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  • 1
    Keywords: CELLS ; ENDOTHELIAL-CELLS ; INHIBITOR ; CELL ; IN-VIVO ; PATHWAY ; MICE ; MACROPHAGES ; MECHANISM ; STAGE ; PERMEABILITY ; ORIGIN ; BASEMENT-MEMBRANE ; INCREASE ; MATRIX METALLOPROTEINASES ; MMP-9 ; PROSTAGLANDIN SYNTHESIS ; cyclooxygenase ; PROSTAGLANDIN E-2 ; macrophage ; E ; ENDOTHELIAL-CELL ; DEPLETION ; peritonitis ; METALLOPROTEINASE ; CYSTEINYL-LEUKOTRIENES ; gelatinase B ; MAST-CELLS ; peritoneal inflammation ; VASCULAR-PERMEABILITY ; metalloproteinase-9 ; prostaglandin ; SELECTIVE-INHIBITION ; TARGETED GENE DISRUPTION ; vasopermeability ; ZYMOSAN
    Abstract: Increased vascular permeability leading to vascular leakage is a central feature of all inflammatory reactions and is critical for the formation of an inflammatory exudate. The leakage occurs because of gap formation between endothelial cells and breakdown of the basement membrane barriers. The present study aimed to investigate the role of gelatinase B [matrix metalloproteinase 9 (MMP-9)], known to be involved in neutrophil exudation, in changes of vascular permeability at the early stages of acute zymosan peritonitis. We show that although MMP-9 is being released already within the first minutes of peritonitis, its lack, induced pharmacologically or genetically, does not decrease but rather increases vasopermeability. In mice treated with an inhibitor of gelatinases (A and B), a tendency to increased vasopermeability existed, and in MMP-9-/- mice [knockout (KO)], the difference was statistically significant in comparison with their controls. Moreover, in intact KO mice, significantly augmented production of prostaglandin E-2 (PGE(2)) of cyclooxygenase I (COX-1) origin was detected, anti depletion of peritoneal macrophages, but not mast cells, decreased vasopermeability in KO mice. Thus, the increase of vasopermeability observed on KO mice is a result of the increased production of COX-1-derived PGE2 by peritoneal macrophages. We conclude that genetic deficiency in gelatinase B might lead to the development of a compensatory mechanism involving the COX pathway
    Type of Publication: Journal article published
    PubMed ID: 16684893
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  • 2
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; CELL ; INHIBITION ; MODEL ; PROTEIN ; PROTEINS ; ACCUMULATION ; MICE ; TIME ; NF-KAPPA-B ; MACROPHAGES ; MECHANISM ; animals ; mechanisms ; BIOLOGY ; STAGE ; MEMBRANE ; LYMPHOCYTES ; EXTRACELLULAR-MATRIX ; NETHERLANDS ; MEMBRANES ; inflammation ; mast cells ; MATRIX ; INFILTRATION ; basement membrane ; BASEMENT-MEMBRANE ; extracellular matrix ; MATRIX METALLOPROTEINASES ; CASPASE-8 ; MICE LACKING ; COX-1 ; MATRIX-METALLOPROTEINASE-9 ; MMP-9 ; caspases ; cyclooxygenase ; macrophage ; immunology ; peritonitis ; matrix metalloproteinase ; B-DEFICIENT MICE ; gelatinase B ; MAST-CELLS ; peritoneal inflammation ; caspase-3 ; leukocytes ; MATRIX-METALLOPROTEINASE-9 MMP-9 ; LEUKOCYTE INFILTRATION ; neutrophil ; Extracellular ; matrix metalloproteinase-9 ; ZYMOSAN PERITONITIS ; GELATINASE B/MATRIX METALLOPROTEINASE-9
    Abstract: Matrix metalloproteinase 9 (MMP-9) is a Zn2+-dependent endopeptidase that degrades some of the components of basement membranes and extracellular matrix and thus participates in leukocyte infiltration during inflammation. In a model of zymosan peritonitis, neutrophil infiltration in MMP-deficient (MMP-9(-/-)) mice was significantly weaker at the time of their maximal influx in wild-type mice (6 h). However, during the late stages of peritonitis (24 h) an extended accumulation of neutrophils was observed in MMP-9(-/-) versus the wild-type mice. Recently, we reported that the ratio of apoptosis of inflammatory leukocytes is impaired in MMP-9(-/-) mice during late peritonitis and the process depends on COX-1-driven PGE(2). Here we scrutinized the alterations in apoptotic mechanisms by comparisons between MMP-9(-/-) and the wild-type mice. Altered apoptosis occurred only during late (24 h) peritonitis