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TIMP-1
Kinds of TIMP-1 Terms modified by TIMP-1 Selected AbstractsMaternal hypoxia increases the activity of MMPs and decreases the expression of TIMPs in the brain of neonatal ratsDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2010Wenni Tong Abstract A recent study has shown that increased activity of matrix metalloproteinases-2 and metalloproteinases-9 (MMP-2 and MMP-9) has detrimental effect on the brain after neonatal hypoxia. The present study determined the effect of maternal hypoxia on neuronal survivability and the activity of MMP-2 and MMP-9, as well as the expression of tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2) in the brain of neonatal rats. Pregnant rats were exposed to 10.5% oxygen for 6 days from the gestation day 15 to day 21. Pups were sacrificed at day 0, 4, 7, 14, and 21 after birth. Body weight and brain weight of the pups were measured at each time point. The activity of MMP-2 and MMP-9 and the protein abundance of TIMP-1 and TIMP-2 were determined by zymography and Western blotting, respectively. The tissue distribution of MMPs was examined by immunofluorescence staining. The neuronal death was detected by Nissl staining. Maternal hypoxia caused significant decreases in body and brain size, increased activity of MMP-2 at day 0, and increased MMP-9 at day 0 and 4. The increased activity of the MMPs was accompanied by an overall tendency towards a reduced expression of TIMPs at all ages with the significance observed for TIMPs at day 0, 4, and 7. Immunofluorescence analysis showed an increased expression of MMP-2, MMP-9 in the hippocampus at day 0 and 4. Nissl staining revealed significant cell death in the hippocampus at day 0, 4, and 7. Functional tests showed worse neurobehavioral outcomes in the hypoxic animals. © 2009 Wiley Periodicals, Inc. Develop Neurobiol 2010 [source] Peripheral blood level alterations of TIMP-1, MMP-2 and MMP-9 in patients with Type 1 diabetesDIABETIC MEDICINE, Issue 10 2001P. R. Maxwell Abstract Aim To determine the plasma levels of enzymes and inhibitors involved in extracellular matrix turnover in patients with Type 1 diabetes with normal renal function. Methods Plasma levels of matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in 43 Type 1 diabetic subjects and age- and sex-matched controls. Results No significant difference in plasma MMP-2 between diabetic patients and controls was observed. MMP-9 was detected in the plasma of 15 diabetic patients (35%), but undetectable in all control subjects (P < 0.015). Plasma TIMP-1 concentrations were significantly elevated (P < 0.001) in diabetic patients compared to controls. There was no correlation observed between MMP-2, MMP-9 and TIMP-1 and similarly between MMP-2, MMP-9 and TIMP-1 and age, duration of diabetes, blood pressure and glycated haemoglobin (HbA1c). Conclusions This study has demonstrated alterations in several plasma extracellular matrix modulators in the absence of significant vascular disease. Diabet. Med. 18, 777,780 (2001) [source] DIASTOLIC DYSFUNCTION IN HYPERTENSIVES AS ASSESSED BY TISSUE DOPPLER; RELATION TO MATRIX METALLOPROTEINASESECHOCARDIOGRAPHY, Issue 5 2004S. Nadar Objectives: To assess the severity of diastolic dysfunction in hypertensive patients as compared to normal controls and correlate it with plasma matrix metalloproteinases (MMPs). Methods: 52 patients with controlled hypertension (HT) (38 male, age 57+ 11 yrs) and 24 normotensive controls 15 male, mean age 53+ 12 years) had tissue doppler echocardiography to assess diastolic dysfunction (e, and e,/e ratios). They also had plasma MMP-9 and TIMP-1 measured. Results: The HT patients had significantly lower e, and higher e,/e ratios as compared to normotensive controls. They also had higher MMP-9 and TIMP-1 values. There was a significant inverese correlation between MMP-9 and TIMP-1 with e, and a significant positive correlation between the MMPs and e,/e ratio. THe e/a ratios as assessed by pulse wave doppler were also higher in the controls than the hypertensive patients suggesting abnormal diastolic function. Conclusions: There is significant diastolic dysfunction even in controlled hypertensives which can be assessed by tissue doppler. This newer technique compares favourably with established methods such as e/a ratio. The tissue doppler indices also correlate well with abnormalities in the matrix metalloproteinases suggesting that abnormal matrix turnover is responsible for the diastolic dysfunction. [source] Tissue inhibitor of metalloproteinse-1 is a marker of diastolic dysfunction using tissue doppler in patients with type 2 diabetes and hypertensionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2005M. H. Tayebjee Abstract Background, Tissue inhibitor of metalloproteinase-1 (TIMP-1) is associated with increased fibrosis of the extracellular matrix (ECM). Myocardial stiffness is a feature of diastolic dysfunction. We assessed circulating TIMP-1 as a marker of diastolic dysfunction in patients with type 2 diabetes mellitus (DM) and hypertension, who were compared with healthy controls. Methods, We recruited 54 patients (43 males; mean age 68 ± 5 years) with treated type 2 DM (i.e. controlled glycaemia, hypertension, hyperlipidaemia), 35 (30 males; 69 ± 8 years) treated nondiabetic hypertensives, and 31 healthy controls (18 males; 66 ± 5 years). Circulating TIMP-1 was measured by ELISA. Using transthoracic echocardiography, the early (E) diastolic mitral inflow velocity was measured with pulse wave Doppler, and the early mitral annular velocity (e,), a recognized index of diastolic relaxation, was measured with tissue Doppler. The E/A ratio was also calculated and isovolumic relaxation time measured. Results, Mean e, levels differed significantly between controls, diabetics and hypertensives (P < 0·0001). Circulating TIMP-1 was significantly different between patients and controls (P = 0·006), but there was no statistically significant difference between the DM and hypertension group. In both groups, only e, was negatively correlated with TIMP-1 levels, with a stronger correlation among the hypertensive patients (Spearman r = ,0·544, P = 0·001) when compared with the diabetic group (r = ,0·341, P = 0·011). Conclusion, Diastolic relaxation is impaired in diabetes and hypertensive patients. The relationship between TIMP-1 and e, may reflect increased myocardial fibrosis and consequent diastolic dysfunction, which may be more prominent in hypertension. [source] The