Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systems for in vitro culture of Hepatitis C virus (HCV) are essential tools to analyse virus-cell interactions and to investigate relevant pathophysiological aspects of HCV infection. Although the HCV replicon methodology has increased our understanding of HCV biology, this system does not reproduce the natural infection. Recently, tupaia (Tupaia belangeri chinensis) hepatocytes have been utilized for in vitro culture of HCV. In the present work, primary tupaia hepatocytes infected in vitro with HCV were used to analyse the evolution of HCV quasispecies in infected cells and the ability of the virus to influence antiviral and proinflammatory responses in cells sustaining virus replication. The results confirmed the potential of tupaia hepatocytes as a model for HCV infection, although this system is limited by rapid loss of differentiated cell phenotype in culture. These findings revealed an extraordinary plasticity of HCV quasispecies, which underwent rapid evolution to tupaia-tropic variants as early as 24 h after infection. It was also shown that HCV could activate interferon-sensitive genes, albeit modestly in comparison with other viruses such as Semliki Forest virus. Importantly, HCV activated NF-kappaB in primary hepatocytes and upregulated NF-kappaB-responsive genes including the chemokines MCP-1 and CXCL2 (MIP-2). This effect may play a role in induction of the hepatic inflammatory reaction in vivo. In summary, HCV quasispecies adapt rapidly to the specific biology of the host and HCV stimulates a blunted interferon response while inducing a proinflammatory phenotype in the infected cell.
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PMID:Hepatitis C virus infection of primary tupaia hepatocytes leads to selection of quasispecies variants, induction of interferon-stimulated genes and NF-kappaB nuclear translocation. 1622 29

Recognition of Staphylococcus aureus and its cell-wall component peptidoglycan (PGN) by microglia is mediated, in part, by Toll-like receptor 2 (TLR2). However, the pattern recognition receptor (PRR) CD14 can also bind PGN and enhance TLR2-mediated signaling in macrophages, suggesting a similar phenomenon might occur in microglia. To assess the functional significance of CD14 on microglial activation, we evaluated the responses of primary microglia isolated from CD14 knockout (KO) and wild type (WT) mice. PGN-dependent microglial activation was partially CD14-dependent as demonstrated by the attenuated expression of TNF-alpha, macrophage inflammatory protein-2 (MIP-2/CXCL2), and the soluble PRR pentraxin-3 in CD14 KO microglia compared to WT cells. In contrast, microglial responses to intact S. aureus occurred primarily via a CD14-independent manner. Collectively, these findings reveal the complex nature of gram-positive bacterial recognition by microglia, which occurs, in part, via CD14.
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PMID:Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia. 1622 99

In LPS-stimulated human neutrophils, engagement of the adenosine A2A receptor selectively prevented the expression and release of TNF-alpha, MIP-1alpha/CCL3, MIP-1beta/CCL4, MIP-2alpha/CXCL2, and MIP-3alpha/CCL20. In mice lacking the A2A receptor, granulocytes that migrated into the air pouch 4 h after LPS injection expressed higher mRNA levels of TNF-alpha, MIP-1alpha, and MIP-1beta than PMNs from wild-type mice. In mononuclear cells present in the air pouch 72 h after LPS injection, expression of IL-1beta, TNF-alpha, IL-6, and MCP-2/CCL6 was higher in A2AR knockout mice. In addition to highlighting neutrophils as an early and pivotal target for mediating adenosine anti-inflammatory activities, these results identify TNF-alpha and the MIP chemokine family as gene products whose expression is pivotally affected by activation of A2AR in LPS-activated PMNs. Modulation by A2AR in the production of inflammatory signals by PMNs may thus influence the evolution of an inflammatory response by reducing the activation status of inflammatory cells.
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PMID:Immunomodulatory impact of the A2A adenosine receptor on the profile of chemokines produced by neutrophils. 1628 Mar 66

IL-13 is an important stimulator of inflammation and tissue remodeling at sites of Th2 inflammation, which plays a key role in the pathogenesis of a variety of human disorders. We hypothesized that the ubiquitous transcription factor, early growth response-1 (Egr-1), plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of Egr-1 and related moieties in lungs from wild type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of Egr-1 on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 stimulates Egr-1 via an Erk1/2-independent Stat6-dependent pathway(s). They also demonstrate that IL-13 is a potent stimulator of eosinophil- and mononuclear cell-rich inflammation, alveolar remodeling, and tissue fibrosis in mice with wild type Egr-1 loci and that these alterations are ameliorated in the absence of Egr-1. Lastly, they provide insights into the mechanisms of these processes by demonstrating that IL-13 stimulates select CC and CXC chemokines (MIP-1alpha/CCL-3, MIP-1beta/CCL-4, MIP-2/CXCL2/3, MCP-1/CCL-2, MCP-2/CCL-8, MCP-3/CCL-7, MCP-5/CCL-12, KC/CXCL-1, and Lix/CXCL-5), matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and apoptosis regulators (caspase-3, -6, -8, and -9 and Bax) and activates transforming growth factor-beta1 and pulmonary caspases via Egr-1-dependent pathways. These studies demonstrate that Egr-1 plays a key role in the pathogenesis of IL-13-induced inflammatory and remodeling responses.
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PMID:Role of early growth response-1 (Egr-1) in interleukin-13-induced inflammation and remodeling. 1643 63

