Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An imbalance in the matrix metalloproteinase (MMP) : tissue inhibitor of MMP (TIMP) ratio may be associated with tissue injury. Here, we studied the regulation of TIMP and MMP gene expression in primary glial cultures to ascertain the factors involved in the regulation of these genes in conditions of inflammatory neuropathology. Astrocytes were found to basally express TIMP-1 and TIMP-3 mRNA while microglia expressed only TIMP-2 mRNA. TIMP-4 mRNA was not detectable in either cell type. Treatment with interferon-alpha (IFN-alpha), IFN-gamma, interleukin-3 (IL-3), IL-6 or tumor necrosis factor-alpha (TNF-alpha) did not alter expression of the TIMP genes. However, in astrocytes, but not in microglia, serum, IL-1beta or lipopolysaccharide (LPS) evoked a dose- and time-dependent increase in TIMP-1 mRNA and a coincident down-regulation of the TIMP-3 gene. Astrocytes were found to express mRNA constitutively for MMPs -3, -11 and -14. In contrast, microglia expressed only MMP-12 mRNA under basal conditions. IL-1beta enhanced MMP-3 mRNA levels while LPS increased the MMP-3, -9, -12, -13 and -14 mRNAs. Our findings reveal that regulatory control of TIMP and MMP gene expression by glial cells is agonist- and cell-type specific, and suggest that innate immune signals govern the temporal and spatial expression patterns of TIMP and MMP genes in neuroinflammatory conditions of the CNS.
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PMID:Cell and agonist-specific regulation of genes for matrix metalloproteinases and their tissue inhibitors by primary glial cells. 1689 21

To investigate the mechanism of antirheumatic action of mizoribine (MZR), we examined the expression of matrix metalloproteinase-1 (MMP-1) and MMP-3 utilizing THP-1 derived macrophage-like cells (THP-1 macrophages) and human synovial fibroblasts (SFs). The cells were respectively stimulated with lipopolysaccharide (LPS) and interleukin-1beta in the presence or absence of MZR in vitro. The concentrations of MMP-1 and MMP-3 in the supernatant were measured by enzyme-linked immunosorbent assay. The secretion of MMP-1 from SFs, as well as THP-1 macrophages, was inhibited by MZR in a dose-dependent manner. Furthermore, a quantitative real-time polymerase chain reaction revealed that MZR decreased the expression of MMP-1 messenger RNA. These findings may be an explanation for the clinical effect of MZR in patients with rheumatoid arthritis.
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PMID:Inhibitory effect of mizoribine on matrix metalloproteinase-1 production in synovial fibroblasts and THP-1 macrophages. 1702 75

Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine that controls the initiation and progression of inflammatory diseases such as rheumatoid arthritis. Tpl2 is a MAPKKK in the MAPK (i.e. ERK) pathway, and the Tpl2-MEK-ERK signaling pathway is activated by the pro-inflammatory mediators TNFalpha, interleukin (IL)-1beta, and bacterial endotoxin (lipopolysaccharide (LPS)). Moreover, Tpl2 is required for TNFalpha expression. Thus, pharmacologic inhibition of Tpl2 should be a valid approach to therapeutic intervention in the pathogenesis of rheumatoid arthritis and other inflammatory diseases in humans. We have developed a series of highly selective and potent Tpl2 inhibitors, and in the present study we have used these inhibitors to demonstrate that the catalytic activity of Tpl2 is required for the LPS-induced activation of MEK and ERK in primary human monocytes. These inhibitors selectively target Tpl2 in these cells, and they block LPS- and IL-1beta-induced TNFalpha production in both primary human monocytes and human blood. In rheumatoid arthritis fibroblast-like synoviocytes these inhibitors block ERK activation, cyclooxygenase-2 expression, and the production of IL-6, IL-8, and prostaglandin E(2), and the matrix metalloproteinases MMP-1 and MMP-3. Taken together, our results show that inhibition of Tpl2 in primary human cell types can decrease the production of TNFalpha and other pro-inflammatory mediators during inflammatory events, and they further support the notion that Tpl2 is an appropriate therapeutic target for rheumatoid arthritis and other human inflammatory diseases.
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PMID:Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood. 1784 81

Many brain cells secrete MMPs (matrix metalloproteinases), and increased or misregulated MMP levels are found in neurodegenerative disorders. Here we report that MMP-3 transcription and protein secretion were increased in rat brain astrocytes stimulated with lipopolysaccharide, gangliosides or interferon-gamma. Sequential deletion of the MMP-3 promoter revealed that sequences between -0.5 kb and the start codon were crucial for the transcriptional induction of MMP-3. In addition, experiments using pharmacological inhibitors of individual mitogen-activated protein kinases revealed that MMP-3 induction and promoter activity involved Jun N-terminal kinase, a representative upstream signal of AP-1 (activator protein-1). Sequence analyses of the region of the MMP-3 promoter 500 bp from the start codon indicated the presence of three AP-1 binding sequences. Among them, electrophoretic-mobility-shift assays as well as site-directed mutagenesis of individual AP-1 sequences revealed that distal and middle, but not proximal, sequences largely mediated its induction. Together, these results indicate that AP-1 could control MMP-3 induction in brain astrocytes and that its regulation through specific AP-1 elements could be exploited in the treatment of brain pathologies in which increased expression of MMP-3 plays crucial roles.
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PMID:Matrix metalloproteinase-3 induction in rat brain astrocytes: focus on the role of two AP-1 elements. 1807 34