role of exon 5 in fibroblast collagenase (MMP-1) substrate specificity and inhibitor selectivityFEBS JOURNAL, Issue 6 2001Vera Knäuper Interstitial collagen is degraded by members of the matrix metalloproteinase (MMP) family, including MMP-1. Previous work has shown that the region of MMP-1 coded for by exon 5 is implicated both in substrate specificity and inhibitor selectivity. We have constructed a chimeric enzyme, the exon 5 chimera, consisting primarily of MMP-1, with the region coded for by exon 5 replaced with the equivalent region of MMP-3, a noncollagenolytic MMP. Unlike MMP-3, the exon 5 chimera is capable of cleaving type I collagen, but the activity is only 2.2% of trypsin-activated MMP-1. ,Superactivation' of the chimera has no discernible effect, suggesting that the salt bridge formed in ,superactive' MMP-1 is not present. The kinetics for exon 5 chimera cleavage of two synthetic substrates display an MMP-3 phenotype, however, cleavage of gelatin is slightly impaired as compared to the parent enzymes. The Kiapp values for the exon 5 chimera complexed with synthetic inhibitors and N-terminal TIMP-2 also show a more MMP-3-like behaviour. However, the kon values for N-terminal TIMP-1 and N-terminal TIMP-2 are more comparable to those for MMP-1. These data show that the region of MMP-1 coded for by exon 5 is involved in both substrate specificity and inhibitor selectivity and the structural basis for our findings is discussed. [source] Blockade of IL-15 activity inhibits microglial activation through the NF,B, p38, and ERK1/2 pathways, reducing cytokine and chemokine releaseGLIA, Issue 3 2010Diego Gomez-Nicola Abstract Reactive glia formation is one of the hallmarks of damage to the CNS, but little information exists on the signals that direct its activation. Microglial cells are the main regulators of both innate and adaptative immune responses in the CNS. The proinflammatory cytokine IL-15 is involved in regulating the response of T and B cells, playing a key role in regulating nervous system inflammatory events. We have used a microglial culture model of inflammation induced by LPS and IFN, to evaluate the role of IL-15 in the proinflammatory response. Our results indicate that IL-15 is necessary for the reactive response, its deficiency (IL-15-/-) leading to the development of a defective proinflammatory response. Blockade of IL-15, both with blocking antibodies or with the ganglioside Neurostatin, inhibited the activation of the NF,B pathway, decreasing iNOS expression and NO production. Inhibiting IL-15 signaling also blocked the activation of the mitogen-activated protein kinase (MAPK) pathways ERK1/2 and p38. The major consequence of these inhibitory effects, analyzed using cytokine antibody arrays, was a severe decrease in the production of chemokines, cytokines and growth factors, like CCL17, CCL19, IL-12, or TIMP-1, that are essential for the development of the phenotypic changes of glial activation. In conclusion, activation of the IL-15 system seems a necessarystep for the development of glial reactivity and the regulation of the physiology of glial cells. Modulating IL-15 activity opens the possibility of developing new strategies to control gliotic events upon inflammatory stimulation. © 2009 Wiley-Liss, Inc. [source] Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C,HEPATOLOGY, Issue 3 2008Robert J. Fontana This study determined the utility of a panel of serum fibrosis markers along with routine laboratory tests in estimating the likelihood of histological cirrhosis in a cohort of prior nonresponders with chronic hepatitis C. The relationship between serum markers and quantitative hepatic collagen content was also determined. Liver biopsy samples from 513 subjects enrolled in the HALT-C trial were assigned Ishak fibrosis scores. The collagen content of 386 sirius-red stained, nonfragmented biopsy samples was quantified using computerized morphometry. Serum tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), amino-terminal peptide of type III procollagen (PIIINP), hyaluronic acid (HA), and YKL-40 levels were determined using commercially available assays. Sixty-two percent of patients had noncirrhotic fibrosis (Ishak stage 2-4) whereas 38% had cirrhosis (Ishak stage 5,6). Multivariate analysis identified a 3-variable model (HA, TIMP-1, and platelet count) that had an area under the receiver operating curve (AUROC) of 0.81 for estimating the presence of cirrhosis. This model was significantly better than that derived from the cirrhosis discriminant score (AUROC 0.70), the AST-to-platelet ratio (AUROC 0.73), and a prior model developed in HALT-C patients (AUROC 0.79). Multivariate analysis demonstrated that the serum fibrosis markers correlated substantially better with Ishak fibrosis scores than with the log hepatic collagen content (AUROC 0.84 versus 0.72). Conclusion: A 3-variable model consisting of serum HA, TIMP-1, and platelet count was better than other published models in identifying cirrhosis in HALT-C Trial subjects. The stronger correlation of the serum markers with Ishak scores suggests that serum fibrosis markers reflect the pattern of fibrosis more closely than the quantity of hepatic collagen. (HEPATOLOGY 2008.) [source] Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouseHEPATOLOGY, Issue 4 2002Hitoshi Yoshiji It has been suggested that the tissue inhibitor of metalloproteinases-1 (TIMP-1) is involved in spontaneous resolution of liver fibrosis. The aim of this study was to investigate whether TIMP-1 altered spontaneous resolution of liver fibrosis in conjunction with matrix metalloproteinases (MMP) inhibition and hepatic stellate cell (HSC) activation. The livers of liver-targeted TIMP-1 transgenic (TIMP-Tg) and control hybrid (Cont) mice were harvested at 0, 3, 7, and 28 days following spontaneous recovery from CCl4 -induced liver fibrosis. The extent of fibrosis resolution, MMP expression, ,-smooth-muscle actin (,-SMA) positive cells, and procollagen-(I) messenger RNA (mRNA) in the liver were assessed at the respective periods in both groups. We also examined the effect of TIMP-1 on HSC apoptosis. The TIMP-Tg mice showed significantly attenuated resolution of spontaneous liver fibrosis compared with the Cont mice. The hydroxyproline content, number of ,-SMA positive cells, and procollagen-(I) mRNA rapidly decreased with time in the Cont mice, whereas these markers were little changed in TIMP-Tg mice. The level of the active form of metalloproteinases-2 (MMP-2) in