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)

In response to cutaneous injury, expression of collagenase-1 is induced in keratinocytes via alpha2beta1 contact with native type I collagen, and enzyme activity is essential for cell migration over this substratum. However, the cellular mechanism(s) mediating integrin signaling remain poorly understood. We demonstrate here that treatment of keratinocytes cultured on type I collagen with epidermal growth factor receptor (EGFR) blocking antibodies or a specific receptor antagonist inhibited cell migration across type I collagen and the matrix-directed stimulation of collagenase-1 production. Additionally, stimulation of collagenase-1 expression by hepatocyte growth factor, transforming growth factor-beta1, and interferon-gamma was blocked by EGFR inhibitors, suggesting a required EGFR autocrine signaling step for enzyme expression. Collagenase-1 mRNA was not detectable in keratinocytes isolated immediately from normal skin, but increased progressively following 2 h of contact with collagen. In contrast, EGFR mRNA was expressed at high steady-state levels in keratinocytes isolated immediately from intact skin but was absent following 2 h cell contact with collagen, suggesting down-regulation following receptor activation. Indeed, tyrosine phosphorylation of the EGFR was evident as early as 10 min following cell contact with collagen. Treatment of keratinocytes cultured on collagen with EGFR antagonist or heparin-binding (HB)-EGF neutralizing antibodies dramatically inhibited the sustained expression (6-24 h) of collagenase-1 mRNA, whereas initial induction by collagen alone (2 h) was unaffected. Finally, expression of collagenase-1 in ex vivo wounded skin and re-epithelialization of partial thickness porcine burn wounds was blocked following treatment with EGFR inhibitors. These results demonstrate that keratinocyte contact with type I collagen is sufficient to induce collagenase-1 expression, whereas sustained enzyme production requires autocrine EGFR activation by HB-EGF as an obligatory intermediate step, thereby maintaining collagenase-1-dependent migration during the re-epithelialization of epidermal wounds.
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PMID:Keratinocyte collagenase-1 expression requires an epidermal growth factor receptor autocrine mechanism. 1018 26

Collagenase-3 (MMP-13) is characterized by an exceptionally wide substrate specificity and restricted expression. MMP-13 is specifically expressed by transformed human keratinocytes in squamous cell carcinomas in vivo and its expression correlates with their invasion capacity. Here, we show, that interferon-gamma (IFN-gamma) markedly inhibits expression of MMP-13 by human cutaneous SCC cells (UT-SCC-7) and by ras-transformed human epidermal keratinocytes (A-5 cells) at the transcriptional level. In addition, IFN-gamma inhibits collagenase-1 (MMP-1) expression in these cells. IFN-gamma abolished the enhancement of MMP-13 and MMP-1 expression by transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), and inhibited invasion of A-5 cells through type I collagen. IFN-gamma also rapidly and transiently activates extracellular signal-regulated kinase 1,2 (ERK1,2) and blocking ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by specific MEK1,2 inhibitor PD98059 partially (by 50%) prevents Ser-727 phosphorylation of STAT1 and suppression of MMP-13 expression by IFN-gamma. Furthermore, Ser-727 phosphorylation of STAT1 by ERK1,2, or independently of ERK1,2 activation is associated with marked reduction in MMP-13 expression. These observations identify a novel role for IFN-gamma as a potent inhibitor of collagenolytic activity and invasion of transformed squamous epithelial cells, and show that inhibition of MMP-13 expression by IFN-gamma involves activation of ERK1,2 and STAT1.
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PMID:Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-gamma is associated with activation of extracellular signal-regulated kinase-1,2 and STAT1. 1064 3

