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Ghislain Opdenakker - One of the best experts on this subject based on the ideXlab platform.
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<B>GelatinaseB> B/matrix metalloproteinase-9 cleaves interferon-Beta and is a target for immunotherapy.
Brain : a journal of neurology, 2020Co-Authors: Inge Nelissen, Philippe E Van Den Steen, Paul Proost, Erik Martens, Isabelle Ronsse, Ghislain OpdenakkerAbstract:Parenteral administration of interferon (IFN)-Beta is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of <B>GelatinaseB> B, also called matrix metalloproteinase (MMP) 9. <B>GelatinaseB> B is capaBle of destroying the Blood-Brain Barrier, and of cleaving myelin Basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and Being a therapeutic target in multiple sclerosis. Here we demonstrate that <B>GelatinaseB> B proteolytically cleaves IFN-Beta, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-Beta-1B than with IFN-Beta-1a. Furthermore, the tetracycline minocycline, which has a known Blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhiBitors prevent the in vitro degradation of IFN-Beta By <B>GelatinaseB> B. These data provide a novel mechanism and rationale for the inhiBition of <B>GelatinaseB> B in diseases in which IFN-Beta has a Beneficial effect. The comBination of <B>GelatinaseB> B inhiBitors with Better and lower pharmacological formulations of IFN-Beta may reduce the side-effects of treatment with IFN-Beta, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.
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Differential Glycosylation of <B>GelatinaseB> B from Neutrophils and Breast Cancer Cells
Advances in Experimental Medicine and Biology, 2020Co-Authors: Philippe E Van Den Steen, Ghislain Opdenakker, Pauline M Rudd, Mark R Wormald, Louise Royle, Anthony J. C. Leathem, Raymond A. DwekAbstract:The matrix metalloproteases (MMPs) are a family of zinc-dependant endopeptidases (Nagase and Woessner 1999) that are involved in extracellular matrix (ECM) remodelling in a variety of physiological and pathological processes. MMP degradation of ECM proteins is associated with many aspects of cancer progression, including cancer cell growth, differentiation, apoptosis, migration and invasion, as well as regulation of angiogenesis and immune surveillance (EgeBlad and WerB 2002). <B>GelatinaseB> B (MMP-9) is structurally one of the most complex MMPs (Opdenakker, Van den Steen et al. 2001; Van den Steen, DuBois et al. 2002). All MMPs have a prodomain (proteolytically removed to yield active enzyme), an active domain and a zinc-Binding domain. <B>GelatinaseB> B also has a gelatin-Binding fiBronectin domain, a collagen type V-like domain and a carBoxyterminal hemopexin domain. Human natural <B>GelatinaseB> B from neutrophils is heavily glycosylated (Rudd, Mattu
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expression of chemokines and <B>GelatinaseB> B in sympathetic ophthalmia
Eye, 2007Co-Authors: A Abu M Elasrar, Ghislain Opdenakker, Karel Geboes, Sofie Struyf, C Van Den Broeck, J Van Damme, P KestelynAbstract:To examine the expression of <B>GelatinaseB> B (matrix metalloproteinase-9) and the chemokines monocyte chemotactic protein-1 (CCL2/MCP-1) and stromal cell-derived factor-1 (CXCL12/SDF-1) in sympathetic ophthalmia (SO). Five enucleated exciting eyes with a clinical diagnosis and typical histopathological findings of SO were studied By immunohistochemical techniques using a panel of monoclonal antiBodies directed against <B>GelatinaseB> B, MCP-1, and SDF-1. In addition, a panel of monoclonal and polyclonal antiBodies was used to characterize the composition of the inflammatory infiltrate. In all cases, the extensive uveal inflammatory infiltrate was organized as a diffuse infiltrate and as large granulomas consisting of epithelioid cells and multinucleated giant cells. CD20+ B lymphocytes predominated in the diffuse infiltrate and CD3+ T lymphocytes were few. The monocyte/macrophage marker CD68 was expressed in scattered inflammatory mononuclear cells and within granulomas and Dalen–Fuchs nodules. Most of the inflammatory cells were HLA-DR+. Immunoreactivity for <B>GelatinaseB> B, MCP-1, and SDF-1 was oBserved in cells within granulomas and in scattered epithelioid cells. Immunoreactivity for MCP-1 was noted in retinal pigment epithelial cells. Endothelial cells of choriocapillaries showed weak immunoreactivity for SDF-1. <B>GelatinaseB> B, MCP-1, and SDF-1 might have a pathogenic role in the recruitment of leucocytes into the eye in SO.