the TIMP-Tg mice was less than that in the Cont mice. TIMP-1 markedly decreased the nonparenchyma apoptotic cells in the liver fibrosis resolution model, and it also inhibited HSC apoptosis associated with suppression of caspase-3 activity in vitro. In conclusion, TIMP-1 significantly attenuated spontaneous resolution of liver fibrosis by the combination of a net reduction of the MMP activity and suppression of apoptosis in HSC. [source] Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse modelHEPATOLOGY, Issue 6 2000Hitoshi Yoshiji Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP-1 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/enhancer. A model of CCl4 -induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 itself did not induce liver fibrosis. There were no significant differences of pro-(,1)-collagen-I, (,2)-collagen-IV, and ,-smooth muscle actin (,-SMA) mRNA expression in the liver between TIMP-Tg and Cont-mice, suggesting that overexpression of TIMP-1 itself did not cause hepatic stellate cell (HSC) activation. After 4-week treatment with CCl4, however, densitometric analysis revealed that TIMP-Tg-mice had a seven-fold increase in liver fibrosis compared with the Cont-mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP-Tg-mice, whereas CCl4 -induced liver dysfunction was not altered. An active form of matrix metalloproteinases-2 (MMP-2) level in the liver of TIMP-Tg-mice was decreased relative to that in Cont-mice because of the transgenic TIMP-1. Immunohistochemical analysis revealed that collagen-I and collagen-IV accumulation was markedly increased in the liver of CCl4 -treated TIMP-Tg-mice with a pattern similar to that of ,-SMA positive cells. These results suggest that TIMP-1 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development. [source] Preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation in ratsHEPATOLOGY RESEARCH, Issue 7 2008Kazunori Maeda Aim:, The aim of this study was to examine the preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation (BDL) in rats. Methods:, ME3738 (20 mg/day) was administered orally for 21 days immediately after BDL. Fibrosis was assessed by measuring hepatic hydroxyproline (Hyp) content. Activated hepatic stellate cells (HSCs) were assessed by ,-smooth muscle actin (,-SMA) immunostaining. Hepatic thiobarbituric acid-reactive substance (TBARS), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) immunostaining were used to analyze oxidative stress. The gene expressions of collagen-I, transforming growth factor-,1 (TGF-,1), tissue inhibitor of metalloproteinases-1 (TIMP-1), interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) in the liver were examined by real-time reverse transcriptase polymerase chain reaction (RT,PCR). Results:, Hepatic Hyp content and the area of hepatic fibrosis in BDL rats treated with ME3738 were reduced by 24% and 39% compared with non-treated BDL rats (hepatic Hyp, 9.40 ± 2.85 vs. 12.39 ± 3.91 mg/liver; P = 0.036; area of hepatic fibrosis, 13.1 ± 3.8 vs. 21.5 ± 10.9; P = 0.045). Furthermore, ,-SMA-positive cells were significantly reduced by 40% (22.3 ± 14.8 vs. 37.6 ± 14.2; P = 0.011), collagen-I mRNA by 83% (6.5 ± 2.2 vs. 38.3 ± 9.1; P = 0.002), HO-1 mRNA by 58% (4.13 ± 1.22 vs. 9.73 ± 1.80; P = 0.018) and hepatic HO-1 content by 26% (2.13 ± 0.80 vs. 2.87 ± 0.19; P = 0.01) following ME3738 treatment. The hepatic expression of TBARS, 4-HNE, 8-OHdG and mRNA levels of TGF-,1, TIMP-1 and IL-6 in the liver were unchanged by ME3738 treatment. Conclusion:, Oral ME3738 administration may prevent the progression of hepatic fibrosis in BDL rats through suppression of the activation and collagen synthesis of HSC and, in part, oxidative stress. ME3738 has potential as a therapeutic drug for cholestatic liver fibrosis. [source] Expression of matrix metalloproteinases MMP-2, MMP-9 and their tissue inhibitors TIMP-1 and TIMP-2 in the epithelium and stroma of salivary gland pleomorphic adenomasHISTOPATHOLOGY, Issue 3 2009Xiaojun Zhang Aims:, The balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is involved in the morphogenesis of normal salivary gland as well as in the mechanisms of tumour invasion and metastasis. The role of MMPs and TIMPs in pleomorphic adenoma has not been elucidated sufficiently. Our aim was to analyse the mRNA and protein expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 in the epithelium and stroma of pleomorphic adenoma and to evaluate their roles. Methods and results:, In each sample from six patients, cells from the epithelium and stroma were obtained by laser microdissection. The mRNA expression of MMPs and TIMPs was determined by real-time quantitative reverse transcriptase-polymerase chain reaction and protein expression was confirmed by immunohistochemistry. Results showed that mRNA expression of MMPs and TIMPs was significantly higher in stroma than in epithelium in most patients. MMPs and TIMPs were immunoreactive mainly in epithelium rather than in stroma. Conclusions:, Our results provide preliminary evidence that stromal myoepithelium may be the primary source of MMPs and that the stroma has the potential to play a more important role than ductal epithelium in biological behaviour of pleomorphic adenomas. These findings seem worthy of further investigation. [source] Effect of the anti-tumor necrosis factor-, antibody infliximab on the ex vivo mucosal matrix metalloproteinase,proteolytic phenotype in inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 2 2007Martin J. Meijer MSc Abstract Background: Previous studies have shown an upregulation of matrix metalloproteinases (MMPs) in intestinal tissue of patients with inflammatory bowel disease (IBD) and significant clinical improvement after administration of the anti-TNF-, antibody infliximab. The aims of our study were to determine expression and secretion of MMP-1, -2, -3, -9, and their inhibitors TIMP-1, -2 by IBD versus control intestinal mucosa ex vivo and to assess the regulatory capacity by infliximab of the proteolytic phenotype. Methods: Intestinal mucosal explants from 20 IBD and 15 control patients were cultured with or without infliximab and/or the T-cell activator pokeweed mitogen (PWM). Explants and culture supernatants were analyzed for MMPs, TIMPs, and TNF-, protein, activity and/or mRNA levels. All patients were genotyped for functional TNF-,, MMP, and TIMP single nucleotide polymorphism (SNP) loci. Results: Expression of MMP and TIMP protein/activity in basal medium was higher in IBD versus control