and concerned only neutrophils, and not macrophages, mast cells or lymphocytes. Furthermore, expression and activity of caspases was altered in MMP-9(-/-) animals, delayed for caspase-8 and -9, and decreased in the case of caspase-3. Also the expression of Bax/Bcl-2 proteins was changed in MMP-9(-/-) mice. These changes, and in particular the impaired neutrophil apoptosis and weaker caspase-3 activity, were restored by the selective COX-1 inhibition. We conclude that in mice lacking MMP-9 the enhanced COX-1-PGE(2) decreases caspase-3 expression and activity leading to impaired apoptosis of inflammatory neutrophils resulting in abnormal accumulation of the cells at the inflammatory focus. The data also reinforce the notion that MMP-9 is a key enzyme in neutrophil biology. (C) 2009 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19682497
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  • 3
    Abstract: The enzymes gelatinase A/matrix metalloproteinase-2 (MMP-2) and gelatinase B/MMP-9 are essential for induction of neuroinflammatory symptoms in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS); in the absence of these enzymes, the disease does not develop. We therefore investigated the cellular sources and relative contributions of MMP-2 and MMP-9 to disease at early stages of EAE induction. We demonstrated that MMP-9 from an immune cell source is required in EAE for initial infiltration of leukocytes into the central nervous system and that MMP-9 activity is a reliable marker of leukocyte penetration of the blood-brain barrier. We then developed a molecular imaging method to visualize MMP activity in the brain using fluorescent- and radioactive-labeled MMP inhibitors (MMPis) in EAE animals and used the radioactive MMP ligand for positron emission tomography (PET) imaging of MMP activity in patients with MS. In contrast to traditional T1-gadolinium contrast-enhanced MRI, MMPi-PET enabled tracking of MMP activity as a unique feature of early lesions and ongoing leukocyte infiltration. MMPi-PET therefore allows monitoring of the early steps of MS development and provides a sensitive, noninvasive means of following lesion formation and resolution in murine EAE and human MS.
    Type of Publication: Journal article published
    PubMed ID: 27831901
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  • 4
    Keywords: CELLS ; MODEL ; MODELS ; THERAPY ; SYSTEM ; DISEASE ; RISK ; GENE ; PROTEIN ; gene therapy ; MICE ; PATIENT ; TOLERANCE ; antibodies ; antibody ; NEUTRALIZING ANTIBODIES ; HUMAN GENOME ; PRODUCT ; GENE-THERAPY ; TRENDS ; COMPLEMENT FACTOR-H ; GELATINASE-B ; HEMOLYTIC-UREMIC SYNDROME ; HEMOPHILIA
    Abstract: In a host with a normal immune system and a complete gene defect, the nondefective gene product will be immunogenic. Consequently, neutralizing antibodies against the respective protein can arise either 'spontaneously' or after immunization, as shown in patients and in animal models, such as knockout mice. Accordingly, patients with X-linked or homozygous autosomal gene defects are at risk of developing neutralizing antibodies, in particular after protein substitution or gene therapy. This Review compares and exemplifies the various genetic and immunological contexts that lead to 'neutralizing and generated by gene defect' or 'nagged' antibodies, and outlines implications and solutions for therapeutic strategies
    Type of Publication: Journal article published
    PubMed ID: 12547507
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  • 5
    Keywords: CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; IN-VITRO ; INHIBITOR ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; IN-VIVO ; THERAPY ; VITRO ; cell line ; TISSUE ; TUMORS ; LINES ; MICE ; TIME ; PATIENT ; SERA ; primary ; animals ; TISSUES ; T cell ; T-CELL ; CELL-LINES ; culture ; FORM ; STAGE ; LYMPHOMA ; MALIGNANCIES ; UP-REGULATION ; MEMBRANE ; CELL-LINE ; leukemia ; LINE ; MIGRATION ; cell lines ; TUMOR CELLS ; MEMBRANES ; HIGH-LEVEL ; MMP ; INHIBITORS ; YOUNG ; SERUM ; MALIGNANCY ; ONCOLOGY ; TUMOR-GROWTH ; THERAPIES ; basement membrane ; BASEMENT-MEMBRANE ; PATIENT SURVIVAL ; MATRIX METALLOPROTEINASES ; endothelial cells ; development ; KNOCKOUT MICE ; LEVEL ; TUMOR-CELL ; MATRIX-METALLOPROTEINASE-9 ; MMP-9 ; DEFICIENT ; MARROW-DERIVED CELLS ; CANCERS ; ENDOTHELIAL-CELL ; animal ; host ; DES ; T-cell leukemia ; CONSEQUENCES ; EXPERIMENTAL THYMIC LYMPHOMA ; GELATINASE B MMP-9 ; MMP-9 GENE-EXPRESSION ; THYMIC LYMPHOMA