Recently, matrix metalloproteinases (MMPs) are emerging as important molecules in neuroinflammation as well as neuronal cell death. However, the role of MMPs in activated microglia remains unclear. In the present study, we found that expressions of MMP-1, -3, -8 and -9 were significantly induced by single or combined treatment of immunostimulants lipopolysaccharide (LPS) or phorbol myristate acetate (PMA) in primary cultured microglia and BV2 microglial cells. Inhibition of MMP-3 or -9 significantly suppressed the expression of iNOS and pro-inflammatory cytokines and the activities of NF-kappaB, AP-1, and MAPK in LPS-stimulated microglia. The results suggest that MMP-3 and -9 both mediate LPS-induced inflammatory reactions. Inhibition of reactive oxygen species (ROS) by N-acetyl-cysteine or diphenylene iodonium significantly suppressed the expression of MMP-3, MMP-9, NO and TNF-alpha in LPS-stimulated microglia, suggesting that ROS is an early signaling inducer in LPS-stimulated microglial cells. MMP inhibitors also suppressed ROS production, suggesting a cross-talk between ROS and MMPs. Collectively, the present study demonstrates that MMP-3 and MMP-9 play a role as inflammatory mediators in activated microglia. Pharmacological intervention of MMPs especially MMP-3 and -9 would be a therapeutic strategy for the treatment of inflammatory diseases in the CNS caused by over-activation of microglial cells.
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PMID:Inhibition of MMP-3 or -9 suppresses lipopolysaccharide-induced expression of proinflammatory cytokines and iNOS in microglia. 1841 63

Increased matrix metalloproteinase (MMP) proteolytic activity contributes to the pathogenesis of many neuroinflammatory and neurodegenerative conditions in the CNS. To fully understand this process, it is important to define the MMP expression profile of specific cell types, including the CNS-resident cells astrocytes and microglia. While previous studies have characterized astrocyte MMP expression by using mixed glial cultures, these results are likely complicated by the presence of contaminating microglia within these cultures. In the current study, we sought to clarify this complexity, by taking a novel approach to prepare pure astrocyte cultures entirely devoid of microglia, by promoting neural stem cell (NSC) differentiation into astrocytes. The MMP expression profile of mixed glial cultures, neurosphere-derived astrocytes, and pure microglia was characterized by RNase protection assay. This revealed that MMP gene expression is largely cell-type specific. Astrocytes constitutively expressed MMP-11, MMP-14, and MMP-2 and showed induction of MMP-3 in response to IL-1beta but did not respond to lipopolysaccharide (LPS). In contrast, microglia constitutively expressed high levels of MMP-12 and showed strong induction of MMP-9 and MMP-14 in response to LPS. Gelatin zymography confirmed that LPS and TNF-alpha induced strong expression of MMP-9 in microglia but not astrocytes. In summary, these studies demonstrate that neurosphere-derived astrocytes represent an attractive alternative system in which to study astrocyte behavior in vitro. Using this system, we have shown that astrocytes and microglia express distinct sets of MMP genes and that microglia, not astrocytes, are the major source of MMP-9 in response to LPS or TNF-alpha.
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PMID:A novel method to establish microglia-free astrocyte cultures: comparison of matrix metalloproteinase expression profiles in pure cultures of astrocytes and microglia. 1844 43

The purpose of this study was to investigate the role of muscarinic acetylcholine receptor (mAChR) activity in the regulation of inducible nitric oxide synthase (iNOS) activity, prostaglandin E(2) (PGE(2)), and metalloproteinase-3 (MMP-3) in experimentally induced inflammation of rat incisors dental pulp. Inflammation was induced by application of bacterial lipopolysaccharide (LPS) to the pulp. Extirpated pulp tissue samples were incubated in saline solution until the various experiments were performed. Saline-treated pulp and healthy pulp were used as controls. NOS activity was measured by the production of [U-(14)C]-citrulline from [U-(14)C]-arginine. PGE(2) and MMP-3 production were evaluated by an enzyme-linked immunosorbent assay (ELISA) and cyclooxygenase (cox-1 and cox-2) messenger RNA levels were measured using a reverse-transcriptase polymerase chain reaction by coamplification of target complementary DNA with a single set of primers. The application of LPS to the pulp increased NOS activity, PGE(2), and MMP-3 production associated with iNOS overactivity. Moreover, PGE(2) and MMP-3 production were the result of cox-2 expression. Pilocarpine (5 x 10(-11) mol/L to 5 x 10(-9) mol/L), acting on mAChRs, triggered a negative effect on NOS activity, PGE(2), and MMP-3 production. In control pulp, no action of pilocarpine was observed. Pulpitis changed mAChR conformation, increasing its coupling efficiency to transducing molecules that in turn activate iNOS. The capacity of pilocarpine to prevent iNOS activity, PGE(2), and MMP-3 by acting on mAChR mutation induced by pulpitis might be useful therapeutically as a local treatment.
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PMID:Cholinoceptor modulation on nitric oxide regulates prostaglandin E(2) and metalloproteinase-3 production in experimentally induced inflammation of rat dental pulp. 1934 99