explants. Dependent on genotype at SNP loci, infliximab downregulated MMP-1, -3, and -9 relative to TIMP-1 and -2 and also decreased MMP-1 and -3 activities, while PWM enhanced these levels, partly counteracted again by infliximab. The expression of MMP-2 relative to TIMP did not change by treatment with infliximab and/or PWM. Conclusions: The high expression of MMPs in patients with IBD suggests a role for these proteinases in the pathogenesis of this disease. Infliximab seems to induce a genotype-associated matrix protective phenotype, which may contribute to the observed therapeutic efficacy of this drug in IBD, particularly at the mucosal surface. (Inflamm Bowel Dis 2007) [source] Enhanced expression of MMP-7 and MMP-13 in inflammatory bowel disease: A precancerous potential?INFLAMMATORY BOWEL DISEASES, Issue 11 2006Dr. Timo Rath PhD Abstract Matrix metalloproteinases (MMPs) are responsible for the turnover and degradation of extracellular matrix. They play a crucial role in the growth and migration of colorectal carcinoma cells. Colorectal carcinomas are characterized by enhanced expression of MMP-2, MMP-9, MMP-7, and MMP-13. The aim of this study was to determine the expression levels of MMP-2, MMP-9, MMP-7, MMP-13, and MMP-14 and their specific inhibitor TIMP-1 in inflammatory bowel diseases and precancerous lesions of the colon, i.e., Crohn's disease and ulcerative colitis, and in adenomatous polyps (APs) for comparison. Biopsy samples of pathological and healthy tissue were obtained from 40 patients with inflammatory bowel disease (ulcerative colitis, n = 17; Crohn's disease, n = 23) and from 19 patients with APs. mRNA was measured by quantitative real-time polymerase chain reaction to study MMP and TIMP-1 gene expression in both pathological and normal mucosal specimens. For MMP-2, MMP-9, and TIMP-1, protein expression also was quantified with sandwich enzyme-linked immunosorbent assay. In biopsy specimens of Crohn's disease and ulcerative colitis, significantly increased levels of MMP-2, MMP-7, and MMP-13 mRNA were found. MMP-2 and MMP-9 showed enhanced secretion on the protein level. AP revealed an increased transcription of MMP-7 and MMP-13 genes. MMP-14 mRNA was decreased in APs. MMPs, especially MMP-7 and MMP-13, which are expressed primarily on the tumor cell surface, are elevated in inflammatory bowel disease, which may have more chance to evolve into malignancy than normal tissue. In APs, increased expression of MMP-7 and MMP-13 may serve as an early indicator for colorectal carcinogenesis. [source] Combined effect of the finasteride and doxazosin on rat ventral prostate morphology and physiologyINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 3 2010Luis A. Justulin Jr Summary Finasteride (Fin) and Doxazosin (Dox), alone or in combination, have been widely used in treatment of benign prostatic hyperplasia (BPH) symptoms and recently have been suggested as potential drugs for prostate cancer (PCa)prevention and treatment. However, little is known about the effects of the combination therapy on prostate tissue morphology, physiology and matrix metalloproteinases (MMPs) activity, a special set of enzymes closely related to PCa progression and metastasis. In this study, adult Wistar rats were treated with Fin + Dox (25 mg/kg per day) and the ventral prostate (VP) was excised at days 3 and 30 of treatment to evaluate morphology, cell proliferation, death, transforming growth factor-beta1 (TGF-,1) protein expression, MMP-2, MMP-9 activities and MMP-2, MMP-9, TIMP-1 and TIMP-2 mRNA expression. Fin + Dox treatment induced a transient increase in testosterone (T) plasma concentration and a permanent reduction in dihydrotestosterone (DHT). The VP and epithelial cell proliferation were reduced and the stromal collagen fibre volume fraction and apoptosis of the epithelial cell were increased. Fin + Dox treatment also increased the TGF-,1 immunoreaction in the epithelium and in the stroma. The mRNAs for MMP-2, TIMPs-1 and -2 expressions after 30 days of treatment were decreased. The mRNA for MMP-9 was not detected in any of the groups analysed. Fin + Dox treatment for 30 days promoted a decrease in gelatinolytic activity of MMP-2 and an increase in MMP-9. In conclusion, combined treatment with Fin and Dox interferes in the epithelial cell behaviour and in the MMPs activity, potentially via TGF-,1-mediated and androgen pathways. Our results contribute to a better understanding of the clinical data and also of the molecular mechanisms behind isolated or combined Fin and Dox long-term treatment. [source] Loss of intercellular adhesion activates a transition from low- to high-grade human squamous cell carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 4 2006Alexander Margulis Abstract The relationship between loss of intercellular adhesion and the biologic properties of human squamous cell carcinoma is not well understood. We investigated how abrogation of E-cadherin-mediated adhesion influenced the behavior and phenotype of squamous cell carcinoma in 3D human tissues. Cell-cell adhesion was disrupted in early-stage epithelial tumor cells (HaCaT-II-4) through expression of a dominant-negative form of E-cadherin (H-2Kd -Ecad). Three-dimensional human tissue constructs harboring either H-2Kd -Ecad-expressing or control II-4 cells (pBabe, H-2Kd -Ecad,C25) were cultured at an air-liquid interface for 8 days and transplanted to nude mice; tumor phenotype was analyzed 2 days and 2 and 4 weeks later. H-2Kd -Ecad-expressing tumors demonstrated a switch to a high-grade aggressive tumor phenotype characterized by poorly differentiated tumor cells that infiltrated throughout the stroma. This high-grade carcinoma revealed elevated cell proliferation in a random pattern, loss of keratin 1 and diffuse deposition of laminin 5 ,2 chain. When II-4 cell variants were seeded into type I collagen gels as an in vitro assay for cell migration, we found that only E-cadherin-deficient cells detached, migrated as single cells and expressed N-cadherin. Function-blocking studies demonstrated that this migration was matrix metalloproteinase-dependent, as GM-6001 and TIMP-2, but not TIMP-1, could block migration. Gene expression profiles revealed that E-cadherin-deficient II-4 cells demonstrated increased expression of proteases and cell-cell and cell-matrix proteins. These findings showed that loss of E-cadherin-mediated adhesion plays a causal role in the transition from low- to high-grade squamous cell carcinomas and that the