    Abstract: Previous studies have shown that high levels of MMP-9 can be detected in the serum of patients with various lymphoid malignancies and in leukemia/lymphoma culture supernatants. Indeed, aggressive forms of lymphoma constitutively produce MMP-9 and its elevated levels in the serum or in tissues correlate with advanced stage and poor patient survival. In vitro, MMP-9, which is also produced by the host peritumoral cells in response to the presence of tumors, plays an important role in migration of tumor cells through artificial basement membranes or endothelial cells. In this study, using MMP-9-deficient mice, we show that absence of MMP-9 does not prevent the development of primary T-cell leukemia. Furthermore, MMP-9-deficient cell lines retained their tumorigenic potential, as shown by their ability to induce thymic lymphoma in young syngeneic wild-type animals. In addition, these MMP-9-deficient tumor cells disseminate in normal mice, or mice that are deficient for MMP-9, indicating that tumor growth and dissemination can occur in total absence of MMP-9. These results show for the first time than lymphoma growth can occur in total absence of MMP-9 and have consequences for therapy of invasive cancers with inhibitors of MMPs
    Type of Publication: Journal article published
    PubMed ID: 17805326
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  • 6
    Keywords: APOPTOSIS ; CELLS ; SURVIVAL ; PROTEIN ; MICE ; NEPHRITIS ; T-CELLS ; AUTOANTIBODIES ; AUTOANTIGEN ; FAS ; SUBSTRATE ; lupus ; MATRIX-METALLOPROTEINASE-9 ; PROTEOLYSIS ; MATRIX METALLOPROTEINASE-2 ; erythematosus ; Lymphoproliferation ; NEGATIVE T-CELLS ; NEUTROPHIL GELATINASE ; Systemic autoimmunity
    Abstract: Gelatinase B/matrix metalloproteinase-9 (MMP-9) is a key enzyme involved in inflammatory, hematological, vascular and neoplastic diseases. In previous studies, we explored the intracellular substrate set or 'degradome' of MMP-9 and found many systemic autoantigens as novel intracellular gelatinase B substrates. Little is known, however, about the functional role of MMP-9 in the development of systemic autoimmunity in vivo. B6(lpr/lpr) mice with defective Fas-mediated apoptosis were used to investigate the functions of MMP-9 in lymphocyte proliferation and in the development of systemic autoimmunity. Combined Fas and gelatinase B deficiency resulted in extreme lymphoproliferative disease with enhanced lymphadenopathy and splenomegaly, and significantly reduced survival compared with single Fas deficiency. At the cellular level, this was corroborated by increased lymph node accumulation of 'double negative' T cells, B cells and myeloid cells. In addition, higher autoantibody titers and more pronounced autoimmune tissue injury were found in the absence of MMP-9, culminating in chronically enhanced systemic lupus erythematosus (SLE)-like autoimmunity. After cleavage by MMP-9 the SLE autoantigens U1snRNP A and ribosomal protein P0 were hardly recognized by plasma samples of both B6(lpr/lpr).MMP-9(-/-) and B6(lpr/lpr).MMP-9(++) mice, pointing to a destruction of B cell epitopes by MMP-9-mediated proteolysis. In addition, the same loss of immunodominant epitopes was observed with plasma samples from SLE patients, suggesting that MMP-9 suppresses systemic antibody-mediated autoimmunity by clearance of autoepitopes in immunogenic substrates. Thus, new protective functions for MMP-9 were revealed in the suppression of lymphoproliferation and dampening of systemic autoimmunity, cautioning against the long-term use of MMP inhibitors in autoimmune lymphoproliferative syndrome (ALPS) and SLE.
