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Radislav Sedlacek - One of the best experts on this subject based on the ideXlab platform.
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Differential expression and processing of Matrix Metalloproteinase 19 marks progression of gastrointestinal diseases.
Folia biologica, 2014Co-Authors: Cervinková M, Horák P, Ivan Kanchev, Matěj R, J. Fanta, R. Sequens, Petr Kasparek, Sarnová L, Turečková J, Radislav SedlacekAbstract:Matrix Metalloproteinases (MMPs), responsible for extracellular Matrix remodelling and processing of numerous soluble and cell-surface proteins, appear to play important roles in pathogenesis of gastrointestinal diseases. MMPs influence migration of inflammatory cells, mucosal destruction, Matrix deposition and degradation. In this study, we analysed the expression of MMP-19 in the main forms of gastrointestinal diseases including inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease, and colorectal carcinoma. We identified prominent MMP-19 expression in unaffected areas of intestinal epithelia and macrophages but not in other cells or tissues. Abundant expression of MMP-19 was also found in the endothelium of blood and lymphatic vessels of inflamed intestinal tissue. High MMP-19 immunoreactivity was also associated with macrophages in inflamed areas and myenteric plexuses. In comparison to the intestinal epithelium, all these cell types and compartments appeared to express MMP-19 irrespective of the disease pathogenesis and progression. Intestinal epithelia exhibited striking differential immunoreactivity for MMP-19. While immunoreactivity of monoclonal antibody recognizing the propeptide domain declined in virtually all IBD and colorectal carcinoma samples, other polyclonal antibodies against the hinge region and propetide domain did not show such an obvious decrease. Additional Western blotting analysis revealed that the antibodies against MMP-19 recognize differently processed forms of this MMP. The disappearance of immunoreactivity of the monoclonal anti-propeptide domain antibody does not mean down-regulation of MMP-19, but processing of the immature form. As this processing likely leads to the activation of this MMP, the differential staining pattern may be an important sign of disease progression.
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catalytic activity of Matrix Metalloproteinase 19 is essential for tumor suppressor and anti angiogenic activities in nasopharyngeal carcinoma
International Journal of Cancer, 2011Co-Authors: King Chi Chan, Radislav Sedlacek, Hong Lok Lung, Zengfeng Zhang, Dian-zhong Luo, Zhen-bo Feng, Shuang Chen, Honglin Chen, Kwok Wah Chan, Sai Wah TsaoAbstract:The association of Matrix Metalloproteinase-19 (MMP19) in the development of nasopharyngeal carcinoma (NPC) was identified from differential gene profiling, which showed MMP19 was one of the candidate genes down-regulated in the NPC cell lines. In this study, quantitative RT-PCR and Western blot analysis showed MMP19 was down-regulated in all seven NPC cell lines. By tissue microarray immunohistochemical staining, MMP19 appears down-regulated in 69.7% of primary NPC specimens. Allelic deletion and promoter hypermethylation contribute to MMP19 down-regulation. We also clearly demonstrate that the catalytic activity of MMP19 plays an important role in antitumor and antiangiogenesis activities in comparative studies of the wild-type and the catalytically inactive mutant MMP19. In the in vivo tumorigenicity assay, only the wild-type (WT), but not mutant, MMP19 transfectants suppress tumor formation in nude mice. In the in vitro colony formation assay, WT MMP19 dramatically reduces colony-forming ability of NPC cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells (HMEC-1), secreted WT MMP19, but not mutant MMP19, induces reduction of tube-forming ability in endothelial cells with decreased vascular endothelial growth factor (VEGF) in conditioned media detected by enzyme-linked immunosorbent assay (ELISA). The anti-angiogenic activity of WT MMP19 is correlated with suppression of tumor formation. These results now clearly show that catalytic activity of MMP19 is essential for its tumor suppressive and anti-angiogenic functions in NPC.