absence of E-cadherin is an important prognostic marker in the progression of this disease. © 2005 Wiley-Liss, Inc. [source] Changes in concentrations of type IV collagen and tissue inhibitor of metalloproteinase-1 in patients with paraquat poisoningJOURNAL OF APPLIED TOXICOLOGY, Issue 6 2001Tsukasa Nakamura Abstract Respiratory failure is one of the major causes of death in patients with paraquat poisoning. In paraquat-poisoned lungs, abnormal extracellular matrix regulation occurs. The aim of the present study is to determine whether serum concentrations of type IV collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) are altered during the course of paraquat poisoning and whether haemoperfusion therapy affects these concentrations. Twenty-one patients were admitted within 3 h after ingestion of paraquat and all patients received direct haemoperfusion therapy. Five out of 21 patients survived and 16 patients died within 28 days. Plasma paraquat concentrations in non-survivors (5740 ± 380 µg l,1) were not significantly different from those in survivors ( 5920 ± 280 µg l,1) before treatment. Haemoperfusion reduced these concentrations in both non-survivors (120 ± 7 µg l,1) as well as survivors (136 ± 9 µg l,1) on day 5. Serum concentrations of type IV collagen and TIMP-1 in survivors showed little change between day 1 (type IV collagen, 90.4 ± 3.6 ng ml,1; TIMP-1, 172.2 ± 7.0 ng ml,1) and day 5 (type IV collagen, 92.6 ± 4.2 ng ml,1; TIMP-1, 174.2 ± 7.2 ng ml,1). In contrast, these concentrations in non-survivors on day 5 (type IV collagen, 143.6 ± 7.8 mg ml,1; TIMP-1, 246.8 ± 13.6 ng ml,1) were significantly higher than those on day 1 (type IV collagen, 88.4 ± 4.2 ng ml,1, P < 0.01; TIMP-1, 170.6 ± 9.2 ng ml,1, P < 0.05). These data suggest that serum concentrations of type IV collagen and TIMP-1 may be useful indicators for the development of respiratory failure in patients with paraquat poisoning. Copyright © 2001 John Wiley & Sons, Ltd. [source] Ascorbic Acid Induces Collagenase-1 in Human Periodontal Ligament Cells but Not in MC3T3-E1 Osteoblast-Like Cells: Potential Association Between Collagenase Expression and Changes in Alkaline Phosphatase Phenotype,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2003Momotoshi Shiga Abstract Ascorbic acid (AA) enhances osteoblastic differentiation by increasing collagen accumulation, which in turn, results in increased alkaline phosphatase (AP) expression in some osteogenic cells. However, in other cells, including human periodontal ligament (PDL) cells, additional osteoinductive agents are required for this response. To understand the potential basis for the maintenance of the AP phenotype of PDL cells exposed to AA, we examined the modulation of the tissue-degrading matrix metalloproteinases (MMPs) and their inhibitors by AA in short-term cell cultures. Early passage PDL cells in serum-free medium were exposed to AA for 5 days. The samples were analyzed for MMPs and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), AP, collagen I(,1), and osteocalcin. We found that AA dose-dependently increased the expression of collagenase-1, and minimally TIMP-1, but not stromelysin-1 or TIMP-2. Additionally, AA caused substantial increases in levels of type I collagen. AA was unable to increase AP activity or osteocalcin messenger RNA in PDL cells. However, the cells retained the ability to show a significantly greater AP expression in high- versus low-density cultures, and increased osteocalcin as well as AP levels when cultured in the presence of dexamethasone. Moreover, in cells exposed to dexamethasone, increases in AP and osteocalcin were accompanied by a repression of collagenase-1 expression. In contrast to PDL cells, AA did not induce collagenase but produced a significant increase in AP expression in MC3T3-E1 cells. These findings provide the first evidence that AA, by modulating both collagen and collagenase-1 expression in PDL cells, most likely contributes to a net matrix remodeling response in these cells. Furthermore, the relationship between changes in collagenase expression and alterations in AP activity in PDL and MC3T3-E1 cells suggests a potential role for collagenase in modulating the AP phenotype of cells with osteoblastic potential. [source] A subpopulation of peritoneal macrophages form capillary-like lumens and branching patterns in vitroJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2006Mirela Anghelina Abstract Objective: We have previously shown that monocytes/macrophages (MC/Mph) influence neovascularization by extracellular matrix degradation, and by direct incorporation into growing microvessels. To date, neither the phenotype of these cells, nor the stages of their capillary-like conversion were sufficiently characterized. Methods: We isolated mouse peritoneal Mph from transgenic mice expressing fluorescent proteins either ubiquitously, or specifically in the myelocytic lineage. These Mph were embedded in Matrigel which contained fluorescent protease substrates, exposed to an MCP-1 chemotactic gradient, and then examined by confocal microscopy after various intervals. Results: Within 3 hrs after gel embedding, we detected TIMP-1 and MMP-12 dependent proteolysis of the matrix surrounding Mph, mostly in the direction of high concentrations of MCP-1. After 2 days, Mph developed intracellular vacuoles containing degradation product. At 5 days these vacuoles were enlarged and/or fused to generate trans-cellular lumens in approximately 10% of cells or more (depending on animal's genetic background). At this stage, Mph became tubular, and occasionally organized in three-dimensional structures resembling branched microvessels. Conclusion: Isolated mouse peritoneal Mph penetrate Matrigel and form tunnels via a metalloprotease-driven proteolysis and phagocytosis. Following a morphological adjustment driven by occurrence, enlargement and/or fusion process of intracellular vacuoles, similar to that described in bona fide endothelium, a subpopulation of these cells end up by lining a capillary-like lumen in vitro. Thus we show that adult Mph, not only the more primitive ,endothelial progenitors', have functional properties until now considered defining of the endothelial phenotype. [source] Homocysteine induces metalloproteinase and shedding of ,-1 integrin in microvessel endothelial cells,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2004Suresh Shastry Abstract Although studies have suggested microvessel endothelial cells (MVEC) activation and