    Type of Publication: Journal article published
    PubMed ID: 21376533
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  • 7
    Keywords: IN-VITRO ; INHIBITOR ; CEREBROSPINAL-FLUID ; CENTRAL-NERVOUS-SYSTEM ; MYELIN BASIC-PROTEIN ; PROTEOLYSIS ; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS ; NEUTROPHIL GELATINASE ; MATRIX METALLOPROTEINASE EXPRESSION ; MULTIPLE-SCLEROSIS LESIONS
    Abstract: 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 gelatinase B gene by replacing the catalytic and zinc-binding domains with an antisense-oriented neomycin resistance gene. Adult gelatinase 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 gelatinase B-deficient mice were resistant to this tail pathology. Gelatinase 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 gelatinase 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.
    Type of Publication: Journal article published
    PubMed ID: 10587514
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  • 8
    Keywords: CELLS ; EXPRESSION ; INHIBITOR ; CELL ; IN-VIVO ; MODEL ; POPULATION ; PROTEIN ; ACCUMULATION ; MICE ; MACROPHAGES ; MEMBRANE ; MIGRATION ; POPULATIONS ; inflammation ; GELATINASE-B ; mast cells ; MATRIX ; ACUTE LUNG INJURY ; BASEMENT-MEMBRANE ; MATRIX METALLOPROTEINASES ; DEFICIENT MICE ; macrophage ; METALLOPROTEINASES ; gelatinase B ; MAST-CELLS ; peritoneal inflammation ; EARLY VASCULAR-PERMEABILITY ; EXTRACELLULAR TRAPS ; MATRIX METALLOPROTEASE-9 ; ZYMOSAN-INDUCED PERITONITIS
    Abstract: Extracellular proteolysis of basement membranes and matrix is required for leukocyte diapedesis and migration to the inflammatory focus. Neutrophil elastase (NE) and matrix metalloproteinases (MMPs) are among the enzymes involved in these processes, as shown in mice genetically deprived of such enzymes. However, studies with MMP-9(-/-) mice revealed that albeit neutrophil influx is impaired initially in these animals versus controls, neutrophilia is subsequently augmented during later stages of zymosan peritonitis. MMP-9 as a MMP and NE as a serine protease belong to different enzyme classes. As MMP-9 and NE are produced by neutrophils and have similar biological effects on matrix remodeling, it was evaluated whether enhanced NE activity might compensate for the lack of MMP-9. In genetically uncompromised mice, two waves of NE expression and activity during zymosan peritonitis were observed in inflammatory neutrophils and macrophages at the time of influx of the respective cell populations into the peritoneum. Additionally, NE expression was associated with the activity of resident peritoneal mast cells and macrophages, as their depletion reduced NE activity. Most importantly, the NE mRNA and protein expression and activity were enhanced significantly in MMP-9(-/-) mice during late stages of zymosan peritonitis. In addition, the application of a selective NE inhibitor restrained enhanced neutrophil accumulation significantly. In conclusion, during acute peritoneal inflammation, NE expression and activity increase gradually, facilitating leukocyte influx. Moreover, increased NE activity might compensate for a genetic lack of MMP-9 (as detected in MMP-9(-/-) mice), resulting in delayed accumulation of neutrophils during late zymosan peritonitis. J. Leukoc. Biol. 85: 374-381; 2009
    Type of Publication: Journal article published
    PubMed ID: 19088179
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  • 9
    Keywords: APOPTOSIS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; IN-VIVO ; INHIBITION ; VITRO ; PROTEIN ; RNA ; ACCUMULATION ; MICE ; NF-KAPPA-B ; MESSENGER-RNA ; MOLECULAR-BIOLOGY ; BONE-MARROW ; MOUSE ; STAGE ; COX-2 ; protein expression ; inflammation ; INHIBITORS ; INFILTRATION ; PRODUCTS ; DEPENDENCE ; MICE LACKING ; MATRIX-METALLOPROTEINASE-9 ; MMP-9 ; USA ; BONE ; cyclooxygenase ; PROSTAGLANDIN E-2 ; immunology ; MAST-CELLS ; peritoneal inflammation ; EARLY VASCULAR-PERMEABILITY ; MARROW ; neutrophil ; Genetic ; ZYMOSAN-INDUCED PERITONITIS ; GENE DISRUPTION ; matrix metalloproteinase-9 ; prostaglandin D-2 ; ZYMOSAN PERITONITIS