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Matrix Metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen
BMC Biochemistry, 2011Co-Authors: Rena Brauer, Inken M. Beck, Martin Roderfeld, Elke Roeb, Radislav SedlacekAbstract:Background Angiogenesis is the process of forming new blood vessels from existing ones and requires degradation of the vascular basement membrane and remodeling of extracellular Matrix (ECM) in order to allow endothelial cells to migrate and invade into the surrounding tissue. Matrix Metalloproteinases (MMPs) are considered to play a central role in the remodeling of basement membranes and ECM. However, MMPs contribute to vascular remodeling not only by degrading ECM components. Specific MMPs enhance angiogenesis via several ways; they help pericytes to detach from vessels undergoing angiogenesis, release ECM-bound angiogenic growth factors, expose cryptic pro-angiogenic integrin binding sites in the ECM, generate promigratory ECM component fragments, and cleave endothelial cell-cell adhesions. MMPs can also negatively influence the angiogenic process through generating endogenous angiogenesis inhibitors by proteolytic cleavage. Angiostatin, a proteolytic fragment of plasminogen, is one of the most potent antagonists of angiogenesis that inhibits migration and proliferation of endothelial cells. Reports have shown that metalloelastase, pancreas elastase, plasmin reductase, and plasmin convert plasminogen to angiostatin. Results We report here that MMP-19 processes human plasminogen in a characteristic cleavage pattern to generate three angiostatin-like fragments with a molecular weight of 35, 38, and 42 kDa. These fragments released by MMP-19 significantly inhibited the proliferation of HMEC cells by 27% (p = 0.01) and reduced formation of capillary-like structures by 45% (p = 0.05) compared with control cells. As it is known that angiostatin blocks hepatocyte growth factor (HGF)-induced pro-angiogenic signaling in endothelial cells due to structural similarities to HGF, we have analyzed if the plasminogen fragments generated by MMP-19 interfere with this pathway. As it involves the activation of c-met, the receptor of HGF, we could show that MMP-19-dependent processing of plasminogen decreases the phosphorylation of c-met. Conclusion Altogether, MMP-19 exhibits an anti-angiogenic effect on endothelial cells via generation of angiostatin-like fragments.
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Matrix Metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen
BMC biochemistry, 2011Co-Authors: Rena Brauer, Inken M. Beck, Martin Roderfeld, Elke Roeb, Radislav SedlacekAbstract:Angiogenesis is the process of forming new blood vessels from existing ones and requires degradation of the vascular basement membrane and remodeling of extracellular Matrix (ECM) in order to allow endothelial cells to migrate and invade into the surrounding tissue. Matrix Metalloproteinases (MMPs) are considered to play a central role in the remodeling of basement membranes and ECM. However, MMPs contribute to vascular remodeling not only by degrading ECM components. Specific MMPs enhance angiogenesis via several ways; they help pericytes to detach from vessels undergoing angiogenesis, release ECM-bound angiogenic growth factors, expose cryptic pro-angiogenic integrin binding sites in the ECM, generate promigratory ECM component fragments, and cleave endothelial cell-cell adhesions. MMPs can also negatively influence the angiogenic process through generating endogenous angiogenesis inhibitors by proteolytic cleavage. Angiostatin, a proteolytic fragment of plasminogen, is one of the most potent antagonists of angiogenesis that inhibits migration and proliferation of endothelial cells. Reports have shown that metalloelastase, pancreas elastase, plasmin reductase, and plasmin convert plasminogen to angiostatin. We report here that MMP-19 processes human plasminogen in a characteristic cleavage pattern to generate three angiostatin-like fragments with a molecular weight of 35, 38, and 42 kDa. These fragments released by MMP-19 significantly inhibited the proliferation of HMEC cells by 27% (p = 0.01) and reduced formation of capillary-like structures by 45% (p = 0.05) compared with control cells. As it is known that angiostatin blocks hepatocyte growth factor (HGF)-induced pro-angiogenic signaling in endothelial cells due to structural similarities to HGF, we have analyzed if the plasminogen fragments generated by MMP-19 interfere with this pathway. As it involves the activation of c-met, the receptor of HGF, we could show that MMP-19-dependent processing of plasminogen decreases the phosphorylation of c-met. Altogether, MMP-19 exhibits an anti-angiogenic effect on endothelial cells via generation of angiostatin-like fragments.
