TNFalpha) (175+/-6 pg/mL) compared to that measured in shams (72+/-9 pg/mL, P < 0.05); burn trauma also increased cardiac myocyte secretion of interleukin 1beta (IL-1beta) (sham: 2+/-0.5; burn: 22+/-1 pg/mL, P < 0.05) and IL-6 (sham: 70+/-6; burn: 148+/-16 pg/mL, P < 0.05). Anti-TNFalpha strategies prevented burn-mediated cardiac contractile deficits. Burn trauma altered Ca2+ homeostasis in murine cardiomyocytes (Fura-2 AM loading). [Ca2+]i in myocytes from burns (185+/-4 nM) was higher than values measured in myocytes from shams (86+/-nM, P < 0.05). These data confirm that the murine burn model provides a reasonable approach to study the molecular and cell biology of inflammation in organ dysfunction after burn trauma.
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PMID:Development of an acute burn model in adult mice for studies of cardiac function and cardiomyocyte cellular function. 1150 64

Stroke is a common cause of death and disability in our society. Stroke is associated with changes in immune responses within the central nervous system as well as systemically. The cells contributing to such changes as well as the factors contributing to formation of the inflammatory infiltrate observed in stroke remain to be clarified. In this study, blood monocytes and corresponding mononuclear cells (MNC) were separated and examined in parallel within 4 days and 1-3 months after onset of ischemic stroke. Numbers of TNF-alpha-, IL-12-, IL-6-, and IL-10-secreting cells and of cells expressing mRNA for matrix metalloproteinase (MMP)-1, -2, -7, -9 and tissue inhibitor of MMP (TIMP)-1 were studied. The TNF-alpha-, IL-12-, and IL-6-secreting monocytes and MNC were elevated during the acute phase compared to healthy controls. Such differences were not observed when stroke patients were examined during convalescence. The IL-10-secreting monocytes did not change over the course of stroke. Levels of monocytes expressing MMP-1, MMP-7 and TIMP-1 mRNA were elevated in the acute phase of stroke patients compared to convalescence and healthy controls, as were levels of MMP-1, -2, -7, -9 and TIMP-1 mRNA expressing blood MNC. The MMP-2 and -9 activity as measured by zymography also was higher in MNC supernatants in the acute phase of stroke compared to convalescence. The high levels of proinflammatory cytokines and MMPs in blood monocytes and MNC further demonstrate the presence of systemic aberrations in the acute phase of stroke. Such changes may contribute to the influx of blood-borne cells into the ischemic lesions during the acute phase of stroke.
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PMID:Matrix metalloproteinase and cytokine profiles in monocytes over the course of stroke. 1172 9

Despite the anti-TNF alpha based progress in the treatment of RA, it is necessary to further optimize study designs and reports (Etanercept/MTX combination with results of radiological progression; publication of D2E7 trials; combination of D2E7 with MTX). Moreover, innovative immunobiologicals (PEG-TNFRI, PEG-TNF alpha antibody fragments, soluble TNFRI, CTLA4-Ig, CD40 ligand antibody, antibodies against IFN-gamma, IL-6, IL-12, IL-15, IL-18, complements), inhibitors of TNF alpha translation (peptides, anti-sense constructs) or TNF alpha synthesis (targeting NF kappa B, p38 MAP-kinase, phosphodiesterase IV, TNF alpha converting enzyme) are forthcoming. Principally different are inhibitors of complement convertases or collagenase as well as vaccination studies or trials trying to induce T cell anergy. Furthermore, for patients with MTX side effects, alternative DMARDs need to be tested along with TNF alpha blockers. Combination studies of TNF alpha constructs with other immunobiologicals (anti-CD4, IL-4, IL-10, IL-1RA) should be evaluated. To date, TNF alpha blockers have been evaluated in very early RA. Finally, a step-down trial will test whether--after induction of remission with a TNF alpha blocker plus MTX--replacement of the TNF alpha blocker with MTX alone or in combination with leflunomide will be able to keep disease activity suppressed for a longer duration.
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PMID:[New therapy developments in rheumatoid arthritis]. 1175 32