In Parkinson disease (PD), the dopaminergic (DAergic) neurons in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is still not completely understood, neuronal apoptosis and inflammation are thought to play roles. We have recently obtained evidence that matrix metalloproteinase (MMP)-3 plays a crucial role in the apoptotic signal in DAergic cells as well as activation of microglia. The present study tested whether doxycycline might modulate MMP-3 and provide neuroprotection of DAergic neurons. Doxycycline effectively suppressed the expression of MMP-3 induced in response to cellular stress in the DAergic CATH.a cells. This was accompanied by protection of CATH.a cells as well as primary cultured mesencephalic DAergic neurons via attenuation of apoptosis. The active form of MMP-3, released under the cell stress condition, was also decreased in the presence of doxycycline. In addition, doxycycline led to downregulation of MMP-3 in microglial BV-2 cells exposed to lipopolysaccharide (LPS). This was accompanied by suppression of production of nitric oxide and TNF-alpha, as well as gene expression of iNOS, TNF-alpha, IL-1beta, and COX-2. In vivo, doxycycline provided neuroprotection of the nigral DAergic neurons following MPTP treatment, as assessed by tyrosine hydroxylase immunocytochemistry and silver staining, and suppressed microglial activation and astrogliosis as assessed by Iba-1 and GFAP immunochemistry, respectively. Taken together, doxycycline showed neuroprotective effect on DAergic system both in vitro and in vivo and this appeared to derive from anti-apoptotic and anti-inflammatory mechanisms involving downregulation of MMP-3.
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PMID:Doxycycline is neuroprotective against nigral dopaminergic degeneration by a dual mechanism involving MMP-3. 1958 34

In multiple sclerosis (MS) matrix metalloproteinases (MMP) are believed to be involved in the disruption of the blood brain barrier and demyelination. MMP-9 is increased in the cerebrospinal fluid of MS patients and expressed in MS lesions, indicating an involvement in MS pathogenesis. It is known that activated microglia secrete MMP. Modulation of MMP may thus be of interest for treatment in particular since MMP knock-out mice are less susceptible to experimental allergic encephalomyelitis. In this study we show that intact polyclonal immunoglobulins for intravenous use (IVIg) lead to increased secretion of MMP-9 in unstimulated microglia whereas F(ab')(2) fragments or stimulation with lipopolysaccharide (LPS) had no effect on MMP production at all. We could not detect MMP-2, MMP-3, MMP-7, MMP-10, MMP-11, and MMP-12 by RT-PCR with and without stimulation with LPS. IVIg differentially modulate MMP-9 production in resting and activated microglia suggesting an activation-dependent immune response.
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PMID:Polyclonal immunoglobulins (IVIg) induce expression of MMP-9 in microglia. 1983 95

Cyclooxygenases (COX) -1 and -2 are key regulators of innate immune responses. We recently demonstrated that the expression of proinflammatory cytokines and chemokines is reduced in COX-1 null ((-/-)), and increased in COX-2(-/-) mice compared with their respective wild type controls during lipopolysaccharide (LPS)-induced innate immune activation. As chemokines are involved in leukocyte recruitment into the inflamed brain, we hypothesized that COX-1 and COX-2 deletion will differentially modulate blood-brain barrier (BBB) permeability in response to LPS. In the present study, using quantitative magnetic resonance imaging, we found that LPS-induced BBB disruption was exacerbated in COX-2(-/-) versus COX-2(+/+) mice. In the hippocampus and cortex of LPS-treated mice, matrix metalloproteinase (MMP)-3 activity was significantly decreased in COX-1(-/-) mice, whereas in COX-2(-/-) mice the activity of both MMP-9 and MMP-3, known to mediate BBB breakdown, was increased. Brain mRNA expression of the leukocyte attracting chemokine Cxcl10, the intercellular interaction molecule Icam-1, the pan-leukocyte marker Cd45 was increased in COX-2(-/-) versus COX-2(+/+) mice, whereas Cxcl10 and Cd45 mRNA expression was decreased in COX-1(-/-) versus COX-1(+/+) mice after LPS. Altogether, these results indicate that COX-2 activity modulates MMP-9 and-3 activities and is necessary to maintain BBB integrity during toll-like receptor 4-dependent innate immune activation.
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PMID:Cyclooxygenase-1 and -2 differentially modulate lipopolysaccharide-induced blood-brain barrier disruption through matrix metalloproteinase activity. 1984 42


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