induction of matrix metalloproteinases (MMPs) by homocysteine (Hcy), the transduction mechanism leading to endothelial activation was unclear. We hypothesized that Hcy induced metalloproteinase and altered the levels of integrin in MVEC. MVEC from mouse brain were isolated and characterized by CD-31 (PECAM-1) FITC labeling. The MVEC were activated with different doses (6,40 ,M) of Hcy. The cultured-conditioned-medium was analyzed for MMP activity by gelatin gel-zymography. TIMP-1, -4, ,-1 integrin, and a disintegrin and metalloproteinase-12 (ADAM-12) were quantified by Western blot analysis. We used MVEC in cell culture to study the effect of increasing concentrations of Hcy upon the secretion of various proteins into the culture medium. MMP-9, ,-1 integrin, ADAM-12, and TIMP-1 were found in increased concentrations in the culture medium of Hcy-treated cells whereas TIMP-4 was decreased. We have shown that purified TIMP-4 blocked the increase of ,-1 integrin shedding in Hcy-treated cells. Interestingly, our results suggest that TIMP-1 and TIMP-4 function antagonistically in Hcy-induced signaling pathways. © 2004 Wiley-Liss, Inc. [source] MT1-MMP, but not secreted MMPs, influences the migration of human microvascular endothelial cells in 3-dimensional collagen gelsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2002Teruhiko Koike Abstract Matrix metalloproteinases (MMPs) and their specific inhibitors the TIMPs play significant roles in angiogenesis. We investigated how the expression of specific MMPs and TIMPs by human microvascular endothelial cells (hmECs) was modulated by culture of the cells in 3-dimensional (3D) type I collagen gels versus 2-dimensional (2D) collagen-coated surfaces. By reverse-transcription polymerase chain reaction (RT-PCR), levels of mRNA for MMPs-1, -2, and -13, MT1-MMP, and TIMPs-1 and -2 were similar in 2D versus 3D cultures. By Western blot assay, TIMP-1 and proMMP-1 were present and were expressed similarly in media from 2D versus 3D cultures, whereas active MMPs-1, -9, and -13 were not detected. Active MMP-13 was present in cell lysates (CL) and was increased in lysates from 3D cultures relative to 2D cultures. Relative to 2D cultures, CL and media from 3D cultures exhibited a decrease in expression of TIMP-2 and an increased conversion of proMMP-2 and proMT1-MMP to active or processed forms. The MMP inhibitor GM6001 interfered with the migration of hmECs in 3D cultures, but not in 2D cultures. Addition of active MMP-1 or blocking antibodies to TIMP-1 did not affect the migration of hmECs in 3D collagen. Migration in 3D collagen was decreased by TIMP-2 (an inhibitor of MT1-MMP), but not by TIMP-1 (a poor inhibitor of MT1-MMP, but an efficient inhibitor of MMP-2). Collectively, our data indicate that MT1-MMP contributes significantly to the movement of hmECs through 3D collagen, in contrast to secretory-type MMPs-1, -2, -9, and -13, which are not critical for this movement. J. Cell. Biochem. 86: 748,758, 2002. © 2002 Wiley-Liss, Inc. [source] Evaluation of metalloproteinases 2 and 9 and their inhibitors in physiologic and pre-eclamptic pregnancyJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 2 2009Martina Montagnana Abstract Matrix metalloproteinases (MMPs) are a family of zinc and calcium-dependent endopeptidases involved in remodeling and physiological homeostasis of extracellular matrix (ECM). The metalloproteinases activity is predominantly modulated by specific tissue inhibitors of matrix metalloproteinases (TIMPs). The balance between MMPs and TIMPs is likely to play an important role in remodeling uterine arteries in pregnancy, and it may represent means by which vasodilatation is maintained in later pregnancy. Moreover, increased levels of MMPs and in particular MMP-2 play a role in the vascular alterations induced by hypertension. The aim of this study was the evaluation of MMP-2 and -9, along with their inhibitors TIMP-1 and -2, in pre-eclamptic women compared with normotensive pregnancy and non-pregnant women. Fourteen pre-eclamptic women were compared with 37 normotensive women in different gestational age and 21 non-pregnant women. Multiplexed sandwich enzyme-linked immunosorbent assay was used to measure MMPs and TIMPs simultaneously. MMP-2 levels were significantly higher in pre-eclamptic women vs. both non-pregnant and physiologic pregnant women. MMP-9 concentrations were significantly higher in physiologic pregnant vs. non-pregnant women. The serum levels of TIMP-1 were significantly higher in pre-eclamptic vs. both non-pregnant and physiologic pregnant women. TIMP-2 values were higher in physiologic pregnant women and pre-eclamptic women vs. non-pregnant women. A positive correlation between MMP-9 values and gestational age was observed in normal pregnant women. Results of the present investigation confirm that MMP-2 and TIMP-1 values are significantly higher in preeclampsia. We confirm that the modification of the fine balance between MMPs and their inhibitors plays a greater role in the structural and functional vascular changes of women with complicated pregnancies. J. Clin. Lab. Anal. 23:88,92, 2009. © 2009 Wiley-Liss, Inc. [source] Matrix metalloproteinase-26 is present more frequently in squamous cell carcinomas of immunosuppressed compared with immunocompetent patientsJOURNAL OF CUTANEOUS PATHOLOGY, Issue 9 2009Tiina Kuivanen Background: Skin cancers are the most frequent malignancies in organ transplant recipients (OTRs). Squamous cell carcinomas (SCCs) occur 65,250 times more frequently in OTRs and tend to be aggressive in behavior. Because matrix metalloproteinases (MMPs) have a central role in tumorigenesis and invasion, we investigated the epithelial and stromal MMP and tissue inhibitor of MMP (TIMP) expression profile in SCCs of immunosuppressed (IS) compared with immunocompetent (IC) patients to determine if differences could explain the more aggressive behavior of SCCs in OTRs. Methods: Matched pairs from 20 SCCs of IS and IC patients were studied using immunohistochemistry for MMP-1, MMP-7, MMP-8, MMP-9, MMP-13 and MMP-26 and TIMP-1 and TIMP-3. Results: Among all MMPs studied, only staining for MMP-26 was significantly more intense in cancer cells of the post-transplant group compared with the IC group (p = 0.01), whereas MMP-9 expression was more abundant in stromal macrophages surrounding SCCs of IC patients (p = 0.02). MMP-26 expression in cancer cells (p = 0.04) and that of MMP-9 in neutrophils (p = 0.005) were more abundant in SCCs of patients using