We determined whether the expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMPs (TIMP) in murine macrophages is regulated by the novel synthetic bacterial lipopeptide JBT 3002. Multilamellar liposomes (MLV) encapsulating JBT 3002 (MLV-JBT 3002) stimulated the production of 72-kDa and 92-kDa (gelatinase A and B) type IV collagenase and inhibited the production of murine metalloelastase (MME) in a dose-dependent manner in murine peritoneal macrophages. MLV-JBT 3002 also induced production of TIMP-1. MLV-JBT 3002 did not induce collagenase production in tumor cells. Priming murine macrophages with interferon-gamma (IFN-gamma) inhibited JBT 3002-stimulated production of both MMP-9 and MMP-2 and further inhibited production of MME by a mechanism involving nitric oxide (NO). This conclusion is based on data showing that IFN-gamma failed to inhibit production of MMP in the presence of L-methyl arginine or in macrophages from inducible nitric oxide synthase knockout mice. These data suggest that JBT 3002 differentially regulates the production of various MMPs and TIMP in macrophages.
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PMID:Differential regulation of type IV collagenases and metalloelastase in murine macrophages by the synthetic bacterial lipopeptide JBT 3002. 1072 54

We tested the hypothesis that the inflammatory cytokines can regulate fibroblast extracellular matrix metabolism. Neonatal and adult rat cardiac fibroblasts cultures in vitro were exposed to interleukin (IL)-1beta (4 ng/mL), tumor necrosis factor-alpha (TNF-alpha; 100 ng/mL), IL-6 (10 ng/mL), or interferon-gamma (IFN-gamma; 500 U/mL) for 24 hours. IL-1beta, and to a lesser extent TNF-alpha, decreased collagen synthesis, which was measured as collagenase-sensitive [(3)H]proline incorporation, but had no effect on cell number or total protein synthesis. IL-1beta decreased the expression of procollagen alpha(1)(I), alpha(2)(I), and alpha1(III) mRNA, but increased the expression of procollagen alpha(1)(IV), alpha(2)(IV), and fibronectin mRNA, indicating a selective transcriptional downregulation of fibrillar collagen synthesis. IL-1beta and TNF-alpha each increased total matrix metalloproteinase (MMP) activity as measured by in-gel zymography, causing specific increases in the bands corresponding to MMP-13, MMP-2, and MMP-9. IL-1beta increased the expression of proMMP-2 and proMMP-3 mRNA, suggesting that increased metalloproteinase activity is due, at least in part, to increased transcription. The effects of IL-1beta were not dependent on NO production. Thus, IL-1beta and TNF-alpha decrease collagen synthesis and activate MMPs that degrade collagen. These observations suggest that IL-1beta and TNF-alpha may contribute to ventricular dilation and myocardial failure by promoting the remodeling of interstitial collagen.
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PMID:Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. 1086 17

Subcutaneous implantation of biodegradable hexamethylenediisocyanate crosslinked dermal sheep collagen (HDSC) elicited little foreign-body reaction in mice in contrast to rats. If the factor(s) resulting in this minor foreign-body reaction are better understood, this knowledge can be used to modulate unwanted foreign-body reactions. Therefore, we investigated whether the phagocytic potential of murine macrophages and giant cells could be enhanced. Disks of HDSC were predegraded with collagenase or impregnated with tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma) before implantation in 129 SVEV mice. Explantation was performed on days 7, 14, 21, and 28 and the disks were evaluated at the (immuno) light and transmission electron-microscopic levels. More giant cells were present in the predegraded disks. Cells were associated with the HDSC bundles, and the onset of phagocytosis started on day 28, in contrast to the controls and the disks impregnated with the cytokines. Expression of MHC class II was minimal in all groups. The matrix metalloproteinases MMP-2 and MMP-9 were expressed in all groups although on day 28 MMP-9 expression was higher in the predegraded disks. Thus, predegradation only slightly enhanced the onset of the foreign-body reaction to HDSC in mice, and impregnation with cytokines not at all. This suggests that lack of proteolytic enzymes or TNF-alpha or IFN-gamma is not the cause of the impaired onset of the foreign-body reaction.
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PMID:Enzyme and cytokine effects on the impaired onset of the murine foreign-body reaction to dermal sheep collagen. 1109 83