Although considerable evidence implicates the cytokine interferon (IFN)-gamma in atherogenesis, the proximal inducers and the range of sources of its expression remain unknown. This study tested the hypothesis that interleukin (IL)-18 regulates IFN-gamma expression during atherogenesis. Indeed, human atheroma in situ expressed IL-18 and elevated levels of its receptor subunits, IL-18Ralpha/beta, compared with nondiseased arterial tissue. IL-18 occurred predominantly as the mature, 18-kD form and colocalized with mononuclear phagocytes (MPhi), while endothelial cells (ECs), smooth muscle cells (SMCs), and MPhi all expressed IL-18Ralpha/beta. Correspondingly in vitro, only MPhi expressed IL-18, while all three cell types displayed the IL-18Ralpha/beta complex constitutively, exhibiting enhanced expression upon stimulation with LPS, IL-1beta, or tumor necrosis factor (TNF)-alpha. IL-18 signaling evoked effectors involved in atherogenesis, e.g., cytokines (IL-6), chemokines (IL-8), intracellular adhesion molecules (ICAM)-1, and matrix metalloproteinases (MMP-1/-9/-13), demonstrating functionality of the receptor on ECs, SMCs, and MPhi. Finally, IL-18, particularly in combination with IL-12, induced the expression of IFN-gamma in cultured MPhi and, surprisingly, in SMCs (but not in ECs). The expression of functional IL-18 and IL-18 receptor on human atheroma-associated ECs, SMCs, and MPhi, and its unexpected ability to induce IFN-gamma expression in SMCs, suggests a novel paracrine proinflammatory pathway operating during atherogenesis.
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PMID:Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. 1180 51

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is a potent inhibitor of activated matrix metalloproteinases such as gelatinase and collagenase, and thus helps to control extracellular matrix metabolism and deposition by connective tissue cells. We examined the responsiveness of the expression of TIMP-2 to various cytokines in dermal fibroblasts and studied the regulatory and signaling mechanisms of the response. TIMP-2 protein and mRNA expression was induced by IL-4 in a dose- and time-dependent manner, but not by TGF-beta, oncostatin M, or IL-6. IL-4 induction of TIMP-2 expression was dependent upon transcription. The p38 mitogen-activated protein kinase (MAPK) inhibitors SB202190 and SB203580 suppressed IL-4-induced TIMP-2 expression, suggesting the involvement of p38 MAP kinase in the signaling of IL-4 leading to TIMP-2 expression. Immunoblotting analysis using a specific Ab against phosphorylated p38 MAP kinase (Thr(180)/Tyr(182)) showed that IL-4 induced phosphorylation of p38 MAP kinase in human dermal fibroblasts. Furthermore, the p38 MAP kinase assay showed that IL-4 induces p38 MAPK activation in human dermal fibroblasts. The expression of the dominant-negative mutant p38 MAPK represses the IL-4-induced TIMP-2 expression in human dermal fibroblasts. Thus, IL-4 can potentially alter the dermal matrix metabolism by regulating TIMP-2.
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PMID:IL-4 up-regulates the expression of tissue inhibitor of metalloproteinase-2 in dermal fibroblasts via the p38 mitogen-activated protein kinase dependent pathway. 1182 24

In vivo, matrix metalloproteinases are produced in response to ultraviolet B (UV-B) irradiation and are considered to be involved in connective tissue alterations observed in photoaging. The respective roles of keratinocytes and fibroblasts in UV-B-induced MMP-1 production were investigated in monolayer cultures of keratinocytes and fibroblasts as well as in an epidermis model reconstructed in vitro. In contrast to fibroblasts, which secreted MMP-1 in response to UV-B irradiation, no accumulation of MMP-1 was observed after UV-B irradiation of keratinocytes. However, culture medium from UV-B-irradiated keratinocytes, which showed an increase in IL-1alpha and IL-6, induced MMP-1 production by human fibroblasts, suggesting that UV-B irradiation modulates MMP-1 production via both direct and indirect mechanisms.
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PMID:Direct role of human dermal fibroblasts and indirect participation of epidermal keratinocytes in MMP-1 production after UV-B irradiation. 1187 26


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