cyclosporine. Conclusions: We conclude that MMP-26 and MMP-9 may contribute to the more aggressive behavior of SCCs in OTRs. [source] Expression of MMP-9, MMP-10 and TNF-, and lack of epithelial MMP-1 and MMP-26 characterize pyoderma gangrenosumJOURNAL OF CUTANEOUS PATHOLOGY, Issue 12 2007Ville Bister Background:, Pyoderma gangrenosum (PG) is a non-infectious, autoimmune, chronic ulcer of the skin, often co-existing with inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) have been implicated as mediators of tissue destruction in chronic cutaneous and intestinal wounds. Methods:, Twenty-four skin biopsies with clinically and histologically confirmed PG and acute wounds were immunostained for MMP-1, -7, -8, -9, -10 and -26; tissue inhibitors of matrix metalloproteinase (TIMP)-1 and -3 and tumor necrosis factor-, (TNF-,). Results:, MMP-1 was generally expressed by keratinocytes distal from the wound edge, whereas MMP-10 was detected abundantly in the epithelium. MMP-26 was positive in 42% at the migratory front. Abundant stromal expression was evident for MMP-1, -9 and -10, TIMP-1 and -3 and TNF-,. In acute wounds, stromal MMP-1, -9 and -10 and TNF-, were sparse. Conclusions:, Unlike in normally healing cutaneous wounds, MMP-1 and -26 were detected bordering the wound in only a minority of PGs and their lack may thus retard epithelial repair. Particularly, MMP-9 and -10 and TNF-, would be suitable therapeutic targets as they may contribute to the degradation of provisional matrices needed for migration in healing wounds. The presence of MMP-1, -9, -10 and -26 in both PG and IBD ulcers may suggest a similar pathogenesis for cutaneous and mucosal inflammation. [source] Effect of vitamin E and selenium on the tissue inhibitor of metalloproteinase-1 mRNA expression in hepatic stellate cellsJOURNAL OF DIGESTIVE DISEASES, Issue 3 2001Xuanhai Li OBJECTIVE: To investigate the effects of vitamin E and different doses of selenium on the expression of the tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA in the hepatic stellate cells (HSC) of CCl4 -induced hepato-fibrotic rats. The mechanism of these therapeutic actions is investigated at a molecular level. METHODS: Hepatic fibroses were induced by intraperitoneal injection of 40% CCl4 in olive oil and treated by dietary supplementation with vitamin E and different doses of selenium. Liver tissue sections were stained with routine hematoxylin and eosin staining and Masson trichrome staining for collagen. With ,-actin as an internal control, the reverse transcriptase,polymerase chain reaction (RT-PCR) method was applied to quantify the change of TIMP-1 mRNA in HSC. RESULTS: The expression level of TIMP-1 mRNA in HSC was significantly downregulated and collagenous fiber proliferation in the liver was also significantly reduced in the groups of rats treated with vitamin E (250 mg/kg) and low dosages of selenium (0.2 mg/kg). However, the expression of TIMP-1 mRNA was upregulated, but not significantly, in the group treated with high dosages of selenium (1.0 mg/kg). CONCLUSIONS: The expression level of TIMP-1 mRNA in HSC was significantly downregulated and collagenous fiber proliferation in the liver was significantly reduced in the groups of rats treated with vitamin E and appropriate dosages of selenium. This did not occur in groups with high dosages of selenium. [source] Bcl-2 overexpression in hepatic stellate cell line CFSC-2G, induces a pro-fibrotic stateJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2010Viridiana Y González-Puertos Abstract Background and Aim:, Development of hepatic fibrosis is a complex process that involves oxidative stress (OS) and an altered balance between pro- and anti-apoptotic molecules. Since Bcl-2 overexpression preserves viability against OS, our objective was to address the effect of Bcl-2 overexpression in the hepatic stellate cells (HSC) cell-line CFSC-2G under acetaldehyde and H2O2 challenge, and explore if it protects these cells against OS, induces replicative senescence and/or modify extracellular matrix (ECM) remodeling potential. Methods:, To induce Bcl-2 overexpression, HSC cell line CFSC-2G was transfected by lipofection technique. Green fluorescent protein-only CFSC-2G cells were used as a control. Cell survival after H2O2 treatment and total protein oxidation were assessed. To determine cell cycle arrest, proliferation-rate, DNA synthesis and senescence were assessed. Matrix metalloproteinases (MMP), tissue-inhibitor of MMP (TIMP), transglutaminases (TG) and smooth muscle a-actin (,-SMA) were evaluated by western blot in response to acetaldehyde treatment as markers of ECM remodeling capacity in addition to transforming growth factor-, (TGF-,) mRNA. Results:, Cells overexpressing Bcl-2 survived , 20% more than control cells when exposed to H2O2 and , 35% proteins were protected from oxidation, but Bcl-2 did not slow proliferation or induced senescence. Bcl-2 overexpression did not change ,-SMA levels, but it increased TIMP-1 (55%), tissue transglutaminases (tTG) (25%) and TGF-, mRNA (49%), when exposed to acetaldehyde, while MMP-13 content decreased (47%). Conclusions:, Bcl-2 overexpression protected HSC against oxidative stress but it did not induce replicative senescence. It increased TIMP-1, tTG and TGF-, mRNA levels and decreased MMP-13 content, suggesting that Bcl-2 overexpression may play a key role in the progression of fibrosis in chronic liver diseases. [source] Polaprezinc attenuates liver fibrosis in a mouse model of non-alcoholic steatohepatitisJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2008Haruko Sugino Abstract Background and Aim:, The effect of polaprezinc, a zinc-carnosine chelate compound, on the development of non-alcoholic steatohepatitis (NASH) was investigated in dietary methionine and choline deficient (MCD) mice. Methods:, Mice were fed the MCD diet with or without polaprezinc (2.2 g/kg diet) for 10 weeks. Liver histopathology, triglyceride and lipid peroxide levels, and the expression of genes linked to fibrosis were then assessed. Results:, MCD mice developed steatohepatitis accompanied by mild fibrosis with an increase in lipid peroxidation, hepatic stellate cell (HSC) activation, and the augmented mRNA expression of tumor necrosis factor-,, transforming growth factor-,1 and procollagen ,1(I). The mRNA expression levels of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 were also enhanced. Histopathologically, polaprezinc supplementation did not influence the development of steatosis