Tumor necrosis factor (TNF) receptor superfamily 14 (TNFRSF14) is the cellular receptor for TNF superfamily 14 (LIGHT). Immunohistochemical staining of human carotid atherosclerotic plaques revealed a high level of expression of the TNFRSF14 in regions rich in macrophages/foam cells. To investigate the role of TNFRSF14 in the functioning of monocytes in relation to atherogenesis, we have analyzed TNFRSF14 expression levels and cellular events after stimulation of TNFRSF14 in peripheral blood monocytes or the human macrophage-like cell line, THP-1. A high level of expression of TNFRSF14 was detected in activated monocytes, in macrophages derived from monocytes, and in THP-1 cells. Concomitant activation of THP-1 cells with interferon-gamma and immobilized anti-TNFRSF14 monoclonal antibody resulted in synergistic induction of proatherogenic cytokines, such as TNF-alpha and interleukin-8. Activation of THP-1 cells with immobilized anti-TNFRSF14 monoclonal antibody induced expression of matrix metalloproteinase (MMP)-1, MMP-9, MMP-13, and tissue inhibitors of metalloproteinase-1 and -2. Furthermore, immunohistochemical staining of atherosclerotic plaques with severe infiltration of foam cells revealed that the expression patterns of TNFRSF14 and MMP-1, -9, and -13 overlapped. Treatment of THP-1 cells with soluble LIGHT also caused induction of MMP-9 and interleukin-8. These data suggest that TNFRSF14 is involved in atherosclerosis via the induction of proatherogenic cytokines and decreasing plaque stability by inducing extracellular matrix-degrading enzymes.
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PMID:Tumor necrosis factor receptor superfamily 14 is involved in atherogenesis by inducing proinflammatory cytokines and matrix metalloproteinases. 1174 58

We reported recently that immune complexes (ICs) induced matrix metalloproteinase-1 (MMP-1) expression in U937 histiocytes. The present study was undertaken to determine the effect of pretreatment of U937 cells with interferon-gamma (IFN-gamma) on IC-induced MMP-1 expression. Our flow cytometry studies showed that IFN-gamma upregulated the surface expression of FcgammaRI, but not FcgammaRII. Results also showed that pretreatment of the cells with IFN-gamma augmented LDL-containing IC (LDL-IC)-induced MMP-1 secretion in a dose- and time-dependent manner. Furthermore, Northern blot analysis revealed that IFN-gamma pretreatment led to a marked increase in MMP-1 mRNA. Finally, we demonstrated that PD98059 was able to block LDL-IC-induced MMP-1 secretion, regardless of whether the cells were pretreated with IFN-gamma or not, suggesting that IFN-gamma pretreatment did not alter the essential role of the ERK signaling pathway in LDL-IC-induced MMP-1 expression. In conclusion, the present study has demonstrated that IFN-gamma pretreatment augments LDL-IC-induced MMP-1 expression in U937 cells, thus elucidating an immune mechanism potentially involved in plaque destabilization.
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PMID:IFN-gamma pretreatment augments immune complex-induced matrix metalloproteinase-1 expression in U937 histiocytes. 1184 63

Human tumour necrosis factor (TNF)-like weak inducer of apoptosis (hTWEAK) and two anti-hTWEAK mAbs were tested for their ability to elicit or block inflammatory responses in cultured human dermal fibroblasts and synoviocytes. Incubation with hTWEAK increased the production of prostaglandin E2, matrix metalloproteinase-1 (MMP-1), IL-6, and the chemokines IL-8, RANTES (regulated on activation, normal T expressed and secreted) and interferon-gamma-inducible protein-10 (IP-10) in culture supernatant of fibroblasts and synoviocytes. In combination with TNF or IL-1beta, hTWEAK further stimulated the secretion of prostaglandin E2, MMP-1, IL-6 and IL-8 up to fourfold, and IP-10 and RANTES up to 70-fold compared to TNF or IL-1beta alone. An anti-hTWEAK mAb, BCB10, blocked the effects of hTWEAK, whereas hTWEAK crosslinked by the anti-hTWEAK mAb, BEB3, further stimulated the inflammatory response of fibroblasts and synoviocytes. The anti-hTWEAK mAbs were ineffective in blocking or increasing the responses of TNF or IL-1beta and blocking anti-TNF mAb was ineffective in preventing the responses to TWEAK. These results were also confirmed at the RNA level for MMP-1, macrophage chemoattractant protein-1, RANTES, macrophage inflammatory protein-1alpha, IP-10 and IL-8. TWEAK in synergism with IL-1 and TNF may be an additional cytokine that plays a role in destructive chronic arthritic diseases.
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PMID:Proinflammatory activity of TWEAK on human dermal fibroblasts and synoviocytes: blocking and enhancing effects of anti-TWEAK monoclonal antibodies. 1187 48

