In Vivo Temporal Expression of Protein Levels of Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) During Prostaglandin F2alpha-Induced Luteolysis in Sheep.

We have recently demonstrated that tissue inhibitor of metalloproteinase-3 (TIMP-3) decreases neonatal cardiomyocyte proliferation (Hammoud L, Xiang F, Lu X, Brunner F, Leco K, Feng Q. Cardiovasc Res 75: 359–368, 2007). The aim of the present study was to delineate a pathway through which TIMP-3 exerts its antiproliferative effect. Experiments were conducted on neonatal cardiomyocyte cultures and heart tissues isolated from wild-type (WT) and TIMP-3−/− mice. Deficiency in TIMP-3 decreased p27 expression and increased cardiomyocyte proliferation in cardiomyocytes and neonatal hearts. A TIMP-3/epidermal growth factor (EGF) receptor (EGFR)/c-Jun NH2-terminal kinase (JNK)/SP-1/p27 pathway was investigated. JNK phosphorylation and EGFR protein levels were increased in TIMP-3−/− cardiomyocytes and heart tissues. Treatment with recombinant TIMP-3 decreased JNK phosphorylation and EGFR expression/phosphorylation. Inhibition of JNK activity using SP-600125 decreased SP-1 phosphorylation, increased p27 expression, and decreased cardiomyocyte proliferation. Furthermore, treatment with the EGFR specific inhibitor PD-168393 or the EGF-neutralizing antibody decreased cardiomyocyte proliferation as well as phosphorylation of JNK and SP-1 in both WT and TIMP-3−/− cardiomyocytes. We conclude that TIMP-3 inhibits neonatal mouse cardiomyocyte proliferation by upregulating p27 expression. The effects of TIMP-3 are mediated via inhibition of EGFR expression/phosphorylation, and decreases in JNK and SP-1 signaling.

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Angiogenic potential in vivo by Kaposiʼs sarcoma cell-free supernatants and HIV-1 tat product: inhibition of KS-like lesions by tissue inhibitor of metalloproteinase-2

AIDS ◽

10.1097/00002030-199409000-00004 ◽

1994 ◽

Vol 8 (9) ◽

pp. 1237-1244 ◽

Cited By ~ 108

Author(s):

Adriana Albini ◽

Gabriella Fontanini ◽

Luciana Masiello ◽

Carlo Tacchetti ◽

Daniela Bigini ◽

...

Keyword(s):

Product Inhibition ◽

Tissue Inhibitor Of Metalloproteinase ◽

Sarcoma Cell ◽

Tissue Inhibitor ◽

Angiogenic Potential ◽

Hiv 1

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Interleukin-13 augments transforming growth factor-β1-induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts

AJP Cell Physiology ◽

10.1152/ajpcell.00035.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. C435-C442 ◽

Cited By ~ 23

Author(s):

XiuXia Zhou ◽

John B. Trudeau ◽

Kathryn J. Schoonover ◽

Jessica I. Lundin ◽

Steve M. Barnes ◽

...

Keyword(s):

Growth Factor ◽

Protein Expression ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Tissue Inhibitor Of Metalloproteinase ◽

Tissue Inhibitor ◽

Mrna Stabilization ◽

Protein Levels ◽

Human Airway ◽

Tgf Β1

Tissue inhibitor of metalloproteinase (TIMP)-1 is a potent inhibitor of activated matrix metalloproteinases (MMPs) such as gelatinases and collagenases. TIMP-1 is induced by transforming growth factor-β1 (TGF-β1), but details regarding signaling pathways remain unclear. T-helper-2 cytokines also have profibrotic properties and can interact with TGF-β. In the present study, we examined the effects of interleukin (IL)-13 (2,500 pM) on TGF-β1 (200 pM)-induced expression of TIMP-1 mRNA and protein in primary human airway fibroblasts obtained from 57 human subjects. IL-13 alone had no effect on TIMP-1 mRNA or protein expression. However, IL-13 synergistically augmented TGF-β1-induced TIMP-1 mRNA and protein expression ( P < 0.001 vs. TGF-β1 alone). The upregulation of TIMP-1 by the combination of TGF-β1 and IL-13 involved increased transcription, with little effect on mRNA stabilization. Initial exploration of the pathways leading to the synergy determined that activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway by IL-13 may have a negative effect on TIMP-1 production. The specific PI3K inhibitor LY-294002 in the presence of TGF-β1, IL-13, or the combination of the two caused significant increases in TIMP-1 mRNA expression, while LY-294002 increased TIMP-1 protein levels in the presence of IL-13 alone. These results suggest that IL-13 augments TGF-β1-induced profibrotic responses at both the mRNA and protein levels. Although IL-13 induced activation of PI3K-Akt, the activation did not contribute to the synergy observed with TGF-β1 plus IL-13 in TIMP-1 expression and in fact may dampen it. The mechanisms behind the synergy remain to be determined.

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Systemic Delivery of TNF-Related Apoptosis-Inducing Ligand (TRAIL) Elevates Levels of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and Prevents Type 1 Diabetes in Nonobese Diabetic Mice

Endocrinology ◽

10.1210/en.2009-0478 ◽

2010 ◽

Vol 151 (12) ◽

pp. 5638-5646 ◽

Cited By ~ 15

Author(s):

Soojeong Kang ◽

Eun-Jin Park ◽

Yeonsoo Joe ◽

Eunhui Seo ◽

Mi-Kyoung Park ◽

...