Chemokine receptors represent promising targets to attenuate inflammatory responses and subsequent secondary damage after brain injury. We studied the response of the chemokines CXCL1/CINC-1 and CXCL2/MIP-2 and their receptors CXCR1 and CXCR2 after controlled cortical impact injury in adult rats. Rapid upregulation of CXCL1/CINC-1 and CXCL2/MIP-2, followed by CXCR2 (but not CXCR1), was observed after injury. Constitutive neuronal CXCR2 immunoreactivity was detected in several brain areas, which rapidly but transiently downregulated upon trauma. A second CXCR2-positive compartment, mainly colocalized with the activated microglia/macrophage marker ED1, was detected rapidly after injury in the ipsilateral cortex, progressively emerging into deeper areas of the brain later in time. It is proposed that CXCR2 has a dual role after brain injury: (i) homologous neuronal CXCR2 downregulation would render neurons more vulnerable to injury, whereas (ii) chemotaxis and subsequent differentiation of blood-borne cells into a microglial-like phenotype would be promoted by the same receptor.
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PMID:Differential regulation of the CXCR2 chemokine network in rat brain trauma: implications for neuroimmune interactions and neuronal survival. 1647 49

We examined the role of tumor necrosis factor receptor 1 (TNFR1) in inflammation initiated by the adoptive transfer of central nervous system (CNS)-specific Th1 cells in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. This adoptive transfer paradigm eliminates the confounding effects of bacterial adjuvants in the analysis of inflammation. We found that although T cells could reach the meninges and perivascular space in the absence of TNFR1, recruitment of other inflammatory cells from the blood was dramatically reduced. The reduction in the recruitment of CD11b(hi) cells correlated with a dramatic reduction in the production of the chemokines CCL2 (MCP-1) and CXLC2 (MIP-2) in TNFR1-deficient hosts. Bone marrow chimera experiments demonstrated that TNF can be effectively supplied by either the hematopoietic system or the CNS, but the essential TNFR1-responsive cells reside in the CNS. Previous work has demonstrated that microglia produce CCL2, and here we demonstrate that astrocytes and endothelial cells produced CXCL2 in the early stages of inflammation. Therefore, productive inflammation results from a conversation, or mutually responding signals, between the initiating T cells and cells in the parenchyma of the spinal cord.
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PMID:A tumor necrosis factor receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord. 1656 95

The murine encephalomyelitis virus of Theiler (TMEV) induces demyelination in susceptible strains of mice by a CD4(+) Th1 T cell mediated immunopathologic process. We focused on the production of one chemokine, the macrophage inflammatory protein-2 (MIP-2 or CXCL2), by cultured mouse astrocytes infected with the BeAn strain of TMEV. Analysis of a murine genome DNA hybridized with cRNA from mock- and TMEV-infected astrocytes, revealed up-regulation of three sequences encoding MIP-2. Northern blot analysis indicated increased MIP-2 mRNA expression. Levels of MIP-2 in the supernatants of infected cells as detected by ELISA, varied directly with the multiplicity of infection used. This secreted CXCL2 was biologically active inducing chemoattraction of neutrophils but not of lymphocytes. CXCL2 was specifically induced by TMEV infection, since induction was inhibited by anti TMEV antibodies. The inflammatory cytokines, IL-1alpha and TNF-alpha, which are also induced in astrocytes by TMEV, were very potent inducers of CXCL2. Nevertheless, both mechanisms of induction follows different pathways as antibodies to both cytokines fails to inhibit TMEV-induced CXCL2 up-regulation. Sera from TMEV-infected SJL/J mice with chronic demyelination, but not from BALB/c TMEV-resistant mice, revealed CXCL2 at the peak of clinical disease. Our main novel finding is the strain-dependent differences in CXCL2 expression both in vitro and in vivo. This suggest an role for this chemokine in attracting immune cells within the CNS, which in turn, might trigger demyelination in this experimental model of MS.
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PMID:Theiler's virus induces the MIP-2 chemokine (CXCL2) in astrocytes from genetically susceptible but not from resistant mouse strains. 1668 16

