Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the anti-TNF alpha based progress in the treatment of RA, it is necessary to further optimize study designs and reports (Etanercept/MTX combination with results of radiological progression; publication of D2E7 trials; combination of D2E7 with MTX). Moreover, innovative immunobiologicals (PEG-TNFRI, PEG-TNF alpha antibody fragments, soluble TNFRI, CTLA4-Ig, CD40 ligand antibody, antibodies against IFN-gamma, IL-6, IL-12, IL-15, IL-18, complements), inhibitors of TNF alpha translation (peptides, anti-sense constructs) or TNF alpha synthesis (targeting NF kappa B, p38 MAP-kinase, phosphodiesterase IV, TNF alpha converting enzyme) are forthcoming. Principally different are inhibitors of complement convertases or collagenase as well as vaccination studies or trials trying to induce T cell anergy. Furthermore, for patients with MTX side effects, alternative DMARDs need to be tested along with TNF alpha blockers. Combination studies of TNF alpha constructs with other immunobiologicals (anti-CD4, IL-4, IL-10, IL-1RA) should be evaluated. To date, TNF alpha blockers have been evaluated in very early RA. Finally, a step-down trial will test whether--after induction of remission with a TNF alpha blocker plus MTX--replacement of the TNF alpha blocker with MTX alone or in combination with leflunomide will be able to keep disease activity suppressed for a longer duration.
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PMID:[New therapy developments in rheumatoid arthritis]. 1175 32

Although considerable evidence implicates the cytokine interferon (IFN)-gamma in atherogenesis, the proximal inducers and the range of sources of its expression remain unknown. This study tested the hypothesis that interleukin (IL)-18 regulates IFN-gamma expression during atherogenesis. Indeed, human atheroma in situ expressed IL-18 and elevated levels of its receptor subunits, IL-18Ralpha/beta, compared with nondiseased arterial tissue. IL-18 occurred predominantly as the mature, 18-kD form and colocalized with mononuclear phagocytes (MPhi), while endothelial cells (ECs), smooth muscle cells (SMCs), and MPhi all expressed IL-18Ralpha/beta. Correspondingly in vitro, only MPhi expressed IL-18, while all three cell types displayed the IL-18Ralpha/beta complex constitutively, exhibiting enhanced expression upon stimulation with LPS, IL-1beta, or tumor necrosis factor (TNF)-alpha. IL-18 signaling evoked effectors involved in atherogenesis, e.g., cytokines (IL-6), chemokines (IL-8), intracellular adhesion molecules (ICAM)-1, and matrix metalloproteinases (MMP-1/-9/-13), demonstrating functionality of the receptor on ECs, SMCs, and MPhi. Finally, IL-18, particularly in combination with IL-12, induced the expression of IFN-gamma in cultured MPhi and, surprisingly, in SMCs (but not in ECs). The expression of functional IL-18 and IL-18 receptor on human atheroma-associated ECs, SMCs, and MPhi, and its unexpected ability to induce IFN-gamma expression in SMCs, suggests a novel paracrine proinflammatory pathway operating during atherogenesis.
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PMID:Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. 1180 51

Immortalized hepatocytes are an attractive cell source for hepatocyte transplantation and gene transfer. We compared the phenotype and immunogenicity of freshly isolated (FIH) and immortalized (IMH) rat hepatocytes. Effect of culture and proinflammatory cytokines (TNF-alpha, IFN-gamma) was studied on phenotype. FIH were isolated by collagenase digestion. Two SV40 immortalized hepatocyte cell lines were tested (RH1 and P9). Immunophenotyping was performed by FACS analysis using anti-rat-specific antibodies. Immunogenicity was evaluated by a mixed lymphocyte hepatocyte reaction (MLHR). FIH suspension was an almost homogeneous parenchymal cell population with few (1-2%) CD8+ cells. FIH showed a positive staining for ICAM-1 (20-35%) and for Class I (RT1A, 30-60%) but no staining for Class II (RT1B). After 48 h of culture, the already ICAM-1-positive cells were more strongly stained and additionally 3.6% of the cells (possibly endothelial cells) were Class II positive. IMH showed a consistent expression of Class I (93-97%) and ICAM-1 (95-97%) but no expression of Class II. Culture of IMH for 48 h had no effect on Class II expression but increased ICAM-1 expression. Addition of TNF-alpha at 1000 UI/ml to cultures of FIH or IMH increased Class I and ICAM-1 expression whereas IFN-gamma (50 or 1000 UI/ml) had no evident effect. Hepatocyte immunogenicity, assessed in MLHR and appreciated by the stimulation index (SI) test/SI syngeneic control, was similar for IMH (RH1: 2.68+/-0.89; P9: 2.37+/-0.78) and FIH (2.52+/-0.18). In conclusion, despite some quantitative immunophenotypic differences, FIH and IMH induced the same proliferation rate of allogeneic T lymphocytes. Thus, immortalized hepatocytes may constitute an appropriate cellular model to study the prevention of hepatocyte rejection by gene transfer.
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PMID:Comparative phenotype and immunogenicity of freshly isolated and immortalized rat hepatocytes. 1181 17

Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN-gamma-inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells revealed distinct profiles of expression of these molecules in the different cell subsets. Our results provide insights into the molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell migration, such as anti-VLA-4 Abs, may impact on B cell trafficking.
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PMID:Determinants of human B cell migration across brain endothelial cells. 1270 26

Elevated cytokines, especially TNF-alpha, have been implicated in the pathogenesis of necrotising enterocolitis (NEC). We have previously shown that TNF-alpha drives the production of matrix degrading enzymes, the matrix metalloproteinases (MMPs), in the gut wall. In this study we have therefore investigated the role of MMPs in the pathogenesis of NEC in neonates. Nine newborn infant nonnecrotic resected bowels with confirmed NEC were studied and 8 newborn infants with neonatal bowel obstructions were used as controls. Immunostaining was used to identify the numbers of monocytes, macrophages, neutrophils, and T cells in the tissue. We used quantitative, competitive RT-PCR to analyze the number of TNF-alpha, IFN-gamma, MMP, and TIMP mRNA transcripts and western blotting to analyze MMP and TIMP protein production. Double labeling (immunostaining and in situ hybridization) was used to identify the phenotype of MMP mRNA expressing cells. We found increased numbers of monocytes, macrophages, and neutrophils in NEC tissue compared with controls. The number of T cells was unexpectedly low in NEC as was the number of IFN-gamma transcripts in comparison with the control samples. Increased numbers of transcripts for TNF-alpha were detected in NEC tissue, as was mRNA expression and protein production for stromelysin-1 and TIMP-1 but not collagenase, gelatinases, or TIMP-2. The cellular source of stromelysin-1 in NEC was alpha-smooth muscle actin positive cells. These results suggest that stromelysin-1, which has the ability to degrade the mucosal extra-cellular matrix, may be responsible for the extensive tissue injury in infants with NEC.
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PMID:Matrix metalloproteinases in necrotising enterocolitis. 1273 98

The majority of HIV-1 infections occur via sexual transmission at mucosal epithelia lining the vagina, cervix or rectum. Mucosal tissues also serve as viral reservoirs. However, our knowledge of human mucosal T-cell responses is limited. There is a need for reliable, sensitive, and reproducible methods for assessing mucosal immunity. Here we report on the collaborative efforts of two laboratories to optimize methods for processing, culturing, and analyzing mucosal lymphocytes. Rectal biopsy tissue was obtained by flexible sigmoidoscopy, which is rapid, minimally invasive, and well tolerated. Of the four methods compared for isolating mucosal mononuclear cells (MMC), collagenase digestion reproducibly yielded the most lymphocytes (4-7 x 10(6)). Furthermore, 0.5-1 x 10(6) MMC could be polyclonally expanded to yield 17 x 10(6) CD8+ T cells allowing mapping of responses to overlapping peptides spanning the HIV-1 genome using IFN-gamma enzyme-linked immunospot (ELISpot). Expansion also reduced the spontaneous IFN-gamma production normally detected in fresh MMC. Piperacillin-tazobactam and amphotericin B reduced contamination of MMC cultures to 4%. Taken together, these methods will be useful for studies of mucosal immunity to HIV-1 and other pathogens during natural infection and following vaccination.
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PMID:Optimization of methods to assess human mucosal T-cell responses to HIV infection. 1296 44

IL-12 is key cytokine in innate immunity and participates in tumor rejection by stimulating an IFN-gamma-mediated response characterized by CD8(+) mediated-cytotoxicity, inhibition of angiogenesis, and vascular injury. We previously demonstrated that activated lymphocytes stimulated with IL-12 induced an angiostatic program in cocultured vascular endothelial cells. In this study, we have extended this observation showing that a reciprocal modulation of cellular responses occurs. Actually, the presence of endothelial cells enhanced the inhibitory effect of IL-12 on metalloproteinase-9 expression in activated PBMC as well as their ability to transmigrate across an extracellular matrix. IL-12 triggered intracellular signaling, as indicated by STAT-1 activation, appeared to mainly operative in activated CD4 (+) cells challenged with IL-12, but it was also initiated in CD8(+) lymphocytes in the presence of endothelial cells. On the other hand, stimulated PBMC reduced the expression and the activity of metalloproteinase-9, up-regulated that of tissue inhibitor metalloproteinase-1, and stimulated the STAT-1 pathway in cocultured endothelial cells. We used neutralizing Abs to show that the IFN-inducible protein 10 (CXCL10) and monokine-induced by IFN-gamma (CXCL9) chemokines produced by both PBMC and endothelial cells are pivotal in inducing these effects. Altogether these results suggest the existence of an IL-12-regulated circuit between endothelium and lymphocytes resulting in a shift of proteolytic homeostasis at site of tissue injury.
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PMID:IL-12 regulates an endothelial cell-lymphocyte network: effect on metalloproteinase-9 production. 1450 Jun 72