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Catalytic activity of Matrix Metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma
International journal of cancer, 2011Co-Authors: Chi Chan, Radislav Sedlacek, Hong Lok Lung, Zengfeng Zhang, Dian-zhong Luo, Zhen-bo Feng, Shuang Chen, Honglin Chen, Kwok Wah ChanAbstract:The association of Matrix Metalloproteinase-19 (MMP19) in the development of nasopharyngeal carcinoma (NPC) was identified from differential gene profiling, which showed MMP19 was one of the candidate genes down-regulated in the NPC cell lines. In this study, quantitative RT-PCR and Western blot analysis showed MMP19 was down-regulated in all seven NPC cell lines. By tissue microarray immunohistochemical staining, MMP19 appears down-regulated in 69.7% of primary NPC specimens. Allelic deletion and promoter hypermethylation contribute to MMP19 down-regulation. We also clearly demonstrate that the catalytic activity of MMP19 plays an important role in antitumor and antiangiogenesis activities in comparative studies of the wild-type and the catalytically inactive mutant MMP19. In the in vivo tumorigenicity assay, only the wild-type (WT), but not mutant, MMP19 transfectants suppress tumor formation in nude mice. In the in vitro colony formation assay, WT MMP19 dramatically reduces colony-forming ability of NPC cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells (HMEC-1), secreted WT MMP19, but not mutant MMP19, induces reduction of tube-forming ability in endothelial cells with decreased vascular endothelial growth factor (VEGF) in conditioned media detected by enzyme-linked immunosorbent assay (ELISA). The anti-angiogenic activity of WT MMP19 is correlated with suppression of tumor formation. These results now clearly show that catalytic activity of MMP19 is essential for its tumor suppressive and anti-angiogenic functions in NPC.
Thorsten Sadowski - One of the best experts on this subject based on the ideXlab platform.
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MMP19 is essential for T cell development and T cell-mediated cutaneous immune responses.
PloS one, 2008Co-Authors: Inken M. Beck, Rena Brauer, Rolf Mentlein, Thorsten Sadowski, Markus Mueller, René Rückert, Katja Brandt, Peter Schirmacher, Radislav SedlacekAbstract:Matrix Metalloproteinase-19 (MMP19) affects cell proliferation, adhesion, and migration in vitro but its physiological role in vivo is poorly understood. To determine the function of MMP19, we generated mice deficient for MMP19 by disrupting the catalytic domain of mmp19 gene. Although MMP19-deficient mice do not show overt developmental and morphological abnormalities they display a distinct physiological phenotype. In a model of contact hypersensitivity (CHS) MMP19-deficient mice showed impaired T cell-mediated immune reaction that was characterized by limited influx of inflammatory cells, low proliferation of keratinocytes, and reduced number of activated CD8+ T cells in draining lymph nodes. In the inflamed tissue, the low number of CD8+ T cells in MMP19-deficient mice correlated with low amounts of proinflammatory cytokines, especially lymphotactin and interferon-inducible T cell α chemoattractant (I-TAC). Further analyses showed that T cell populations in the blood of immature, unsensitized mice were diminished and that this alteration originated from an altered maturation of thymocytes. In the thymus, thymocytes exhibited low proliferation rates and the number of CD4+CD8+ double-positive cells was remarkably augmented. Based on the phenotype of MMP19-deficient mice we propose that MMP19 is an important factor in cutaneous immune responses and influences the development of T cells.