Tumor necrosis factor-alpha (TNFalpha) and granulocyte macrophage colony-stimulating factor (GM-CSF) individually enhance monocyte matrix metalloproteinase-9 (MMP-9) but induce MMP-1 only when added in combination. Because interferon-gamma (IFNgamma) is also found at inflammatory sites, we determined its effect on monocyte MMPs in the presence or absence of TNFalpha and GM-CSF. IFNgamma alone did not stimulate monocyte MMP-9 or MMP-1; however, in the presence of GM-CSF it induced MMP-1 and enhanced MMP-1 stimulated by GM-CSF and TNFalpha. IFNgamma induced MMP-1 in the presence of GM-CSF through the stimulation of TNFalpha production through a mechanism involving both p38 and ERK1/2 MAPKs, in which GM-CSF stimulated ERK1/2 whereas IFNgamma activated p38. In support of this conclusion TNFalpha neutralizing antibody and antibodies against TNF receptor I and -II blocked the induction of MMP-1 by GM-CSF and IFNgamma. In contrast to its effects on MMP-1, IFNgamma inhibited TNFalpha-induced MMP-9 through a caspase 8-dependent pathway as demonstrated by the restoration of MMP-9 with caspase 8 inhibitors. Moreover, the phosphorylation of STAT1 by IFNgamma was blocked by an inhibitor of caspase 8, indicating that STAT1 had a suppressive effect on MMP-9. Caspase 8-mediated phosphorylation of STAT1 through p38 MAPK as shown by the inhibition of IFNgamma-induced phosphorylation of p38 by caspase 8 inhibitors. Activation of caspase 8 by IFNgamma did not result in increased apoptosis. Thus IFNgamma in the presence of GM-CSF and/or TNFalpha differentially regulates monocyte MMPs through induction of TNFalpha and a novel mechanism involving caspase 8 that is independent of apoptosis.
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PMID:Interferon-gamma differentially regulates monocyte matrix metalloproteinase-1 and -9 through tumor necrosis factor-alpha and caspase 8. 1296 Jan 56

Herein we describe the case of a man who was diagnosed as having relapsing polychondritis (RP) when he was 18 years of age and was treated over the course of 2 years with numerous immunosuppressive agents, including tumor necrosis factor alpha (TNFalpha) inhibitors. His respiratory symptoms were refractory to treatment. Serum and urine samples were obtained periodically for measurement of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, anti-type II collagen (anti-CII) antibodies, and urinary type II collagen neoepitope (uTIINE) levels. The uTIINE assay is specific for collagenase cleavage products CII present in urine. ESRs and CRP levels varied widely but were rarely normal. Anti-CII antibody titers were high initially and decreased slowly and steadily for a year following the start of immunosuppressive medication, remaining low throughout the remainder of the patient's monitored disease course. The uTIINE levels were elevated prior to the initiation of TNFalpha inhibitors. Upon initiation of etanercept, they decreased abruptly to normal and stayed nearly normal. The uTIINE levels rose abruptly again upon discontinuation of TNFalpha inhibitor treatment. The dramatic decline in CII degradation, coincident with the administration of the TNFalpha inhibitors, suggested that this treatment dramatically reduced the chondritis. Serum levels of Th1 cytokines (interferon-gamma, interleukin-12 [IL-12], and IL-2) paralleled changes in uTIINE levels, while those of Th2 cytokines (IL-4, IL-5, IL-6, and IL-10) showed little or no association with disease state or uTIINE levels. These results indicate that RP might be a Th1-mediated disease process. Moreover, the uTIINE assay appears to provide an objective measure of the severity of chondritis that could assist clinical decisions regarding adjustments of steroid and other immunosuppressive therapy. This outcome measure merits investigation in a broader spectrum of RP patients.
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PMID:Urinary type II collagen neoepitope as an outcome measure for relapsing polychondritis. 1455 1


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