Microglia, the innate immune effector cells of the CNS parenchyma, express TLR that recognize conserved motifs of microorganisms referred to as pathogen-associated molecular patterns (PAMP). All TLRs identified to date, with the exception of TLR3, use a common adaptor protein, MyD88, to transduce activation signals. Recently, we reported that microglial activation in response to the Gram-positive bacterium Staphylococcus aureus was not completely attenuated following TLR2 ablation, suggesting the involvement of additional receptors. To assess the functional role of alternative TLRs in microglial responses to S. aureus and its cell wall product peptidoglycan as well as the Gram-negative PAMP LPS, we evaluated primary microglia from MyD88 knockout (KO) and wild-type mice. The induction of TNF-alpha, IL-12 p40, and MIP-2 (CXCL2) expression by S. aureus- and peptidoglycan-stimulated microglia was MyD88 dependent, as revealed by the complete inhibition of cytokine production in MyD88 KO cells. In addition, the expression of additional pattern recognition receptors, including TLR9, pentraxin-3, and lectin-like oxidized LDL receptor-1, was regulated, in part, via a MyD88-dependent manner as demonstrated by the attenuated expression of these receptors in MyD88 KO microglia. Microglial activation was only partially inhibited in LPS-stimulated MyD88 KO cells, suggesting the involvement of MyD88-independent pathways. Collectively, these findings reveal the complex mechanisms for microglia to respond to diverse bacterial pathogens, which occur via both MyD88-dependent and -independent pathways.
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PMID:Central role for MyD88 in the responses of microglia to pathogen-associated molecular patterns. 1670 40

Reactive astrocytes display decreased glutamate transporters, such as GLT-1, and as a result synaptic glutamate clearance is impaired. In addition, these activated astrocytes are immunocompetent and release algesic mediators that can sensitize neurons in the spinal cord. Currently, we evaluated the effect of propentofylline (PPF), an experimental antiallodynic agent, on the phenotype and glutamate transporter expression of astrocytes. Primary astrocyte cultures, which represent an activated phenotype with a polygonal morphology and low GLT-1 expression, were treated for 3 or 7 days with 10, 100, or 1,000 microM PPF or dibutyryl-cAMP (db-cAMP), a known inducer of GLT-1 expression. PPF dose-dependently induced astrocytes to display a mature phenotype, with elongated processes and a stellate shape, as well as increased GLT-1 and GLAST immunoreactivity, similar to that seen with db-cAMP. Real time RT-PCR and Western blot analysis clearly demonstrated that PPF caused a potent dose-dependent induction of GLT-1 and GLAST mRNA and protein in these astrocytes. Importantly, the observed increase in glutamate transporters was found to have a functional effect, with significantly enhanced glutamate uptake in astrocytes treated with 100 or 1,000 microM PPF that was sensitive to dihydrokainate inhibition, suggesting it is GLT-1 mediated. Finally, the effect of PPF on lipopolysaccharide-induced chemokine release was investigated. Interestingly, PPF was able to dampen both MCP-1 (CCL2) and MIP-2 (CXCL2) release from astrocytes while db-cAMP significantly enhanced this chemokine expression. These findings suggest that PPF is capable of differentiating astrocytes to a homeostatic, mature phenotype, competent for glutamate clearance and distinct from that induced by db-cAMP.
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PMID:Induction of astrocyte differentiation by propentofylline increases glutamate transporter expression in vitro: heterogeneity of the quiescent phenotype. 1681 65

Brain abscesses arise from a focal parenchymal infection by various pathogens, particularly Staphylococcus aureus. We have shown that astrocytes are activated upon exposure to S. aureus and may contribute to the excessive tissue damage characteristic of brain abscess. Therefore, modulating astrocyte activation may facilitate a reduction in brain abscess severity. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists are potent inhibitors of microglial activation; however, the effects of these compounds on S. aureus-dependent astrocyte activation have not yet been examined. Here, we demonstrate that two chemically distinct PPAR-gamma agonists, 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, suppress the production of several pro-inflammatory molecules in S. aureus-stimulated astrocytes including interleukin-1beta and nitric oxide (NO). Interestingly, 15d-PGJ2 attenuated Toll-like receptor 2 (TLR2) and inducible nitric oxide synthase expression, but failed to modulate macrophage inflammatory protein-2 (MIP-2/CXCL2) production, suggesting that 15d-PGJ2 is not a global inhibitor of astrocyte activation. Another novel finding of this study was the fact that both 15d-PGJ2 and ciglitazone were capable of attenuating pre-existing astrocyte activation, indicating their potential benefit in a therapeutic setting. Importantly, 15d-PGJ2 and ciglitazone were still capable of inhibiting S. aureus-induced pro-inflammatory mediator release in PPAR-gamma-deficient astrocytes, supporting PPAR-gamma-independent effects of these compounds. Collectively, these results suggest that 15d-PGJ2 and ciglitazone exert their anti-inflammatory actions on astrocytes primarily independent of the PPAR-gamma pathway.
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PMID:15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone modulate Staphylococcus aureus-dependent astrocyte activation primarily through a PPAR-gamma-independent pathway. 1707 64


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