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Matrix Metalloproteinase-19 Expression in Keratinocytes Is Repressed by Transcription Factors Tst-1 and Skn-1a: Implications for Keratinocyte Differentiation
The Journal of investigative dermatology, 2006Co-Authors: Inken M. Beck, Rolf Mentlein, Matthias Müller, Thorsten Sadowski, Markus Mueller, Ralf Paus, Radislav SedlacekAbstract:Matrix Metalloproteinase-19 (MMP-19), unlike other members of the MMP family, is expressed in basal keratinocytes of intact epidermis whereas keratinocytes in suprabasal and higher epidermal layers express this enzyme only during cutaneous disorders. As the activity of MMP-19 effects proliferation, migration, and adhesion of keratinocytes we examined whether transcription factors involved in keratinocyte differentiation repress the expression of MMP-19. Using luciferase reporter assays, POU transcription factors Tst-1 (Oct-6) and Skn-1a (Oct-11) markedly downregulated the activity of MMP-19 promoter in COS-7 cells and HaCaT keratinocytes. Tst-1 alone was able to inhibit 85% of the promoter activity. Skn-1a exhibited a weak inhibitory effect although it synergistically increased effects of Tst-1. HaCaT cells stably transfected with Tst-1 showed a strong decrease of activity of MMP-19 promoter that correlated with suppression of MMP-19, cytokeratin 14 and 5, decreased cell proliferation, and altered expression of involucrin and loricrin. The expression of MMP-9 was also significantly reduced in Tst-1 expressing keratinocytes. MMP-2 was substantially affected during its activation whereas the expression of MMP-28 was unchanged. Our results suggest that Tst-1 and Skn-1a regulate expression of MMPs in keratinocytes and effect both the expression and activation of these proteolytic enzymes.
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Matrix Metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration
Cellular and Molecular Life Sciences, 2005Co-Authors: Thorsten Sadowski, Sebastian Dietrich, Ehrhardt Proksch, F Koschinsky, Andreas Ludwig, B Titz, R SedlacekAbstract:In this study we analyzed the proteolytic activity of MMP-19 and its impact on keratinocyte migration. In the HaCaT keratinocyte cell line overexpressing wild-type MMP-19 (HaCaT-WT), transmigration through fibrin and type IV collagen matrices was significantly increased compared to cells harboring a catalytically inactive mutant (HaCaT-EA). Studying the expression of MMP-19 in early stages of squamous cell cancer (SCC), we found co-localization of MMP-19 and laminin 5 at the invading tumor front but not in suprabasal epidermis of the tumor. Examination of laminin 5 processing revealed increased processing of the γ2 chain in the medium and Matrix of HaCaT-WT cells and degradation by recombinant human MMP-19 to 105-kDa and 80-kDa fragments. Parental HaCaT grown on the Matrix of HaCaT-WT and HaCaT-EA cells displayed differential tyrosine phosphorylation. Using integrin blocking and stimulating antibodies we could attribute these differences to a shift from β4-integrin-dependent signaling on the HaCaT-EA Matrix toward α3-integrin-dependent signaling on the HaCaT-WT Matrix. As a consequence, parental HaCaT showed increased migration on the Matrix of HaCaT-WT cells. These data suggest that the MMP-19-dependent processing of the γ2 chains leads to the integrin switch favoring epithelial migration and that MMP-19 actively participates in the early stages of SCC invasion.