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PECAM-1 and <B>GelatinaseB> B coexist in vascular cuffs of multiple sclerosis lesions
Neuropathology and Applied Neurobiology, 2006Co-Authors: Inge Nelissen, D Gveric, J. M. Van Noort, Ml Cuzner, Ghislain OpdenakkerAbstract:In multiple sclerosis (MS), the matrix metalloprotease (MMP) <B>GelatinaseB> B/MMP-9 and platelet endothelial cell adhesion molecule (PECAM)-1 have Both Been implicated in trans-endothelial infiltration of leucocytes into the Brain, But their functional connection has not yet Been investigated. We investigated the expression of <B>GelatinaseB> B and PECAM-1 in post mortem Brains of MS patients By immunohistochemistry. Because increased soluBle PECAM-1 serum levels have Been oBserved in MS patients, we also tested in vitro whether this could Be due to cleavage of PECAM-1 By <B>GelatinaseB> B or matrilysin-1/MMP-7. Constitutive expression of PECAM-1 was found on Brain endothelial cells, whilst in active MS lesions cell-Bound PECAM-1 was highly up-regulated on foamy macrophages in perivascular infiltrates and co-localized with <B>GelatinaseB> B. However, human THP-1 monocyte-Bound or soluBle recomBinant PECAM-1 were Both resistant to proteolytic cleavage By <B>GelatinaseB> B or matrilysin-1 in vitro, as demonstrated By Western Blot analysis and flow cytometry. These results suggest that PECAM-1 and <B>GelatinaseB> B may complement each other during the transmigration of the Blood-Brain Barrier By mononuclear cells.
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<B>GelatinaseB> B/matrix metalloproteinase-9 provokes cataract By cleaving lens βB1 crystallin
The FASEB Journal, 2005Co-Authors: Francis J Descamps, Philippe E Van Den Steen, Jo Van Damme, Sofie Starckx, Paul Proost, Erik Martens, Ghislain OpdenakkerAbstract:Cataract is a common cause of Blindness and results from destruction of the microarchitecture of the lens. It is oBserved in many genetic syndromes, infections, inflammatory diseases and during aging. Fluctuations in lens density and light scattering By altered refraction index form the physical Basis for this process, But the pathogenesis is poorly understood. Increased levels of <B>GelatinaseB> B/matrix metalloproteinase-9 have Been reported for cataract-associated disorders such as eye inflammation and diaBetes. We demonstrate that incuBation of lenses with <B>GelatinaseB> B leads immediately to cataract. In complete eye extracts, βB1 crystallin was identified as the major <B>GelatinaseB> B suBstrate By comBination of proteomics, mass spectrometry, and Edman degradation analysis. The cleavage of βB1 crystallin was also oBserved in vivo after endogenous <B>GelatinaseB> B-induction By the chemokine granulocyte chemotactic protein-2 in wild-type mice But not in <B>GelatinaseB> B−/− mice.—Descamps, F. J., Martens, E., Proost, P., ...
Robert M - One of the best experts on this subject based on the ideXlab platform.
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<B>GelatinaseB> B is required for alveolar Bronchiolization after intratracheal Bleomycin
American Journal of Pathology, 2000Co-Authors: Tomoko Betsuyaku, Y Fukuda, William C Parks, Michael J Shipley, Robert MAbstract:Increased expression of matrix metalloproteinases, particularly <B>GelatinaseB> B (MMP-9), has Been descriBed in the lungs in pulmonary fiBrosis. Intratracheal Bleomycin is often used experimentally to produce lesions resemBling human fiBrosing alveolitis. To assess the role of <B>GelatinaseB> B in Bleomycin-induced fiBrosing alveolitis, we instilled Bleomycin intratracheally into <B>GelatinaseB> B-deficient mice and <B>GelatinaseB> B+/+ littermates. Twenty-one days after Bleomycin the two groups of mice were indistinguishaBle in terms of pulmonary histology and total lung collagen and elastin. However, the lungs of <B>GelatinaseB> B-deficient mice showed minimal alveolar Bronchiolization, whereas Bronchiolization was prominent in the lungs of <B>GelatinaseB> B+/+ mice. <B>GelatinaseB> B was identified immunohistochemically in terminal Bronchiolar cells and Bronchiolized cells 7 and 14 days after Bleomycin in <B>GelatinaseB> B+/+ mice, and whole lung <B>GelatinaseB> B mRNA was increased at the same times. Many Bronchiolized cells displayed Clara cell features By electron microscopy. Some Bronchiolized cells stained with antiBody to helix transcription factor 4, a factor associated with the ciliated cell phenotype. Thus, fiBrosing alveolitis develops after intratracheal Bleomycin irrespective of <B>GelatinaseB> B. However, <B>GelatinaseB> B is required for alveolar Bronchiolization, perhaps By facilitating migration of Clara cells and other Bronchiolar cells into the regions of alveolar injury.