    Abstract: P〉Matrix metalloproteinase-9 (MMP-9)/gelatinase B plays an important role in neutrophil infiltration during inflammation and cyclooxygenases (COX-1 and COX-2) and their products are important regulators of inflammation. Recently, we reported that a genetic lack of MMP-9 impairs neutrophil infiltration during early zymosan-induced peritonitis but at later stages (〉 24 hr) neutrophils persist in the peritoneal cavity. Here we show that this is the result of impaired apoptosis of MMP-9(-/-)-derived leucocytes. As enhanced COX-1 expression was reported in MMP-9(-/-) mice, we evaluated the hypothesis that altered COX expression induced the above phenomenon as COX-dependent prostaglandins can act either anti-apoptotically (PGE(2)) or pro-apoptotically (PGD(2)). The current data demonstrate that messenger RNA and protein expression of both COX isoforms and their activities are increased in MMP-9(-/-) mice during late peritonitis. Application of selective COX inhibitors revealed enhanced COX-1-dependent PGE(2) production and impaired COX-2-dependent PGD(2) synthesis in MMP-9(-/-) mice. Most importantly, inhibition of COX-1 abolished prolonged neutrophil accumulation in the peritoneal cavity of MMP-9(-/-) mice and increased apoptosis of inflammatory leucocytes. Similarly, weaker apoptosis of MMP-9(-/-) bone marrow neutrophils treated in vitro with zymosan was reversed by COX-1 inhibition. In conclusion, enhanced COX-1 expression is responsible for persistent neutrophil presence in the peritoneum of MMP-9(-/-) mice because of increased synthesis of anti-apoptotic PGE(2). In non-transgenic mice, however, inflammatory leucocytes die apoptotically in the late stages of peritonitis as a result of COX-2-dependent PGD(2) activity. Overall, we show a dependence of COX expression on the presence of MMP-9
    Type of Publication: Journal article published
    PubMed ID: 19175797
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  • 10
    Keywords: tumor ; IN-VIVO ; TISSUE ; MICE ; TIME ; TUMOR-NECROSIS-FACTOR ; MECHANISM ; mechanisms ; MOUSE ; STAGE ; NECROSIS-FACTOR-ALPHA ; MIGRATION ; inflammation ; INCREASED EXPRESSION ; FACTOR-ALPHA ; INFILTRATION ; INCREASE ; MATRIX METALLOPROTEINASES ; LEVEL ; MMP-9 ; function ; METALLOPROTEINASE ; B-DEFICIENT MICE ; chemotaxis ; CYSTEINYL-LEUKOTRIENES ; gelatinase B ; INTERLEUKIN-10 ; leukocyte influx ; MAST-CELLS ; NEUTROPHIL RECRUITMENT ; peritoneal inflammation ; VASCULAR-PERMEABILITY
    Abstract: Murine zymosan-induced peritonitis represents a well-defined model of acute inflammation. However, the molecular mechanisms by which leukocytes degrade basement membranes during extravasation into the peritoneum are not clear. Gelatinase B (MMP-9) is thought to participate in cellular migration, yet its role in leukocyte transmigration through endothelia during inflammation remains controversial. The aim of the present study was to evaluate the role of MMP-9 in the cell influx during zymosan-induced experimental peritonitis. In zymosan-treated Balb/c mice MMP-9 and its natural inhibitor (tissue inhibitor of metalloproteinase 1-TIMP-1) were present in the peritoneal fluid and plasma at the time of peritoneal neutrophil (polymorphonuclear leukocyte-PMN) infiltration and persisted there until the time of monocytes/macrophages influx. To probe the function of gelatinases, gelatinase B-deficient mice (MMP-9(-/-)) were used as well as Balb/c mice treated with cyclic CTTHWGFTLC (INH), a specific peptide inhibitor of gelatinases. The studies revealed that in either group of mice deprived of MMP-9 activity, PMN infiltration was impaired at the time of their maximal extravasation (6 h) while tumor necrosis factor alpha (TNF-alpha), cytokine-Induced neutrophil chemoattractant (KC) and interleukin 10 (IL-10) levels were not changed. At later stages (24h post-zymosan) a significant increase in PMNs was observed in MMP-9(-/-) mice, but not In the inhibitor-treated mice, in comparison to their respective controls. Moreover, intraperitoneal (i.p.) Injection of recombinant mouse pro-MMP-9 induced leukocyte accumulation in peritoneum. Collectively, the findings indicate that gelatinase B participates in leukocyte transmigration; however, its function can be compensated by other mechanisms. (c) 2006 Elsevier GmbH. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16530081
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