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Matrix Metalloproteinase 19 Regulates Insulin-like Growth Factor-mediated Proliferation, Migration, and Adhesion in Human Keratinocytes through Proteolysis of Insulin-like Growth Factor Binding Protein-3
Molecular biology of the cell, 2003Co-Authors: Thorsten Sadowski, Sebastian Dietrich, Felix Koschinsky, Radislav SedlacekAbstract:Unlike most other Matrix Metalloproteinases (MMPs) MMP-19 is expressed in undifferentiated basal keratinocytes of healthy human skin. The human keratinocyte cell line HaCaT, which like basal keratinocytes constitutively expresses MMP-19, down-regulated the expression of MMP-19 at high calcium concentrations. Calcium-regulation occurred through E-cadherin mediated cell-cell contacts because neutralizing anti-E-cadherin antibodies restored MMP-19 expression in high calcium. Overexpression of MMP-19 in HaCaT cells (HaCaT-WT) increased cellular proliferation, as well as migration and adhesion on type I collagen. This was due to proteolysis of the insulin-like growth factor (IGF) binding protein-3 by MMP-19, which augmented signaling through the IGF-I receptor, as evidenced by its increased autophosphorylation. Conversely, these effects were not observed in cells transfected with MMP-2 or a catalytically inactive MMP-19 mutant. As further proof that increased IGF-signaling promoted adhesion and migration in HaCaT-WT cells, we reproduced these effects by treating parental HaCaT with IGF-I. We observed dephosphorylation of the focal adhesion kinase in HaCaT-WT as well as IGF-I-treated HaCaT cells, suggesting that inactivating focal adhesion kinase is a mechanism by which IGF-I enhances adhesion. Furthermore, IGF-I-triggered motility on type I collagen was mediated by MMP activity, which, however, was distinct from MMP-19. Considering the coexpression of IGFBP-3 and MMP-19 in the skin, we conclude that MMP-19 is a likely candidate to be the major IGFBP-3 degrading MMP in the quiescent epidermis. This activity might have widespread consequences for the behavior of epidermal keratinocytes.
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Matrix Metalloproteinase-19 expression in normal and diseased skin: dysregulation by epidermal proliferation.
The Journal of investigative dermatology, 2003Co-Authors: Thorsten Sadowski, Matthias Müller, Sebastian Dietrich, Blanka Havlickova, Michael Schunck, Ehrhardt Proksch, Markus Müller, Radislav SedlacekAbstract:Most of the Matrix Metalloproteinases (MMP) are not expressed in normal intact skin but they are upregulated in inflamed or diseased skin. The recently cloned MMP-19 is one of the few MMP members that are also expressed in healthy epidermis. In this study, we found that MMP-19 is generally coexpressed with cytokeratin 14 that is confined to keratinocytes of the stratum basale. MMP-19 was also detected in hair follicles, sebaceous glands, and eccrine sweat glands. Its expression, however, changed in cutaneous diseases exhibiting increased alternations of epidermal proliferation, such as psoriasis, eczema, and tinea. In the affected area, MMP-19 was also found in suprabasal and spinous epidermal layers. We also studied the regulation of MMP-19 expression at the protein level, as well as by using a promoter assay. The constitutive expression of MMP-19 was upregulated with phorbol myristate acetate and downregulated with retinoic acid and dexamethasone. Tumor necrosis factor-α, interleukin (IL)-6, TGF-β, IL-15, IL-8, and RANTES as well as the bacterial compounds lipopolysaccharide and lipoteichoic acid did not show any profound effect in HaCaT cells. In contrast, type IV and type I collagens upregulated MMP-19 significantly. The dysregulation of MMP-19 expression in epidermis suggests its possible involvement in the perpetuation of cutaneous infections and proliferative disorders such as psoriasis.
Kwok Wah Chan - One of the best experts on this subject based on the ideXlab platform.