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matrix metalloproteinase deficiencies affect contact hypersensitivity stromelysin 1 deficiency prevents the response and <B>GelatinaseB> B deficiency prolongs the response
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Min Wang, Robert M, John S Mudgett, Thomas A Ferguson, Howard G WelgusAbstract:Matrix metalloproteinases (MMPs) are expressed By T cells and macrophages, But there is a paucity of evidence for their role in immune responses. We have studied mice with deficiencies of stromelysin-1 (MMP-3) or <B>GelatinaseB> B (MMP-9) in a dinitrofluoroBenzene (DNFB)-induced model of contact hypersensitivity (CHS). Stromelysin-1-deficient mice showed a markedly impaired CHS response to topical DNFB, although they responded normally to cutaneously applied phenol, an acute irritant. Lymphocytes from lymph nodes of DNFB-sensitized stromelysin-1-deficient mice did not proliferate in response to specific soluBle antigen dinitroBenzenesulfonic acid, But did proliferate identically to lymph node lymphocytes from wild-type mice when presented with the mitogen Con A. An intradermal injection of stromelysin-1 immediately Before DNFB sensitization rescued the impaired CHS response to DNFB in stromelysin-1-deficient mice. Unlike stromelysin-1-deficient mice, <B>GelatinaseB> B-deficient mice exhiBited a CHS response comparaBle to wild-type controls at 1 day postchallenge, But the response persisted Beyond 7 days in contrast to the complete resolution oBserved in wild-type mice By 7 days. However, <B>GelatinaseB> B-deficient mice had a normal rate of resolution of acute inflammation elicited By cutaneous phenol. <B>GelatinaseB> B-deficient mice failed to show IL-10 production at the site of CHS, an essential feature of resolution in control mice. These results indicate that stromelysin-1 and <B>GelatinaseB> B serve important functions in CHS. Stromelysin-1 is required for initiation of the response, whereas <B>GelatinaseB> B plays a critical role in its resolution.
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neutrophil emigration in the lungs peritoneum and skin does not require <B>GelatinaseB> B
American Journal of Respiratory Cell and Molecular Biology, 1999Co-Authors: Tomoko Betsuyaku, Michael J Shipley, Robert MAbstract:Polymorphonuclear leukocytes (PMN) release <B>GelatinaseB> B in response to variaBle stimuli. <B>GelatinaseB> B degrades Basement memBrane components in vitro, and inhiBition of matrix metalloproteinase activity Blunts PMN migration through a prototype Basement memBrane (Matrigel) and amnionic memBranes. Accordingly, it has Been speculated that <B>GelatinaseB> B is necessary for PMN emigration. To test this hypothesis we induced acute inflammation in the lungs, peritoneum, and skin in mice with a null mutation of the <B>GelatinaseB> B gene (<B>GelatinaseB> B−/−) and littermate controls (<B>GelatinaseB> B+/+). At 3, 6, 12, and 24 h after intratracheal instillation of LPS, the emigration of PMN in the lung, as determined By PMN in Bronchoalveolar lavage fluid, was similar in <B>GelatinaseB> B−/− and <B>GelatinaseB> B+/+ mice. The numBer of PMN in the peritoneal cavity 4 h after thioglycollate-induced peritonitis was also comparaBle in <B>GelatinaseB> B−/− and <B>GelatinaseB> B+/+ mice. At 4 h after an intradermal injection of interleukin-8, numerous PMN we...
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<B>GelatinaseB> B deficient mice are resistant to experimental Bullous pemphigoid
Journal of Experimental Medicine, 1998Co-Authors: Michael J Shipley, Thiennu H Vu, Xiaoye Zhou, Luis A Diaz, Zena Werb, Robert MAbstract:Bullous pemphigoid (BP) is an autoimmune suBepidermal Blistering disease characterized By deposition of autoantiBodies at the Basement memBrane zone. In an experimental BP model in mice, the suBepidermal Blistering is mediated By antiBodies directed against the hemidesmosomal protein BP180 (collagen XVII, BPAG2), and depends on complement activation and neutrophil infiltration. <B>GelatinaseB> B is present in BP Blister fluid and can cleave BP180. In this study we investigated the role of <B>GelatinaseB> B in the immunopathogenesis of experimental BP using mice containing targeted disruption of the <B>GelatinaseB> B (MMP-9, 92 kD <B>GelatinaseB>) gene. <B>GelatinaseB> B–deficient mice were resistant to the Blistering effect of intracutaneous anti-mBP180 antiBodies, although these mice showed deposition of autoantiBodies at the Basement memBrane zone and neutrophil recruitment to the skin comparaBle to that oBserved in the control mice. Interleukin 8 given intradermally concomitantly with pathogenic anti-mBP180 elicited a significant neutrophil recruitment into the skin in <B>GelatinaseB> B–deficient mice, But Blistering did not occur. However, <B>GelatinaseB> B–deficient mice reconstituted with neutrophils from normal mice developed Blistering in response to anti-mBP180 antiBodies. These results implicate neutrophil-derived <B>GelatinaseB> B in the pathogenesis of experimental BP and might lead to novel therapeutic strategies for BP.