but it apparently attenuated fibrosis. Polaprezinc slightly reduced lipid peroxidation and suppressed HSC activation as well as the mRNA expression of pro-inflammatory cytokines. Polaprezinc affected the MCD diet-enhanced expression of TIMP-1 even when administered relatively late. Conclusion:, These results suggest that polaprezinc attenuates fibrosis in NASH by reducing inflammation and lipid peroxidation and, during a later phase, promoting fibrolysis via the inhibition of TIMP expression in the liver. Further investigation is required to clarify the clinical efficacy of polaprezinc in patients with NASH. [source] A strong note of caution in using matrix metalloproteinase-1 and its inhibitor, TIMP-1 in serum as biomarkers in systolic heart failureJOURNAL OF INTERNAL MEDICINE, Issue 3 2008K Jung No abstract is available for this article. [source] Matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in the respiratory tracts of human infants following paramyxovirus infectionJOURNAL OF MEDICAL VIROLOGY, Issue 4 2007Matthew B. Elliott Abstract Respiratory syncytial (RSV) and parainfluenza (PIV) viruses are primary causes of acute bronchiolitis and wheezing illnesses in infants and young children. To further understand inflammation in the airways following infection, we tested for the presence of matrix metalloproteinases (MMP) and natural tissue inhibitors of MMP (TIMP) in primary and established human cell lines, and in the nasopharyngeal secretions (NPS) of human infants infected with RSV or PIV. Using ELISA and multiplex-based assays, MMP-9 and TIMP-1 proteins were, respectively, detected in 66/67 and 67/67 NPS. During PIV or RSV infection TIMP-1 concentrations were associated with hypoxic bronchiolitis. TIMP-1 amounts were also negatively correlated with O2 saturation, and positively correlated with IL-6, MIP-1,, and G-CSF amounts following RSV infection. IL-6, MIP-1,, and G-CSF were negatively correlated with O2 saturation during RSV infection. Acute respiratory tract disease was not associated with MMP-9 protein/protease activity. Additional studies using real-time quantitative PCR suggested that MMP-9 mRNA copy numbers were elevated in normal human bronchial epithelial (NHBE) cells infected with RSV, while TIMP-1 and TIMP-2 were not increased. However, ELISA did not reveal MMP-9 protein in the NHBE cell culture supernatants. Hence, the data implied that airway epithelial cells were not the primary source of MMP or TIMP following paramyxovirus infection. Taken together, the data suggested that paramyxovirus infection perturbs MMP-9/TIMP-1 homeostasis that in turn may contribute to the severity of respiratory tract disease. J. Med. Virol. 79:447,456, 2007. © 2007 Wiley-Liss, Inc. [source] Retinal pigment epithelial cells promote spatial reorganization and differentiation of retina photoreceptorsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 16 2008Olga L. German Abstract Retina differentiation involves the acquisition of a precise layered arrangement, with RPE cells in the first layer in intimate contact with photoreceptors in the second layer. Here, we developed an in vitro coculture model, to test the hypothesis that RPE cells play a pivotal role in organizing the spatial structure of the retina. We cocultured rat retinal neurons with ARPE-19 epithelial cells under various experimental conditions. Strikingly, when seeded over RPE cells, photoreceptors attached to their apical surfaces and proceeded with their development, including the increased synthesis of rhodopsin. Conversely, when we seeded RPE cells over neurons, the RPE cells rapidly detached photoreceptors from their substrata and positioned themselves underneath, thus restoring the normal in vivo arrangement. Treatment with the metalloproteinase inhibitor TIMP-1 blocked this reorganization, suggesting the involvement of metalloproteinases in this process. Reorganization was highly selective for photoreceptors because 98% of photoreceptors but very few amacrine neurons were found to redistribute on top of RPE cells. Interestingly, RPE cells were much more efficient than other epithelial or nonepithelial cells in promoting this reorganization. RPE cells also promoted the growth of photoreceptor axons away from them. An additional factor that contributed to the distal arrangement of photoreceptor axons was the migration of photoreceptor cell bodies along their own neurites toward the RPE cells. Our results demonstrate that RPE and photoreceptor cells interact in vitro in very specific ways. They also show that in vitro studies may provide important insights into the process of pattern formation in the retina. © 2008 Wiley-Liss, Inc. [source] Novel role of TGF-, in differential astrocyte-TIMP-1 regulation: Implications for HIV-1-dementia and neuroinflammationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 7 2006Alok Dhar Abstract Astrocyte production of tissue inhibitor of metalloproteinase (TIMP)-1 is important in central nervous system (CNS) homeostasis and inflammatory diseases such as HIV-1-associated dementia (HAD). TIMPs and matrix metalloproteinases (MMPs) regulate the remodeling of the extracellular matrix. An imbalance between TIMPs and MMPs is associated with many pathologic conditions. Our recently published studies uniquely demonstrate that HAD patients have reduced levels of TIMP-1 in the brain. Astrocyte-TIMP-1 expression is differentially regulated in acute and chronic inflammatory conditions. In this and the adjoining report (Gardner et al., 2006), we investigate the mechanisms that may be involved in differential TIMP-1 regulation. One mechanism for TIMP-1 downregulation is the production of anti-inflammatory molecules, which can activate signaling pathways during chronic inflammation. We investigated the contribution of transforming growth factor (TGF)-signaling in astrocyte-MMP/TIMP-1-astrocyte regulation. TGF-,1 and ,2 levels were upregulated in HAD brain tissues. Co-stimulation of astrocytes with IL-1, and TGF-, mimicked the TIMP-1 downregulation observed with IL-1, chronic activation. Measurement of astrocyte-MMP protein levels showed that TGF-, combined with IL-1, increased MMP-2 and decreased proMMP-1 expression compared to IL-1, alone. We propose that one of the mechanisms involved in TIMP-1 downregulation may be through TGF-signaling in chronic immune activation. These studies show a novel extracellular regulatory loop in astrocyte-TIMP-1 regulation. © 2006 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||||||||