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catalytic activity of Matrix Metalloproteinase 19 is essential for tumor suppressor and anti angiogenic activities in nasopharyngeal carcinoma
International Journal of Cancer, 2011Co-Authors: King Chi Chan, Radislav Sedlacek, Hong Lok Lung, Zengfeng Zhang, Dian-zhong Luo, Zhen-bo Feng, Shuang Chen, Honglin Chen, Kwok Wah Chan, Sai Wah TsaoAbstract:The association of Matrix Metalloproteinase-19 (MMP19) in the development of nasopharyngeal carcinoma (NPC) was identified from differential gene profiling, which showed MMP19 was one of the candidate genes down-regulated in the NPC cell lines. In this study, quantitative RT-PCR and Western blot analysis showed MMP19 was down-regulated in all seven NPC cell lines. By tissue microarray immunohistochemical staining, MMP19 appears down-regulated in 69.7% of primary NPC specimens. Allelic deletion and promoter hypermethylation contribute to MMP19 down-regulation. We also clearly demonstrate that the catalytic activity of MMP19 plays an important role in antitumor and antiangiogenesis activities in comparative studies of the wild-type and the catalytically inactive mutant MMP19. In the in vivo tumorigenicity assay, only the wild-type (WT), but not mutant, MMP19 transfectants suppress tumor formation in nude mice. In the in vitro colony formation assay, WT MMP19 dramatically reduces colony-forming ability of NPC cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells (HMEC-1), secreted WT MMP19, but not mutant MMP19, induces reduction of tube-forming ability in endothelial cells with decreased vascular endothelial growth factor (VEGF) in conditioned media detected by enzyme-linked immunosorbent assay (ELISA). The anti-angiogenic activity of WT MMP19 is correlated with suppression of tumor formation. These results now clearly show that catalytic activity of MMP19 is essential for its tumor suppressive and anti-angiogenic functions in NPC.
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Catalytic activity of Matrix Metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma
International journal of cancer, 2011Co-Authors: Chi Chan, Radislav Sedlacek, Hong Lok Lung, Zengfeng Zhang, Dian-zhong Luo, Zhen-bo Feng, Shuang Chen, Honglin Chen, Kwok Wah ChanAbstract:The association of Matrix Metalloproteinase-19 (MMP19) in the development of nasopharyngeal carcinoma (NPC) was identified from differential gene profiling, which showed MMP19 was one of the candidate genes down-regulated in the NPC cell lines. In this study, quantitative RT-PCR and Western blot analysis showed MMP19 was down-regulated in all seven NPC cell lines. By tissue microarray immunohistochemical staining, MMP19 appears down-regulated in 69.7% of primary NPC specimens. Allelic deletion and promoter hypermethylation contribute to MMP19 down-regulation. We also clearly demonstrate that the catalytic activity of MMP19 plays an important role in antitumor and antiangiogenesis activities in comparative studies of the wild-type and the catalytically inactive mutant MMP19. In the in vivo tumorigenicity assay, only the wild-type (WT), but not mutant, MMP19 transfectants suppress tumor formation in nude mice. In the in vitro colony formation assay, WT MMP19 dramatically reduces colony-forming ability of NPC cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells (HMEC-1), secreted WT MMP19, but not mutant MMP19, induces reduction of tube-forming ability in endothelial cells with decreased vascular endothelial growth factor (VEGF) in conditioned media detected by enzyme-linked immunosorbent assay (ELISA). The anti-angiogenic activity of WT MMP19 is correlated with suppression of tumor formation. These results now clearly show that catalytic activity of MMP19 is essential for its tumor suppressive and anti-angiogenic functions in NPC.