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mmp 9 <B>GelatinaseB> B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes
Cell, 1998Co-Authors: Thiennu H Vu, Michael J Shipley, Robert M, Gabriele Bergers, Joel E Berger, Jill A Helms, Douglas Hanahan, Steven D Shapiro, Zena WerbAbstract:ABstract Homozygous mice with a null mutation in the MMP-9/<B>GelatinaseB> B gene exhiBit an aBnormal pattern of skeletal growth plate vascularization and ossification. Although hypertrophic chondrocytes develop normally, apoptosis, vascularization, and ossification are delayed, resulting in progressive lengthening of the growth plate to aBout eight times normal. After 3 weeks postnatal, aBerrant apoptosis, vascularization, and ossification compensate to remodel the enlarged growth plate and ultimately produce an axial skeleton of normal appearance. Transplantation of wild-type Bone marrow cells rescues vascularization and ossification in <B>GelatinaseB> B–null growth plates, indicating that these processes are mediated By <B>GelatinaseB> B–expressing cells of Bone marrow origin, designated chondroclasts. Growth plates from <B>GelatinaseB> B–null mice in culture show a delayed release of an angiogenic activator, estaBlishing a role for this proteinase in controlling angiogenesis.
Inge Nelissen - One of the best experts on this subject based on the ideXlab platform.
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<B>GelatinaseB> B/matrix metalloproteinase-9 cleaves interferon-Beta and is a target for immunotherapy.
Brain : a journal of neurology, 2020Co-Authors: Inge Nelissen, Philippe E Van Den Steen, Paul Proost, Erik Martens, Isabelle Ronsse, Ghislain OpdenakkerAbstract:Parenteral administration of interferon (IFN)-Beta is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of <B>GelatinaseB> B, also called matrix metalloproteinase (MMP) 9. <B>GelatinaseB> B is capaBle of destroying the Blood-Brain Barrier, and of cleaving myelin Basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and Being a therapeutic target in multiple sclerosis. Here we demonstrate that <B>GelatinaseB> B proteolytically cleaves IFN-Beta, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-Beta-1B than with IFN-Beta-1a. Furthermore, the tetracycline minocycline, which has a known Blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhiBitors prevent the in vitro degradation of IFN-Beta By <B>GelatinaseB> B. These data provide a novel mechanism and rationale for the inhiBition of <B>GelatinaseB> B in diseases in which IFN-Beta has a Beneficial effect. The comBination of <B>GelatinaseB> B inhiBitors with Better and lower pharmacological formulations of IFN-Beta may reduce the side-effects of treatment with IFN-Beta, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.
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PECAM-1 and <B>GelatinaseB> B coexist in vascular cuffs of multiple sclerosis lesions
Neuropathology and Applied Neurobiology, 2006Co-Authors: Inge Nelissen, D Gveric, J. M. Van Noort, Ml Cuzner, Ghislain OpdenakkerAbstract:In multiple sclerosis (MS), the matrix metalloprotease (MMP) <B>GelatinaseB> B/MMP-9 and platelet endothelial cell adhesion molecule (PECAM)-1 have Both Been implicated in trans-endothelial infiltration of leucocytes into the Brain, But their functional connection has not yet Been investigated. We investigated the expression of <B>GelatinaseB> B and PECAM-1 in post mortem Brains of MS patients By immunohistochemistry. Because increased soluBle PECAM-1 serum levels have Been oBserved in MS patients, we also tested in vitro whether this could Be due to cleavage of PECAM-1 By <B>GelatinaseB> B or matrilysin-1/MMP-7. Constitutive expression of PECAM-1 was found on Brain endothelial cells, whilst in active MS lesions cell-Bound PECAM-1 was highly up-regulated on foamy macrophages in perivascular infiltrates and co-localized with <B>GelatinaseB> B. However, human THP-1 monocyte-Bound or soluBle recomBinant PECAM-1 were Both resistant to proteolytic cleavage By <B>GelatinaseB> B or matrilysin-1 in vitro, as demonstrated By Western Blot analysis and flow cytometry. These results suggest that PECAM-1 and <B>GelatinaseB> B may complement each other during the transmigration of the Blood-Brain Barrier By mononuclear cells.
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functional roles and therapeutic targeting of <B>GelatinaseB> B and chemokines in multiple sclerosis
Lancet Neurology, 2003Co-Authors: Ghislain Opdenakker, Inge Nelissen, Jozef Van DammeAbstract:Summary Multiple sclerosis (MS) is a demyelinating disease of the CNS of unknown cause. Pathogenetic mechanisms, such as chemotaxis, suBsequent activation of autoreactive lymphocytes, and skewing of the extracellular proteinase Balance, are targets for new therapies. Matrix metalloproteinase <B>GelatinaseB> B (MMP-9) is upregulated in MS and was recently shown to degrade interferon Beta, one of the drugs used to treat MS. Consequently, the effect of endogenously produced interferon β or parenterally given interferon Beta may Be increased By <B>GelatinaseB> B inhiBitors. Blockage of chemotaxis or cell adhesion molecule engagement, and inhiBition of hydoxymethyl-glutarylcoenzyme- A reductase to lower expression of <B>GelatinaseB> B, may Become effective treatments of MS, alone or in comBination with interferon Beta. This may allow interferon Beta to Be used at lower doses and prevent side-effects.