Keyword(s):

Type 1 Diabetes ◽

Blood Glucose ◽

Gelatin Zymography ◽

Nod Mice ◽

Tissue Inhibitor Of Metalloproteinase ◽

Tissue Inhibitor ◽

Nonobese Diabetic ◽

Induced Apoptosis

Recent studies have demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is a modulator of the immune response. The relation between TRAIL and type 1 diabetes (T1D) as an autoimmune inflammatory disease in vivo is relatively unknown. To explore the potential role of TRAIL in the development of T1D, we examined its in vivo effects in nonobese diabetic (NOD) mice. NOD mice at 7 wk of age were iv injected with an adenovirus carrying either human TRAIL (Ad.hTRAIL) or β-galactosidase genes. Blood glucose was monitored weekly, and the expression of hTRAIL was evaluated in plasma and liver of mice. To investigate whether hTRAIL elicits its effect through the induction of tissue inhibitor of metalloproteinase-1 (TIMP-1), we examined the concentration of plasma TIMP-1 by ELISA and the inhibition of matrix metalloproteinase (MMP) by gelatin zymography. Here, we show that Ad.hTRAIL-transduced mice had significantly reduced blood glucose levels and markedly increased production of TIMP-1 compared with control β-galactosidase animals. Pancreatic tissue isolated from Ad.hTRAIL-treated NOD mice showed reduced MMP activities associated with significantly improved insulitis. In addition, TIMP-1 in vitro suppressed cytokine-induced apoptosis in insulin-producing INS-1 cells. These results indicate that T1D can be prevented by TRAIL overexpression through enhancement of TIMP-1 function. Elevated TIMP-1 production inhibits the activity of MMPs, which may contribute to suppress the transmigration of diabetogenic T cells into the pancreatic islets and protects pancreatic β-cells from cytokine-induced apoptosis. Therefore, TRAIL and TIMP-1 induction may be potential targets to prevent development of T1D.

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952. Delivery of Tissue Inhibitor of Metalloproteinase 3 Inhibits Growth of Lung Cancer Tumours In Vivo

Molecular Therapy ◽

10.1016/j.ymthe.2004.06.894 ◽

2004 ◽

Vol 9 ◽

pp. S364

Keyword(s):

Lung Cancer ◽

Tissue Inhibitor Of Metalloproteinase ◽

Tissue Inhibitor

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Elevated Levels of Matrix Metalloproteinase 9 and Tissue Inhibitor of Metalloproteinase 1 during the Acute Phase of Kawasaki Disease

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.2.308-314.2003 ◽

2003 ◽

Vol 10 (2) ◽

pp. 308-314 ◽

Cited By ~ 22

Author(s):

Pong Kian Chua ◽

Marian E. Melish ◽

Qigui Yu ◽

Richard Yanagihara ◽

Kara S. Yamamoto ◽

...

Keyword(s):

Kawasaki Disease ◽

Matrix Metalloproteinase ◽

Acute Phase ◽

Matrix Metalloproteinase 9 ◽

Tissue Inhibitor Of Metalloproteinase ◽

Unknown Etiology ◽

Tissue Inhibitor ◽

Protein Levels ◽

Aneurysm Formation ◽

Metalloproteinase 9

ABSTRACT Kawasaki disease (KD) is an acute, self-limiting, multisystem vasculitis of unknown etiology affecting infants and young children. Unless treated promptly with high-dose intravenous gamma globulin and aspirin, patients frequently develop coronary aneurysms. Previously, matrix metalloproteinase 9 (MMP-9), which is secreted complexed to tissue inhibitor of metalloproteinase 1 (TIMP-1), has been implicated in abdominal aortic aneurysm formation. Since the clinical and pathological features of KD include inflammation and weakening of blood vessels, we analyzed acute- and convalescent-phase paired plasma or serum samples from 31 KD patients, 7 patients who did not completely meet the criteria for KD, and 26 non-KD controls (9 febrile and 17 afebrile patients) for pro-MMP-9 (92 kDa) enzyme activity by gelatin zymography and for active MMP-9 (83 kDa), pro-MMP-9, and TIMP-1 protein levels by enzyme-linked immunosorbent assay. Statistical analysis was performed by using Student t tests, linear regression, and the Wilcoxon rank-sum test. Markedly elevated pro-MMP-9 enzymatic activity, pro-MMP-9 protein levels, and TIMP-1 protein levels were found during the acute phase of illness in patients with clinically established KD and in patients who were suspected of having KD but did not meet all of the criteria. There was no significant difference in active MMP-9 levels. Furthermore, pro-MMP-9 and TIMP-1 protein levels were significantly elevated among KD patients, compared to those of febrile and afebrile non-KD controls. The significantly elevated pro-MMP-9 enzyme and protein levels during the acute phase of KD may reflect vascular remodeling or an inflammatory response to a microbial agent, suggesting a pathophysiological role for MMP-9 in coronary aneurysm formation.

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