H. De Vries - One of the best experts on this subject based on the ideXlab platform.
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Matrix Metalloproteinase 19 is highly expressed in active multiple sclerosis lesions
Neuropathology and Applied Neurobiology, 2006Co-Authors: J. Van Horssen, C M P Vos, L Admiraal, E. S. Van Haastert, Lisette Montagne, P. Van Der Valk, H. De VriesAbstract:Matrix Metalloproteinases (MMPs) are proteases known for their capacity to degrade extracellular Matrix (ECM) components. MMPs have been implicated in several central nervous system (CNS) diseases, including multiple sclerosis (MS). Microarray analysis has demonstrated significant increased mRNA levels of MMP-19 in chronic MS lesions, suggesting a role of MMP-19 in MS pathogenesis. Therefore, in this study, we investigated the expression pattern and cellular localization of MMP-19 protein in various well-characterized MS lesion stages. In normal control patient white matter, MMP-19 was constitutively expressed by microglia throughout the brain parenchyma, suggesting a physiological role for this MMP family member. Likewise, MMP-19 was expressed by microglia in (p)reactive MS lesions, albeit more intense. In highly active demyelinating MS lesions, parenchymal and perivascular myelin-laden macrophages were strongly immunoreactive for MMP-19, whereas reactive astrocytes were occasionally immunopositive. Astrocytes in chronic inactive lesions were weakly stained for MMP-19. In vitro, MMP-19 was expressed in cultures of primary human microglia, not in astrocyte cultures. As MMP-19 is able to degrade basement membrane constituents and other ECM proteins, it is conceivable that this relatively novel MMP family member contributes to MS pathology by remodelling the ECM of the CNS, thereby influencing leucocyte infiltration, axonal regeneration and astrogliosis.
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Matrix Metalloproteinase‐19 is highly expressed in active multiple sclerosis lesions
Neuropathology and applied neurobiology, 2006Co-Authors: J. Van Horssen, C M P Vos, L Admiraal, E. S. Van Haastert, Lisette Montagne, P. Van Der Valk, H. De VriesAbstract:Matrix Metalloproteinases (MMPs) are proteases known for their capacity to degrade extracellular Matrix (ECM) components. MMPs have been implicated in several central nervous system (CNS) diseases, including multiple sclerosis (MS). Microarray analysis has demonstrated significant increased mRNA levels of MMP-19 in chronic MS lesions, suggesting a role of MMP-19 in MS pathogenesis. Therefore, in this study, we investigated the expression pattern and cellular localization of MMP-19 protein in various well-characterized MS lesion stages. In normal control patient white matter, MMP-19 was constitutively expressed by microglia throughout the brain parenchyma, suggesting a physiological role for this MMP family member. Likewise, MMP-19 was expressed by microglia in (p)reactive MS lesions, albeit more intense. In highly active demyelinating MS lesions, parenchymal and perivascular myelin-laden macrophages were strongly immunoreactive for MMP-19, whereas reactive astrocytes were occasionally immunopositive. Astrocytes in chronic inactive lesions were weakly stained for MMP-19. In vitro, MMP-19 was expressed in cultures of primary human microglia, not in astrocyte cultures. As MMP-19 is able to degrade basement membrane constituents and other ECM proteins, it is conceivable that this relatively novel MMP family member contributes to MS pathology by remodelling the ECM of the CNS, thereby influencing leucocyte infiltration, axonal regeneration and astrogliosis.
Rolf Mentlein - One of the best experts on this subject based on the ideXlab platform.
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Matrix Metalloproteinase-19 is highly expressed in astroglial tumors and promotes invasion of glioma cells.
Journal of neuropathology and experimental neurology, 2010Co-Authors: Imke Lettau, Kirsten Hattermann, Janka Held-feindt, Rena Brauer, Radislav Sedlacek, Rolf MentleinAbstract:Glial tumors exhibit a high morbidity and mortality because of their invasive nature. Matrix Metalloproteinase 19 (MMP19) is a secreted protease that together with epilysin (MMP28) forms a structural subgroup of MMPs. We analyzed their expression by quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry in tumor and normal control brain tissues and in glioblastoma (GB) cells and performed MMP19 silencing functional assays. Matrix Metalloproteinase 28 was transcribed to the same extent in normal brain samples and gliomas but was undetectable in GB cell lines. In contrast, MMP19 was detected by immunohistochemistry in normal brain samples only in endothelial cells but was found at high levels in astrocytomas of different World Health Organization grades in situ and in GB cells in vitro. Matrix Metalloproteinase 19 was upregulated in GB cells after exposure to proinflammatory cytokines. In Transwell invasion assays, MMP19-silenced cells migrated more slowly through laminin-, basal lamina-, and brevican-coated membranes than controls. Matrix Metalloproteinase 19-silenced GB cells also migrated into brain tissue slices compared with control cells. Brevican, a brain-specific proteoglycan and major component of brain extracellular Matrix, was degraded by recombinant human MMP19. Taken together, these results indicate that MMP19 is highly expressed in proliferating astrocytoma/glioma cells, and that its expression may facilitate their invasion through brain extracellular Matrix components.