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<B>GelatinaseB> B matrix metalloproteinase 9 cleaves interferon β and is a target for immunotherapy
Brain, 2003Co-Authors: Inge Nelissen, Philippe E Van Den Steen, Paul Proost, Erik Martens, Isabelle Ronsse, Ghislain OpdenakkerAbstract:Parenteral administration of interferon (IFN)‐β is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of <B>GelatinaseB> B, also called matrix metalloproteinase (MMP) 9. <B>GelatinaseB> B is capaBle of destroying the Blood–Brain Barrier, and of cleaving myelin Basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and Being a therapeutic target in multiple sclerosis. Here we demonstrate that <B>GelatinaseB> B proteolytically cleaves IFN‐β, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN‐β‐1B than with IFN‐β‐1a. Furthermore, the tetracycline minocycline, which has a known Blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhiBitors prevent the in vitro degradation of IFN‐β By <B>GelatinaseB> B. These data provide a novel mechanism and rationale for the inhiBition of <B>GelatinaseB> B in diseases in which IFN‐β has a Beneficial effect. The comBination of <B>GelatinaseB> B inhiBitors with Better and lower pharmacological formulations of IFN‐β may reduce the side‐effects of treatment with IFN‐β, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.
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<B>GelatinaseB> B/matrix metalloproteinase‐9 cleaves interferon‐β and is a target for immunotherapy
Brain, 2003Co-Authors: Inge Nelissen, Philippe E Van Den Steen, Paul Proost, Erik Martens, Isabelle Ronsse, Ghislain OpdenakkerAbstract:Parenteral administration of interferon (IFN)‐β is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of <B>GelatinaseB> B, also called matrix metalloproteinase (MMP) 9. <B>GelatinaseB> B is capaBle of destroying the Blood–Brain Barrier, and of cleaving myelin Basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and Being a therapeutic target in multiple sclerosis. Here we demonstrate that <B>GelatinaseB> B proteolytically cleaves IFN‐β, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN‐β‐1B than with IFN‐β‐1a. Furthermore, the tetracycline minocycline, which has a known Blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhiBitors prevent the in vitro degradation of IFN‐β By <B>GelatinaseB> B. These data provide a novel mechanism and rationale for the inhiBition of <B>GelatinaseB> B in diseases in which IFN‐β has a Beneficial effect. The comBination of <B>GelatinaseB> B inhiBitors with Better and lower pharmacological formulations of IFN‐β may reduce the side‐effects of treatment with IFN‐β, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.
Stefan Masure - One of the best experts on this subject based on the ideXlab platform.
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<B>GelatinaseB> B functions as regulator and effector in leukocyte Biology
Journal of Leukocyte Biology, 2001Co-Authors: Ghislain Opdenakker, Stefan Masure, Benedicte Dubois, Paul Proost, Van Den Steen, I Nelissen, Van Coillie E, Van Damme JAbstract:Matrix metalloproteinases (MMPs) form a family of enzymes with major actions in the re- modeling of extracellular matrix (ECM) compo- nents. <B>GelatinaseB> B (MMP-9) is the most complex family memBer in terms of domain structure and regulation of its activity. <B>GelatinaseB> B activity is under strict control at various levels: transcription of the gene By cytokines and cellular interactions; activation of the pro-enzyme By a cascade of en- zymes comprising serine proteases and other MMPs; and regulation By specific tissue inhiBitors of MMPs (TIMPs) or By unspecific inhiBitors, such as a2-macrogloBulin. Thus, remodeling ECM is the result of the local protease load, i.e., the net Bal- ance Between enzymes and inhiBitors. Glycosyla- tion has a limited effect on the net activity of gela- tinase B, and in contrast to the all-or-none effect of enzyme activation or inhiBition, it results in a higher-level, fine-tuning effect on the ECM cataly- sis By proteases in mammalian species. Fast de- granulation of consideraBle amounts of intracellu- larly stored <B>GelatinaseB> B from neutrophils, induced By various types of chemotactic factors, is another level of control of activity. Neutrophils are first- line defense leukocytes and do not produce gelati- nase A or TIMP. Thus, neutrophils contrast sharply with mononuclear leukocytes, which pro- duce <B>GelatinaseB> A constitutively, synthesize gelati- nase B de novo after adequate triggering, and over- produce TIMP-1. <B>GelatinaseB> B is also endowed with functions other than cleaving the ECM. It has Been shown to generate autoimmune neo-epitopes and to activate pro-IL-1B into active IL-1B. Gela- tinase B aBlation in the mouse leads to altered Bone remodeling and suBfertility, results in resistance to several induced inflammatory or autoimmune pa- thologies, and indicates that the enzyme plays a crucial role in development and angiogenesis. The major human neutrophil chemoattractant, IL-8, stimulates fast degranulation of <B>GelatinaseB> B from neutrophils. <B>GelatinaseB> B is also found to function as a regulator of neutrophil Biology and to truncate IL-8 at the aminoterminus into a tenfold more potent chemokine, resulting in an important posi- tive feedBack loop for neutrophil activation and chemotaxis. The CXC chemokines GRO-a, CTAP- III, and PF-4 are degraded By <B>GelatinaseB> B, whereas the CC chemokines MCP-2 and RANTES are not cleaved. J. Leukoc. Biol. 69: 851-859; 2001.