Inflamed synovium of rheumatoid arthritis (RA) has been associated with a T helper (Th)1 cytokine profile but the blood situation remains to be clarified. We studied the differential IFN-gamma producing activity of peripheral blood mononuclear cells (PBMCs) from RA patients (RA-PBMCs) and from healthy controls (H-PBMCs) in response to IL-12 and IL-18. RA-PBMCs had a decreased IFN-gamma production in response to IL-12 and IL-18 when compared with H-PBMCs. RA-PBMCs activated with phytohemagglutinin and phorbol 12-myristate 13-acetate showed an increased sensitivity to IL-12 and IL-18, but still the RA-PBMC response was lower. IL-18 increased IL-12-stimulated IFN-gamma production from RA synovium cells obtained after collagenase digestion more effectively than that of RA- or H-PBMCs. A specific inhibitor of IL-18 bioactivity, IL-18-binding protein (IL-18BP), down-regulated IL-12-induced IFN-gamma production by RA- or H-PBMCs and had a remarkable effect on RA synovium cells. In conclusion, RA disease combines a polarized immune response with an active Th1 in inflamed joints and a reduced Th1 pattern in peripheral circulation.
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PMID:Decreased response to IL-12 and IL-18 of peripheral blood cells in rheumatoid arthritis. 1497 36

A reproducible and original method for the preparation of chicken intestine epithelial cells from 18-day-old embryos for long-term culture was obtained by using a mechanical isolation procedure, as opposed to previous isolation methods using relatively high concentrations of trypsin, collagenase, or EDTA. Chicken intestine epithelial cells typically expressed keratin and chicken E-cadherin, in contrast to chicken embryo fibroblasts, and they increased cell surface MHC II after activation with crude IFN-gamma containing supernatants, obtained from chicken spleen cells stimulated with concanavalin A or transformed by reticuloendotheliosis virus. Eimeria tenella was shown to be able to develop until the schizont stage after 46 hr of culture in these chicken intestinal epithelial cells, but it was not able to develop further. However, activation with IFN-gamma containing supernatants resulted in strong inhibition of parasite replication, as shown by incorporation of [3H]uracil. Thus, chicken enterocytes, which are the specific target of Eimeria development in vivo, could be considered as potential local effector cells involved in the protective response against this parasite.
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PMID:Chicken primary enterocytes: inhibition of Eimeria tenella replication after activation with crude interferon-gamma supernatants. 1552 84

Matrix metalloproteinases (MMPs) are a family of endopeptidases playing a key role in tissue remodelling in both physiological and pathological conditions. Since little information is available about their role in celiac disease (CD), our aims were to quantify their expression/activity and to investigate their relation to proinflammatory cytokines in this condition. Duodenal biopsies from untreated, treated celiac patients and controls were used to quantify the expression of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, MMP-14, their inhibitor TIMP-1, IFN-gamma and TNF-alpha by using real-time reverse transcription-polymerase chain reaction and the gelatin/casein/elastin activities by gel zymography, and to isolate lamina propria mononuclear cells (LPMCs). These cells and myofibroblasts isolated from jejunal specimens were incubated in the absence or presence of IFN-gamma and TNF-alpha. MMP-1 and MMP-12 mRNA levels were significantly increased in active CD compared to treated (P<0.01 and P<0.0005, respectively) and normal mucosa (P<0.01 and P<0.0005, respectively), and this was paralleled by an upregulation of caseinolytic and elastolytic activities. Furthermore, MMP-12 levels significantly (P<0.05) correlated with those of IFN-gamma and the degree of villous flattening. MMP-2 turned out to be significantly (P<0.05) reduced in untreated and treated celiacs compared to controls. In active CD, transcripts of TIMP-1 were higher than in treated and controls (P<0.005 and P<0.05, respectively), such as those of IFN-gamma (P<0.05), whereas TNF-alpha levels were suppressed (P=0.0001). In physiological condition, myofibroblasts represent the main source of MMP-2, whereas LPMCs produce almost all MMPs only after cytokine stimulation. Conversely, cells isolated from active patients constitutively express MMPs without any increase after cytokine stimulation, while those from treated patients are in a resting condition. In conclusion, our results show the presence of a peculiar MMP pattern in active CD strongly dominated by MMP-12, correlating either with IFN-gamma or the degree of mucosal damage.
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PMID:Matrix metalloproteinase pattern in celiac duodenal mucosa. 1560 60


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