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MMP19 is essential for T cell development and T cell-mediated cutaneous immune responses.
PloS one, 2008Co-Authors: Inken M. Beck, Rena Brauer, Rolf Mentlein, Thorsten Sadowski, Markus Mueller, René Rückert, Katja Brandt, Peter Schirmacher, Radislav SedlacekAbstract:Matrix Metalloproteinase-19 (MMP19) affects cell proliferation, adhesion, and migration in vitro but its physiological role in vivo is poorly understood. To determine the function of MMP19, we generated mice deficient for MMP19 by disrupting the catalytic domain of mmp19 gene. Although MMP19-deficient mice do not show overt developmental and morphological abnormalities they display a distinct physiological phenotype. In a model of contact hypersensitivity (CHS) MMP19-deficient mice showed impaired T cell-mediated immune reaction that was characterized by limited influx of inflammatory cells, low proliferation of keratinocytes, and reduced number of activated CD8+ T cells in draining lymph nodes. In the inflamed tissue, the low number of CD8+ T cells in MMP19-deficient mice correlated with low amounts of proinflammatory cytokines, especially lymphotactin and interferon-inducible T cell α chemoattractant (I-TAC). Further analyses showed that T cell populations in the blood of immature, unsensitized mice were diminished and that this alteration originated from an altered maturation of thymocytes. In the thymus, thymocytes exhibited low proliferation rates and the number of CD4+CD8+ double-positive cells was remarkably augmented. Based on the phenotype of MMP19-deficient mice we propose that MMP19 is an important factor in cutaneous immune responses and influences the development of T cells.
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Matrix Metalloproteinase-19 Expression in Keratinocytes Is Repressed by Transcription Factors Tst-1 and Skn-1a: Implications for Keratinocyte Differentiation
The Journal of investigative dermatology, 2006Co-Authors: Inken M. Beck, Rolf Mentlein, Matthias Müller, Thorsten Sadowski, Markus Mueller, Ralf Paus, Radislav SedlacekAbstract:Matrix Metalloproteinase-19 (MMP-19), unlike other members of the MMP family, is expressed in basal keratinocytes of intact epidermis whereas keratinocytes in suprabasal and higher epidermal layers express this enzyme only during cutaneous disorders. As the activity of MMP-19 effects proliferation, migration, and adhesion of keratinocytes we examined whether transcription factors involved in keratinocyte differentiation repress the expression of MMP-19. Using luciferase reporter assays, POU transcription factors Tst-1 (Oct-6) and Skn-1a (Oct-11) markedly downregulated the activity of MMP-19 promoter in COS-7 cells and HaCaT keratinocytes. Tst-1 alone was able to inhibit 85% of the promoter activity. Skn-1a exhibited a weak inhibitory effect although it synergistically increased effects of Tst-1. HaCaT cells stably transfected with Tst-1 showed a strong decrease of activity of MMP-19 promoter that correlated with suppression of MMP-19, cytokeratin 14 and 5, decreased cell proliferation, and altered expression of involucrin and loricrin. The expression of MMP-9 was also significantly reduced in Tst-1 expressing keratinocytes. MMP-2 was substantially affected during its activation whereas the expression of MMP-28 was unchanged. Our results suggest that Tst-1 and Skn-1a regulate expression of MMPs in keratinocytes and effect both the expression and activation of these proteolytic enzymes.