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resistance of young <B>GelatinaseB> B deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions
Journal of Clinical Investigation, 1999Co-Authors: Benedicte Dubois, Stefan Masure, L. Paemen, Joost Van Den Oord, Ursula Hurtenbach, Hubertine Heremans, Raf Sciot, Thorsten Meinhardt, Gunter J Hammerling, Ghislain OpdenakkerAbstract:Regulated expression of matrix metalloproteinases (MMPs) and their inhiBitors (TIMPs) plays a role in various physiological processes. To determine in vivo how unBalanced expression of these factors can promote or affect the course of pathologies, we knocked out the mouse <B>GelatinaseB> B gene By replacing the catalytic and zinc-Binding domains with an antisense-oriented neomycin resistance gene. Adult <B>GelatinaseB> B–deficient mice and wild-type controls could Be induced to develop experimental autoimmune encephalomyelitis (EAE) with similar scores for neurologic disease, Blood-Brain Barrier permeaBility, and central nervous system histopathology. However, whereas diseased control animals showed necrotizing tail lesions with hyperplasia of osteocartilaginous tissue, adult <B>GelatinaseB> B–deficient mice were resistant to this tail pathology. <B>GelatinaseB> B–deficient mice younger than 4 weeks of age were significantly less susceptiBle to the development of EAE than were age matched controls and, even as they aged, they remained resistant to tail lesions. These data illustrate that <B>GelatinaseB> B expression plays a role in the development of the immune system and that, in ontogenesis, the propensity to develop autoimmunity is altered By the aBsence of this MMP. J. Clin. Invest. 104:1507–1515 (1999).
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glycosylation of natural human neutrophil <B>GelatinaseB> B and neutrophil <B>GelatinaseB> B associated lipocalin
Biochemistry, 1999Co-Authors: Pauline M Rudd, Taj S Mattu, Stefan Masure, Tomas Bratt, Philippe E Van Den Steen, Mark R Wormald, Bernard Kuster, David J Harvey, Niels Borregaard, Jo Van DammeAbstract:<B>GelatinaseB> B is a matrix metalloproteinase (MMP-9) involved in tissue remodeling, development, cancer, and inflammation. Neutrophils produce three major forms of (pro)<B>GelatinaseB> B: 92 kDa monomers, homodimers, and complexes of <B>GelatinaseB> B covalently Bound to neutrophil <B>GelatinaseB> B-associated lipocalin (NGAL). In contrast to the case for other proteinases, little information aBout the glycosylation of any natural human MMP is availaBle. Here, Both <B>GelatinaseB> B and NGAL were purified from human peripheral Blood neutrophils, and the entire contents of the released N- and O-glycan pools were analyzed simultaneously using recently developed high-performance liquid chromatography-Based technology. The results are discussed within the context of the domain structure of <B>GelatinaseB> B and a molecular model of NGAL Based on data from this study and the three-dimensional nuclear magnetic resonance (NMR) structure of the protein. More than 95% of the N-linked glycans attached to Both <B>GelatinaseB> B and NGAL were part...
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Production and Characterization of RecomBinant Active Mouse <B>GelatinaseB> B from Eukaryotic Cells and in vivo Effects after Intravenous Administration
FEBS Journal, 1997Co-Authors: Stefan Masure, Jo Van Damme, L. Paemen, Paul Proost, Use Van Aelst, Pierre Fiten, Alfons Billiau, Ghislain OpdenakkerAbstract:<B>GelatinaseB> B is a matrix metalloproteinase involved in tissue remodelling. When mouse cells are triggered in vitro with interleukin-1, Bacterial endotoxin, virus-mimicking douBle-stranded RNA or cytokine inducers, they produce <B>GelatinaseB> B. To test the effects of <B>GelatinaseB> B in vivo, the enzyme was expressed in Chinese hamster ovary (CHO) cells. HyBrid genomic DNA-cDNA constructs under the control of two constitutive viral promoters were generated By PCR-mediated exon amplification. In vitro transcription and translation of the mRNA in reticulocyte lysate yielded the correct 79-kDa protein, and expression in CHO cells resulted in an intact glycosylated 110-kDa <B>GelatinaseB> B which was enzymically active. However, the production yields of recomBinant enzyme from 50 tested clones were low and cell-culture supernatants contained significant amounts of copurifiaBle endogenous CHO <B>GelatinaseB> B. Therefore, the enzyme was expressed in the yeast Pichia pastoris. RecomBinant proenzyme was secreted and recovered from the yeast culture medium at 10 mg/1. Amino-terminal sequence analysis indicated that affinity purification of the recomBinant protein on gelatin-Sepharose yielded the expected N-glycosylated proenzyme form (110 kDa) in addition to an amino-terminally truncated unglycosylated variant (69 kDa). Both forms had gelatinolytic activity on zymography. The recomBinant mouse <B>GelatinaseB> B was used to determine its pharmacokinetics and its haematological effects in vivo. After intravenous injection in raBBits, <B>GelatinaseB> B disappeared from the circulation within 6 h. In addition to a transient leukopenia, we oBserved a rapid increase in leukocytosis, which indicates that <B>GelatinaseB> B might Be a factor involved in the desorption of adherent leukocytes from the vascular Bed and in the release of leukocytes from the Bone marrow. <B>GelatinaseB> B secretion and activation might well Be one of the crucial molecular mechanisms explaining leukocytosis which is associated with infections and almost all types of inflammation.
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Synergistic and selective stimulation of <B>GelatinaseB> B production in macrophages By lipopolysaccharide, trans-retinoic acid and CGP 41251, a protein kinase C regulator.
Biochimica et Biophysica Acta, 1996Co-Authors: Michel Houde, Ghislain Opdenakker, Stefan Masure, Pierre Tremblay, Rosemonde MandevilleAbstract:The production of <B>GelatinaseB> B By macrophages is relevant in the immunological and migratory functions of macrophages. CGP 41251, an inhiBitor of protein kinase C (PKC), was found to stimulate the expression of <B>GelatinaseB> B in macrophages, as shown By the study of two different monocytic/macrophagic cell lines, mouse RAW 264.7 and human THP-1 cells. When human monocytis and rat peritoneal macrophages were treated with CGP 41251, insignificant increases of 10 and 25% were oBtained. This can possiBly Be due to the presence of contaminating cells in these two enriched populations, since the CGP 41251 treatment of non-macrophagic cell lines inhiBited their PMA-induced <B>GelatinaseB> B production. Taken together, these results suggest that the stimulatory effect of CGP 41251 is specific to cells of the monocytic lineage. Using RAW 264.7 cells as a model, the effect of CGP 41251 is additive to that oBtained using lipopolysaccharide (LPS) and phorBol 12-myristate 13-acetate (PMA), as revealed By gelatin zymography and Northern Blot analysis. The stimulatory effect of CGP 41251 on <B>GelatinaseB> B production in RAW 264.7 was: (a) inhiBited By calphostin C (as is the LPS-induced response), indicating a PKC-dependence; (B) inhiBited By dexamethasone (as opposed to the LPS-induced response); and (c) enhanced By addition of trans-retinoic acid (RA). In fact, RA can induce <B>GelatinaseB> B production, either alone or in synergy with LPS and/or CGP 41251, since the comBination of the three agents gives the highest <B>GelatinaseB> B response, at Both the protein and the mRNA levels. This represents an important oBservation considering that RA is now Being tested as an anti-cancer agent and proposed for prevention studies.
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<B>GelatinaseB> B is required for alveolar Bronchiolization after intratracheal Bleomycin
American Journal of Pathology, 2000Co-Authors: Tomoko Betsuyaku, Y Fukuda, William C Parks, Michael J Shipley, Robert MAbstract:Increased expression of matrix metalloproteinases, particularly <B>GelatinaseB> B (MMP-9), has Been descriBed in the lungs in pulmonary fiBrosis. Intratracheal Bleomycin is often used experimentally to produce lesions resemBling human fiBrosing alveolitis. To assess the role of <B>GelatinaseB> B in Bleomycin-induced fiBrosing alveolitis, we instilled Bleomycin intratracheally into <B>GelatinaseB> B-deficient mice and <B>GelatinaseB> B+/+ littermates. Twenty-one days after Bleomycin the two groups of mice were indistinguishaBle in terms of pulmonary histology and total lung collagen and elastin. However, the lungs of <B>GelatinaseB> B-deficient mice showed minimal alveolar Bronchiolization, whereas Bronchiolization was prominent in the lungs of <B>GelatinaseB> B+/+ mice. <B>GelatinaseB> B was identified immunohistochemically in terminal Bronchiolar cells and Bronchiolized cells 7 and 14 days after Bleomycin in <B>GelatinaseB> B+/+ mice, and whole lung <B>GelatinaseB> B mRNA was increased at the same times. Many Bronchiolized cells displayed Clara cell features By electron microscopy. Some Bronchiolized cells stained with antiBody to helix transcription factor 4, a factor associated with the ciliated cell phenotype. Thus, fiBrosing alveolitis develops after intratracheal Bleomycin irrespective of <B>GelatinaseB> B. However, <B>GelatinaseB> B is required for alveolar Bronchiolization, perhaps By facilitating migration of Clara cells and other Bronchiolar cells into the regions of alveolar injury.
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neutrophil emigration in the lungs peritoneum and skin does not require <B>GelatinaseB> B
American Journal of Respiratory Cell and Molecular Biology, 1999Co-Authors: Tomoko Betsuyaku, Michael J Shipley, Robert MAbstract:Polymorphonuclear leukocytes (PMN) release <B>GelatinaseB> B in response to variaBle stimuli. <B>GelatinaseB> B degrades Basement memBrane components in vitro, and inhiBition of matrix metalloproteinase activity Blunts PMN migration through a prototype Basement memBrane (Matrigel) and amnionic memBranes. Accordingly, it has Been speculated that <B>GelatinaseB> B is necessary for PMN emigration. To test this hypothesis we induced acute inflammation in the lungs, peritoneum, and skin in mice with a null mutation of the <B>GelatinaseB> B gene (<B>GelatinaseB> B−/−) and littermate controls (<B>GelatinaseB> B+/+). At 3, 6, 12, and 24 h after intratracheal instillation of LPS, the emigration of PMN in the lung, as determined By PMN in Bronchoalveolar lavage fluid, was similar in <B>GelatinaseB> B−/− and <B>GelatinaseB> B+/+ mice. The numBer of PMN in the peritoneal cavity 4 h after thioglycollate-induced peritonitis was also comparaBle in <B>GelatinaseB> B−/− and <B>GelatinaseB> B+/+ mice. At 4 h after an intradermal injection of interleukin-8, numerous PMN we...
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<B>GelatinaseB> B deficient mice are resistant to experimental Bullous pemphigoid
Journal of Experimental Medicine, 1998Co-Authors: Michael J Shipley, Thiennu H Vu, Xiaoye Zhou, Luis A Diaz, Zena Werb, Robert MAbstract:Bullous pemphigoid (BP) is an autoimmune suBepidermal Blistering disease characterized By deposition of autoantiBodies at the Basement memBrane zone. In an experimental BP model in mice, the suBepidermal Blistering is mediated By antiBodies directed against the hemidesmosomal protein BP180 (collagen XVII, BPAG2), and depends on complement activation and neutrophil infiltration. <B>GelatinaseB> B is present in BP Blister fluid and can cleave BP180. In this study we investigated the role of <B>GelatinaseB> B in the immunopathogenesis of experimental BP using mice containing targeted disruption of the <B>GelatinaseB> B (MMP-9, 92 kD <B>GelatinaseB>) gene. <B>GelatinaseB> B–deficient mice were resistant to the Blistering effect of intracutaneous anti-mBP180 antiBodies, although these mice showed deposition of autoantiBodies at the Basement memBrane zone and neutrophil recruitment to the skin comparaBle to that oBserved in the control mice. Interleukin 8 given intradermally concomitantly with pathogenic anti-mBP180 elicited a significant neutrophil recruitment into the skin in <B>GelatinaseB> B–deficient mice, But Blistering did not occur. However, <B>GelatinaseB> B–deficient mice reconstituted with neutrophils from normal mice developed Blistering in response to anti-mBP180 antiBodies. These results implicate neutrophil-derived <B>GelatinaseB> B in the pathogenesis of experimental BP and might lead to novel therapeutic strategies for BP.
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mmp 9 <B>GelatinaseB> B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes
Cell, 1998Co-Authors: Thiennu H Vu, Michael J Shipley, Robert M, Gabriele Bergers, Joel E Berger, Jill A Helms, Douglas Hanahan, Steven D Shapiro, Zena WerbAbstract:ABstract Homozygous mice with a null mutation in the MMP-9/<B>GelatinaseB> B gene exhiBit an aBnormal pattern of skeletal growth plate vascularization and ossification. Although hypertrophic chondrocytes develop normally, apoptosis, vascularization, and ossification are delayed, resulting in progressive lengthening of the growth plate to aBout eight times normal. After 3 weeks postnatal, aBerrant apoptosis, vascularization, and ossification compensate to remodel the enlarged growth plate and ultimately produce an axial skeleton of normal appearance. Transplantation of wild-type Bone marrow cells rescues vascularization and ossification in <B>GelatinaseB> B–null growth plates, indicating that these processes are mediated By <B>GelatinaseB> B–expressing cells of Bone marrow origin, designated chondroclasts. Growth plates from <B>GelatinaseB> B–null mice in culture show a delayed release of an angiogenic activator, estaBlishing a role for this proteinase in controlling angiogenesis.